A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and Safety of LY3209590 Administered Weekly Using a Fixed Dose Escalation Compared to Insulin Glargine in Insulin-Naïve Adults With Type 2 Diabetes
Phase: PHASE3
Conditions: Type 2 Diabetes, T2D
Sponsor: Eli Lilly and Company

Protocol: I8H-MC-BDCW 
 
 
 
 
A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and 
Safety of LY3209590 Administered Weekly Using a Fixed Dose Escalation Compared to Insulin 
Glargine in Insulin-Naïve Adults with Type 2 Diabetes 
 
 
 
NCT05662332 
 
 
 
Approval Date: 31-May-2023 

CONFIDENTIAL 
I8H-MC-BDCW (a) 
1 
Title Page  
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. 
Protocol Title:  
A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy 
and Safety of LY3209590 Administered Weekly Using a Fixed Dose Escalation Compared to 
Insulin Glargine in Insulin-Naïve Adults with Type 2 Diabetes 
Protocol Number: I8H-MC-BDCW 
Amendment Number: a  
Compound: LY3209590 
Brief Title:  
Efficacy and Safety of LY3209590 Administered Weekly Using a Fixed Dose Escalation 
Compared to Insulin Glargine in Adults with Type 2 Diabetes Who Are Starting Basal Insulin 
Therapy for the First Time 
Study Phase: 3 
Acronym: QWINT-1   
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): 
IND: 129390 
Document ID: VV-CLIN-109083 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below.  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
2 
Medical Monitor Name and Contact Information will be provided separately.  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
3 
Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
18-May-2022 
Amendment [a] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The rationale for this amendment is to clarify dosing recommendation in response to FDA 
feedback.  
Changes and rationale are summarized in this table. Minor editorial changes are not included in 
this table. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Number of and duration of 
treatment with 
antihyperglycemic medicines 
updated and tirzepatide and 
sulfonylureas added as not 
allowed diabetes treatments  
Additional clarity related to 
inclusion/exclusion criteria 
1.3. Schedule of 
Activities (SoA) 
Information added about visit 
interval tolerances for Visit 2 
and 3. 
Comment added for Visit 6 
Additional clarity to set definitive visit 
window tolerance 
2.3.1. Risk Assessment 
Statements added about the use 
of personal glucometer or 
continuous glucose monitoring 
not being allowed, and 
investigator may prescribe a 
dose of basal insulin other than 
the recommended dose. 
Additional clarity that only study 
glucometer should be used for glucose 
measurement 
To emphasize that investigators may use 
their discretion to select appropriate 
doses based on their clinical judgment 
4.1. Overall Design 
Statement detailing that PK 
sample is to be collected at Visit 
5 for those on LY3209590 or 
insulin glargine and timing of 
collection cannot be the same as 
Visit 6 
Clarification that Visit 5 PK sample 
should be collected for both the 
LY3209590 and insulin glargine 
treatment arms 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
4 
Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
Number and duration of 
treatment with 
antihyperglycemic medications 
that must be at stable 
prescreening doses updated 
Statement about use of personal 
glucometer or continuous 
glucose monitoring  device not 
allowed added 
Additional clarity related to inclusion 
criteria 
5.2. Exclusion Criteria 
Dual glucose dependent 
insulinotropic peptide 
(GIP)/glucagon-like peptide-1 
(GLP-1) receptor agonist (RA) 
(for example, tirzepatide) added 
to excluded prior or concomitant 
medications list 
Added clarification that GIP/GLP-1 RA 
(for example, tirzepatide) are excluded 
medications following marketing 
approval since initial protocol approval 
6.5. Dose Modification 
Clarified instruction that median 
FBG is to be determined from 
the 3 most recently recorded 
FBG readings from the 7-day 
period prior to the site visit 
Statements about investigator 
having discretion to prescribe 
basal insulin doses other than 
protocol recommended that they 
should review hypoglycemic 
episodes when assessing dose, 
and treatment/clinical 
management of hypoglycemia 
were added. 
To address any potential confusion 
regarding timing of FBG readings used 
for dose assessment 
 
 
To emphasize that investigators may use 
their discretion to select appropriate 
doses based on their clinical judgment 
and to guide investigators for the 
treatment and clinical management of 
hypoglycemia 
6.5.1.2. LY3209590 
Dose Adjustments 
Based on Fasting Blood 
Glucose  
Dose adjustments for 
participants on a fixed 
dose administered by 
the autoinjector 
Row indicating no dosing 
change for participants with 
median fasting blood glucose 
<80 mg/dL but no 
hypoglycemia added to dosing 
table, along with guidance for 
clinical management 
Specified the 80-130 mg/dL as 
target 
To provide clear guidance for 
LY3209590 dosing using the autoinjector 
for patients with fasting blood glucose < 
80 mg/dL but not meeting hypoglycemia-
related dose reduction criteria 
 
 
For clarification 
6.5.2.2. Insulin 
Glargine Dose 
Adjustments According 
to Fasting Blood 
Glucose 
Specified the 80-130 mg/dL as 
target 
For clarification 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
5 
Section # and Name 
Description of Change 
Brief Rationale 
6.8.3. 
Antihyperglycemic 
Medications 
Dual GIP/GLP-1 RAs (for 
example, tirzepatide) added to 
list and excluded for all study 
phases except safety follow-up 
Added specific Dual GIP/GLP-1 RAs 
class to table following marketing 
approval since initial protocol approval 
8.1.1. Glucose 
Monitoring 
Added statement that the use of 
personal glucometer or 
continuous glucose monitoring 
is not permitted 
Additional clarity related to 
inclusion/exclusion criteria 
8.1.1.1. Self-
Monitoring of Blood 
Glucose (SMBG) 
Added recommendation to 
increase frequency of blood 
glucose monitoring when fasting 
blood glucose is <80 mg/dL 
To educate participants to help prevent 
hypoglycemia 
11. References 
Reference added for CDC 2021 
References for harmonizing 
Haemoglobin A1c testing and 
UK National Diabetes Audit 
updated 
To update to latest guidance 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
6 
Table of Contents  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
1.3.1. 
Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3-18 ......................................16 
1.3.2. 
Treatment Visits 19 to 33, Early Discontinuation, Unscheduled 
Visits, and Safety Follow-up Visits 801 and 802 ...........................................................24 
2. 
Introduction ...................................................................................................................31 
2.1. 
Study Rationale ...............................................................................................................31 
2.2. 
Background .....................................................................................................................31 
2.3. 
Benefit/Risk Assessment ................................................................................................32 
2.3.1. 
Risk Assessment .............................................................................................................33 
2.3.2. 
Benefit Assessment .........................................................................................................34 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................34 
3. 
Objectives, Endpoints, and Estimands .......................................................................35 
4. 
Study Design ..................................................................................................................38 
4.1. 
Overall Design ................................................................................................................38 
4.2. 
Scientific Rationale for Study Design ............................................................................40 
4.3. 
Justification for Dose ......................................................................................................41 
4.4. 
End of Study Definition ..................................................................................................41 
5. 
Study Population ...........................................................................................................42 
5.1. 
Inclusion Criteria ............................................................................................................42 
5.2. 
Exclusion Criteria ...........................................................................................................43 
5.3. 
Lifestyle Considerations .................................................................................................45 
5.4. 
Screen Failures ................................................................................................................46 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................46 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................47 
6.1. 
Study Intervention(s) Administered................................................................................47 
6.1.1. 
Medical Devices..............................................................................................................48 
6.1.2. 
Rescue Medicine for Management of Severe or Persistent 
Hyperglycemia ................................................................................................................49 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................50 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................50 
6.4. 
Study Intervention Compliance ......................................................................................51 
6.5. 
Dose Modification ..........................................................................................................51 
6.5.1. 
LY3209590 Dose Initiation and Adjustment ..................................................................52 
6.5.2. 
Insulin Glargine Dose Initiation and Adjustment ...........................................................56 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................57 
6.7. 
Treatment of Overdose ...................................................................................................58 
6.8. 
Concomitant Therapy .....................................................................................................59 
6.8.1. 
Medications with Approved Weight Loss Indication .....................................................60 
6.8.2. 
Chronic Systemic Glucocorticoid Medication ................................................................60 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
7 
6.8.3. 
Antihyperglycemic Medications .....................................................................................61 
6.9. 
Nonstudy Treatment after the End of the Study .............................................................62 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................63 
7.1. 
Discontinuation of Study Intervention ............................................................................63 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................64 
7.1.2. 
Hypersensitivity Reactions .............................................................................................64 
7.1.3. 
Temporary Discontinuation of Study Intervention .........................................................64 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................65 
7.3. 
Lost to Follow up ............................................................................................................66 
8. 
Study Assessments and Procedures.............................................................................67 
8.1. 
Efficacy Assessments .....................................................................................................67 
8.1.1. 
Glucose Monitoring ........................................................................................................67 
8.1.2. 
Patient-Reported Outcomes ............................................................................................68 
8.2. 
Safety Assessments .........................................................................................................72 
8.2.1. 
Physical Examinations ....................................................................................................72 
8.2.2. 
Vital Signs .......................................................................................................................72 
8.2.3. 
Electrocardiograms .........................................................................................................72 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................73 
8.2.5. 
Hepatic Monitoring .........................................................................................................73 
8.2.6. 
Pregnancy Testing ...........................................................................................................76 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................76 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................76 
8.3.2. 
Pregnancy ........................................................................................................................78 
8.3.3. 
Cardiovascular Events ....................................................................................................79 
8.3.4. 
Systemic Hypersensitivity Reactions ..............................................................................79 
8.3.5. 
Injection-Site Reactions ..................................................................................................80 
8.3.6. 
Hypoglycemia .................................................................................................................80 
8.4. 
Pharmacokinetics ............................................................................................................81 
8.5. 
Pharmacodynamics .........................................................................................................81 
8.6. 
Genetics ..........................................................................................................................81 
8.7. 
Biomarkers ......................................................................................................................81 
8.8. 
Immunogenicity Assessments.........................................................................................82 
8.9. 
Health Economics ...........................................................................................................82 
9. 
Statistical Considerations .............................................................................................83 
9.1. 
Statistical Hypotheses .....................................................................................................83 
9.2. 
Analyses Sets ..................................................................................................................83 
9.3. 
Statistical Analyses .........................................................................................................84 
9.3.1. 
General Considerations ...................................................................................................84 
9.3.2. 
Primary Endpoint or Estimand Analysis.........................................................................84 
9.3.3. 
Secondary Endpoint(s) Analysis .....................................................................................86 
9.3.4. 
Tertiary Endpoint(s) Analysis .........................................................................................86 
9.3.5. 
Safety Analyses ...............................................................................................................86 
9.3.6. 
Other Analyses ................................................................................................................88 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
8 
9.3.7.
Sensitivity Analyses ........................................................................................................88
9.4.
Interim Analysis ..............................................................................................................89
9.5.
Sample Size Determination ............................................................................................89
10.
Supporting Documentation and Operational Considerations ..................................90
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................90
10.1.1.
Regulatory and Ethical Considerations ...........................................................................90
10.1.2.
Financial Disclosure........................................................................................................90
10.1.3.
Informed Consent Process ..............................................................................................91
10.1.4.
Data Protection................................................................................................................91
10.1.5.
Committees Structure......................................................................................................91
10.1.6.
Dissemination of Clinical Study Data.............................................................................92
10.1.7.
Data Quality Assurance ..................................................................................................93
10.1.8.
Source Documents ..........................................................................................................94
10.1.9.
Study and Site Start and Closure ....................................................................................95
10.1.10. Publication Policy ...........................................................................................................95
10.1.11. Investigator Information .................................................................................................95
10.1.12. Sample Retention ............................................................................................................96
10.2.
Appendix 2: Clinical Laboratory Tests ...........................................................................97
10.2.1.
Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ..................................................................................................100
10.3.
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ..........................................................................................................101
10.3.1.
Definition of AE ...........................................................................................................101
10.3.2.
Definition of SAE .........................................................................................................102
10.3.3.
Definition of Product Complaints .................................................................................104
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints ....................................................................................................................104
10.3.5.
Reporting of SAEs ........................................................................................................106
10.3.6.
Regulatory Reporting Requirements .............................................................................107
10.4.
Appendix 4: Contraceptive and Barrier Guidance ........................................................108
10.4.1.
Definitions.....................................................................................................................108
10.4.2.
Contraception Guidance................................................................................................109
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ..................................................................................................................111
10.6.
Appendix 6: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..........................................................................113
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................114
10.8. 
Appendix 8: Abbreviations and Definitions .................................................................118
11.
References ....................................................................................................................122
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
9 
1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title:  
A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy 
and Safety of LY3209590 Administered Weekly Using a Fixed Dose Escalation Compared to 
Insulin Glargine in Insulin-Naïve Adults with Type 2 Diabetes  
Brief Title:  
Efficacy and Safety of LY3209590 Administered Weekly Using a Fixed Dose Escalation 
Compared to Insulin Glargine in Adults with Type 2 Diabetes Who Are Starting Basal Insulin 
Therapy for the First Time 
Regulatory Agency Identifier Number(s): 
IND: 129390 
Rationale: 
This Phase 3 study will evaluate the efficacy and safety of LY3209590 administered weekly as a 
fixed dose escalation compared with daily administration of insulin glargine in insulin-naïve 
adult participants with type 2 diabetes (T2D) who are starting basal insulin therapy for the first 
time.   
The fixed dose escalation is a simplified dose escalation scheme using 4 set doses of 100 U, 
150 U, 250 U, and 400 U of LY3209590, with treat-to-target dose adjustments after at least 4 
weeks at each step to achieve the glycemic goals of fasting blood glucose (FBG) between 80 and 
130 mg/dL. 
This study will inform the clinical development of LY3209590.  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
10 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
Demonstrate noninferiority of LY3209590 compared to 
insulin glargine for the treatment of T2D in adults 
Change in HbA1c from baseline to Week 52 
Key Secondary (Gated)  
Demonstrate superiority of LY3209590 compared to 
insulin glargine  
Change in HbA1c from baseline to Week 52 
Other Secondary 
Compare the effect of LY3209590 to insulin glargine 
in parameters of glycemic control 
 
Change from baseline to Week 26 for HbA1c 
 
Change from baseline to Weeks 16, 26, and 52 for 
fasting glucose measured by SMBG 
 
Insulin dose at Weeks 16, 26, and 52 
Compare the effect of LY3209590 to insulin glargine 
on safety endpoints 
 
Incidence and rate of composite of Level 2 and 3 
hypoglycemia events during the treatment period 
 
Incidence and rate of composite of Level 2 and 3 
nocturnal hypoglycemia events during the 
treatment period 
 
Change from baseline to Weeks 26 and 52 in body 
weight  
Compare the effect of LY3209590 to insulin glargine 
on patient-reported outcomes questionnaires 
 
Change from baseline to Weeks 26 and 52 for  
o 
TRIM-D, and  
o 
DTSQ 
 
Treatment experience at Weeks 26 and 52 for  
o 
DID-EQ, and  
o 
SIM-Q.  
Abbreviations: HbA1c = hemoglobin A1c; DID-EQ = Diabetes Injection Device Experience Questionnaire; SMBG 
= self-monitoring of blood glucose; SIM-Q = Simplicity Questionnaire; T2D = type 2 diabetes; TRIM-D = 
Treatment-Related Impact Measure – Diabetes. 
Primary estimand 
United States registration 
The primary clinical question of interest is 
What is the treatment difference between LY3209590 and insulin glargine in HbA1c 
change from baseline to Week 52, in study eligible participants, regardless of treatment 
discontinuation for any reason and regardless of initiation of rescue medication? 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
11 
Registration for countries outside the United States 
The primary clinical question of interest is 
What is the treatment difference between LY3209590 and insulin glargine in HbA1c 
change from baseline to Week 52, in study eligible participants who adhere to the 
randomized treatment without intercurrent events during the study treatment period? 
Overall Design: 
This is a Phase 3, parallel-design, open-label, randomized control study to evaluate the efficacy 
and safety of LY3209590 administered once-weekly compared to insulin glargine administered 
daily in adult participants with T2D that are insulin naïve.  
The study includes a 3-week screening and lead-in period, a 52-week treatment period, and a 5-
week safety follow-up period after the last visit in the treatment period. 
Participants will be randomly assigned to receive daily insulin glargine or weekly insulin 
LY3209590.  
Brief Summary: 
Participants randomly assigned to receive insulin glargine 
Participants randomly assigned to receive insulin glargine will start on 10 U/day and will have 
weekly dose adjustments based on FBG and hypoglycemia events. 
Participants randomly assigned to receive LY3209590 
Participants randomly assigned to receive LY3209590 will be on a fixed dose escalation for at 
least the first 16 weeks of the study. Participants will start LY3209590 on a fixed dose of 100 U 
per week and will escalate the LY3209590 doses every 4 weeks to the set doses of 150, 250, and 
400 U per week, as required, until an FBG of 80 to 130 mg/dL is achieved in the preceding 
week. A fixed-dose autoinjector will be used to administer each dose. 
Treat-to-target dose adjustments will be based on FBG and hypoglycemia events.  
After Week 16, if a participant who has received the fixed dose of 400 U per week for at least 4 
weeks has median FBG levels >130 mg/dL, then the investigator should transition the participant 
to titratable doses using a prefilled pen. This will provide more dosing flexibility and allow dose 
titrations above 400 U per week.  
If a participant transitions from the fixed-dose autoinjector to a prefilled pen, they must continue 
using the prefilled pen for the remainder of the study. 
Study Population: 
In general, an individual may take part in the study if they 
 are ≥18 years of age at screening, or older per local regulations. 
 have a diagnosis of T2D according to the World Health Organization criteria. 
 have an HbA1c of 7.0%-10.0%, inclusive, at screening. 
 are on a stable treatment with 1 to 3 antihyperglycemic medication(s) for at least 3 months 
prior to screening and willing to continue the stable treatment for the duration of the study. 
Therapies must be used in accordance with the corresponding local product label. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
12 
Up to 3 of these antihyperglycemic medications are acceptable 
o DPP-4 inhibitors 
o SGLT2 inhibitors 
o biguanides, such as metformin 
o alpha-glucosidase inhibitors 
o GLP-1 receptor agonists, oral or injectable, or 
o thiazolidinediones. 
 are insulin naïve, and 
 are reliable and willing to make themselves available for the duration of the study and are 
willing and able to follow study procedures as required. 
In general, an individual may not take part in the study if they 
 have a diagnosis of type 1 diabetes, latent autoimmune diabetes, or specific type of 
diabetes other than T2D, for example, monogenic diabetes, diseases of the exocrine 
pancreas, or drug-induced or chemical-induced diabetes. 
 have received these diabetes treatments within 30 days prior to screening 
o glinides 
o pramlintide 
o sulfonylureas 
o GIP/GLP-1 RA (for example, tirzepatide), or 
o insulin or any insulin containing product. 
 are women who are pregnant, lactating, or breastfeeding, or 
 have a history or presence of an underlying disease, or surgical, physical, or medical 
condition that, in the opinion of the investigator, would potentially affect participant 
safety within the study or interfere with the interpretation of data. 
Number of Participants: 
Approximately 670 participants will be randomly assigned to LY3209590 and insulin glargine in 
a 1:1 ratio.  
With the assumption of 15% dropout at Week 52, approximately 284 participants on LY3209590 
and 284 participants on insulin glargine will complete 52 weeks of treatment.  
Intervention Groups and Duration: 
Participants will be randomly assigned to receive daily insulin glargine or weekly insulin 
LY3209590.  
The study includes a 52-week treatment period.  
Ethical Considerations of Benefit/Risk: 
Safety data available to date suggest that there is no increased risk to participants’ safety with 
LY3209590 treatment compared to insulin glargine. 
Participants may benefit from better glucose control by receiving a basal insulin. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
13 
Considering the information available from previous completed clinical studies in people, and 
the measures taken to make sure the participants in this study are safe, the potential risks from 
taking LY3209590 are justified by the potential benefits for insulin-naïve participants with T2D. 
Data Monitoring Committee: Yes 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
14 
1.2. 
Schema  
 
Abbreviations: FBG = fasting blood glucose; U = units. 
 
 
5 weeks
LY3209590 once-weekly dosing
Insulin glargine once-daily dosing
Screening
and
Lead-In 
Safety 
Follow-Up
Treatment Period 52 weeks
3 weeks
Visit 3
Week 0
Randomization
First dose
Visit 1
Visit 33
Week 52
Primary endpoint
Visit 2
Visit 
802
Visit 18
Week 16
Visit 
801
Visit 8
Week 4
Visit 12
Week 8
Visit 16
Week 12
100 U 
Starting dose
150 U 
250 U 
400 U 
LY3209590 dose escalation
Dose assessments every 4 weeks
*Dose increased if FBG >130 mg/dL
autoinjector
Insulin glargine dose assessments every week throughout treatment period
*
*
*
Prefilled pen for tailored dosing if FBG
is uncontrolled at 400 U dose by autoinjector
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
15 
1.3. 
Schedule of Activities (SoA)  
Two tables describe the schedule of activities. 
Table 1 (Section 1.3.1) summarizes procedures for Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3 to 18. 
Table 2 (Section 1.3.2) summarizes Treatment Visits 19 to 33, Early Discontinuation, Unscheduled Visits, and the Safety Follow-Up 
Visits 801 and 802. 
Screening 
Screening procedures may be conducted over 1 to 3 days. 
Telehealth visits 
Telehealth visits may be by telephone or other technology, or on-site if requested by the participant. Gray shaded columns in the SoA tables 
represent telehealth visits. 
Unscheduled visits 
Unscheduled visits may occur as needed. The SoA reflects some of the procedures that may occur during these visits. Perform 
additional procedures per investigator’s discretion. 
Fasting visits 
Participants should not eat or drink anything but water for a minimum of 8 hours before a fasting visit. 
If a participant attends these visits in a non-fasting state, the samples should be collected as non-fasting and this will not be considered 
a protocol deviation. 
Visit Intervals for Visit 2 and Visit 3 
The Visit 2 window will be calculated in reference to Visit 1: 7 days ± 3 days. 
The Visit 3 window will be calculated in reference to Visit 2: 14 days ± 3 days. 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
16 
1.3.1. 
Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3-18  
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
Informed consent 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
The ICF must be signed before any 
protocol-specific tests or procedures are 
performed. See Section 10.1.3 for 
additional details. 
Inclusion or exclusion 
criteria, review and confirm 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm inclusion and exclusion criteria 
prior to randomization and administration 
of first dose of study intervention. 
Demographics 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
Includes ethnicity (where permissible), 
year of birth, sex, and race. 
Preexisting conditions and 
medical history, including 
relevant surgical history  
X 
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
Collect all ongoing conditions and 
relevant past surgical and medical history. 
Prespecified medical 
history (indication and 
history of interest) 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
 
Prior treatments for 
indication 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
 
Substance use  
such as recreational drugs, 
alcohol, caffeine, and 
tobacco use  
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
17 
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs are any events that occur after 
signing the informed consent.  
Hypoglycemia events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment based on participant 
history and e-diary entries. 
Physical Evaluation 
 
Height 
X 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
Participant should remove shoes. 
Weight 
X 
X 
X 
 
 
X 
  
X 
  
 
  
 X 
 
 
  
X 
  
X 
 
Vital signs 
X 
X 
X 
 
 
X 
  
X 
  
 
  
 X 
 
 
  
X 
 
X 
Includes blood pressure and pulse rate. 
Measure 3 times, taken 1 minute apart, 
using the same arm, after participant has 
been sitting at least 5 min and before 
ECG tracing and collection of blood 
samples for laboratory testing. Additional 
vital signs may be measured as necessary 
at investigator’s discretion. 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Excludes pelvic, rectal, and breast 
examinations unless clinically indicated. 
Additional physical examinations may be 
completed as necessary at investigator’s 
discretion. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
18 
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
12-lead ECG (local) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform ECG before any blood sample 
collection. Participants should be supine 
for approximately 5 to 10 min before 
ECG collections and remain supine but 
awake during the ECG collection.  
ECGs may be repeated at the 
investigator’s discretion at any visit. 
Participant Education 
 
Diabetes counseling, 
training, and education 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes SMBG and hypoglycemia (see 
Sections 8.1.1 and 8.3.6).  
After Visit 3, conduct as needed. 
SMBG-6 point collection 
training and reminder 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
e-diary, glucometer training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, conduct as needed. 
Electronic Participant Diary and Blood Glucose Meter 
 
Dispense e-diary and 
glucometer  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense supplies as needed. 
Diary compliance check 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review entries of blood glucose, 
hypoglycemia events, and insulin dose. If 
participant is not compliant, study 
personnel will re-educate the participant 
on study requirements for continued 
study participation. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
19 
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
Review SMBG 6-point 
profiles 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Review profiles collected in preceding 
week. See Section 8.1.1.1. 
Paper Patient-Reported Outcomes 
 
Treatment-Related Impact 
Measure - Diabetes  
(TRIM-D) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
c At Visit 18 or after, if a participant 
changes from the autoinjector to the 
prefilled pen, conduct this procedure on 
the day the change occurs. 
Diabetes Injection Device 
Experience Questionnaire 
(DID-EQ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X c 
c At Visit 18 or after, if a participant 
changes from the autoinjector to the 
prefilled pen, conduct this procedure on 
the day the change occurs. 
Electronic Patient-Reported Outcomes 
 
Diabetes Treatment 
Satisfaction Questionnaire 
– Status (DTSQ-s)  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes Treatment 
Satisfaction Questionnaire 
– Change (DTSQ-c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X c 
c At Visit 18 or after, if a participant 
changes from the autoinjector to the 
prefilled pen, conduct this procedure on 
the day the change occurs. 
Simplicity of Diabetes 
Treatment Questionnaire 
(SIM-Q) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X c 
c At Visit 18 or after, if a participant 
changes from the autoinjector to the 
prefilled pen, conduct this procedure on 
the day the change occurs. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
20 
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
Basal Insulin Experience 
Likelihood of incorporating 
into routine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X c 
c At Visit 18 or after, if a participant 
changes from the autoinjector to the 
prefilled pen, conduct this procedure on 
the day the change occurs. 
Laboratory Tests and Sample Collections 
 
Hematology 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Hemoglobin A1c (HbA1c) 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Clinical chemistry  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Glucose 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Lipid panel 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect for WOCBP only. 
Urine pregnancy (local) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The result must be available within 24 
hours prior to first dose of intervention.  
Perform additional pregnancy tests if a 
menstrual period is missed, if there is 
clinical suspicion of pregnancy, or as 
required by local law or regulation. 
Follicle-stimulating 
hormone (FSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform as needed to confirm 
postmenopausal status. Definition is 
given in Section 10.4. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
21 
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
C-Peptide 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR (CKD-EPI)  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
UACR 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacokinetic (PK) 
samples 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Visit 3: collect sample at least 15 min 
after dosing. 
Visit 5: collect sample 3 (±1) days after 
Visit 4 dose. 
For all other visits: collect at any time 
during the visit.  
Immunogenicity (ADA) 
samples 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Visit 3: collect sample before dosing. 
If an immediate or nonimmediate 
systemic drug hypersensitivity reaction 
occurs, collect additional unscheduled 
samples as detailed in Section 10.2.1.  
Stored Samples 
 
Exploratory biomarker 
samples  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect before dosing. 
Dosing-Related Activities 
 
Process visit in IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization using 
IWRS 
  
  
X 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
22 
Study I8H-MC-BDCW 
Table 1 
Screen 
& Lead-
in 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
1a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
aVisit 5 occurs 3 days after Visit 4 ± 1 
day. 
Visit Interval Tolerance 
(days) 
 
±3 
— ±3 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
bVisit 6 must not occur on the same day 
as Visit 5. 
Visit Detail 
 
 
F 
T 
 
 
T 
F 
T 
T 
T 
F 
T 
T 
T 
F 
T 
F 
T = telehealth visit 
F = fasting visit 
Dispense LY3209590 or 
insulin glargine 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Dispense ancillary supplies 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense as needed. 
Dosing and injection 
training  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct as needed and if the participant 
changes from the autoinjector to the 
prefilled pen at Week 16 (Visit 18). 
LY3209590 or insulin 
glargine administered at 
site 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the participant changes from the 
autoinjector to the prefilled pen, 
administer the first dose at the site. 
Confirm participant 
administers intervention on 
day of visit  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Planned LY3209590 dose 
assessment or adjustment 
or documentation  
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
See Section 6.5 for details. 
Dose adjustments for hypoglycemia may 
occur at any time. 
Insulin glargine dose 
assessment or adjustment 
or documentation 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess dosing compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant returns unused 
LY3209590 or insulin 
glargine  
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
23 
Abbreviations: ADA = antidrug antibody; eGFR (CKD-EPI) = estimated glomerular filtration rate (chronic kidney disease epidemiology collaboration); ECG = 
electrocardiogram; ICF = informed consent form; IWRS = interactive web-response system; SMBG = self-monitoring of blood glucose; UACR = urinary 
albumin/creatinine ratio; WOCBP = women of childbearing potential. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
24 
1.3.2. 
Treatment Visits 19 to 33, Early Discontinuation, Unscheduled Visits, and Safety Follow-up Visits 801 and 802  
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 10.3, Appendix 
3. 
Hypoglycemia events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment based on 
participant history and e-
diary entries. 
Physical Evaluation 
 
Weight 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
Vital signs 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
Include blood pressure and 
pulse rate. Measure 3 times, 
taken 1 min apart, using the 
same arm, after participant 
has been sitting at least 
5 min and before ECG 
tracing and collection of 
blood samples for laboratory 
testing. Additional vital signs 
may be measured as 
necessary at investigator’s 
discretion. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
25 
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
Excludes pelvic, rectal, and 
breast examinations unless 
clinically indicated. 
Additional physical 
examinations may be 
completed as necessary at 
investigator’s discretion. 
12-lead ECG (local) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Participants should be supine 
for approximately 5 to 10 
min before ECG collections 
and remain supine but awake 
during the ECG collection.  
ECGs may be repeated at the 
investigator’s discretion at 
any visit. 
Participant Education 
 
Diabetes counseling, training, 
and education 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct as needed. 
SMBG 6-point collection 
training and reminder 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
e-diary, glucometer training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct as needed. 
Electronic Participant Diary and Blood Glucose Meter 
 
Dispense e-diary, glucometer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense supplies as needed. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
26 
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Diary compliance check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review entries of blood 
glucose, hypoglycemia 
events, and insulin dose. If 
participant is not compliant, 
study personnel will re-
educate the participant on 
study requirements for 
continued study 
participation. 
Review SMBG 6-point profile 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
Review profiles collected in 
preceding week. See Section 
8.1.1.1. 
Required diary return 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
The diary must be returned 
on the last participant visit.  
Paper Patient-Reported Outcomes 
 
Treatment-Related Impact 
Measure - Diabetes  
(TRIM-D)a 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
a If a participant changes 
from the autoinjector to the 
prefilled pen, conduct this 
procedure on the day the 
change occurs. 
Diabetes Injection Device 
Experience Questionnaire  
(DID-EQ)a 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
a If a participant changes 
from the autoinjector to the 
prefilled pen, conduct this 
procedure on the day the 
change occurs. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
27 
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Electronic Patient-Reported Outcomes 
 
Diabetes Treatment 
Satisfaction Questionnaire – 
Change (DTSQ-c)a 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 a If a participant changes 
from the autoinjector to the 
prefilled pen, conduct this 
procedure on the day the 
change occurs. 
Simplicity Questionnaire 
(SIM-Q)a  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
Basal Insulin Experience 
Likelihood of incorporating 
into routinea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Laboratory Tests and Sample Collections 
 
Hematology 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Hemoglobin A1c (HbA1c)a 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
X 
a If a participant changes 
from the autoinjector to the 
prefilled pen, collect a 
sample on the day the change 
occurs.  
Clinical chemistry  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Glucoseb 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
b If a participant changes 
from the autoinjector to the 
prefilled pen, collect a 
sample on the day the change 
occurs and before dosing. 
Collect a fasted sample, if 
possible. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
28 
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Lipid panel 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Urinalysis  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Urine pregnancy (local) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Perform additional 
pregnancy tests if a 
menstrual period is missed, if 
there is clinical suspicion of 
pregnancy, or as required by 
local law or regulation. 
C-Peptide 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
eGFR (CKD-EPI)  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
UACR 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Pharmacokinetic (PK) 
samplesc 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
c Collect sample at any time 
during the visit. 
If a participant changes from 
the autoinjector to the 
prefilled pen, collect a 
sample on the day the change 
occurs. 
Immunogenicity (ADA) 
samples 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
If an immediate or 
nonimmediate systemic drug 
hypersensitivity reaction 
occurs, collect additional 
unscheduled samples as 
detailed in Section 10.2.1.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
29 
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Stored Samples 
 
Exploratory biomarker 
samples  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Dosing-Related Activities 
 
Process visit in IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Visit UV:  process if study 
intervention dispensing is 
needed.  
Dispense LY3209590 or 
insulin glargine 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Dispense as needed. 
Dispense ancillary supplies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense as needed. 
Dosing and injection training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct as needed.  
If a participant changes from 
the autoinjector to the 
prefilled pen, conduct this 
procedure when the change 
occurs. 
Observe participant 
administer LY3209590 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the participant changes 
from the autoinjector to the 
prefilled pen, administer the 
first dose at the site. 
Planned LY3209590 dose 
assessment or adjustment and 
documentation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
See Section 6.5 for details. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
30 
Study I8H-MC-BDCW 
Table 2 
Treatment 
 
 
Safety 
Follow-up 
 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
ED 
UV 
801 
802 
 
Weeks from Randomization 
17 
18 
19 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
50 
52 
-- 
-- 
54 
57 
 
Visit Interval Tolerance 
(days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±
7 
±
7 
±
7 
±
3 
±
3 
±
3 
±
3 
-- 
-- 
±7 
±7 
 
Visit Detail 
T 
T 
T 
 
T 
 
F 
T 
T 
F 
T 
T 
 
T 
F 
F 
 
T 
 
T=telehealth visit 
F=fasting visit 
Insulin glargine dose 
assessment or adjustment or 
documentation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Assess dosing compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Participant returns unused 
LY3209590 or insulin 
glargine 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
Poststudy treatment 
assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
Abbreviations: ADA = antidrug antibody; ED = early discontinuation; eGFR (CKD-EPI) = estimated glomerular filtration rate (chronic kidney disease 
epidemiology collaboration); ECG = electrocardiogram; IWRS = interactive web-response system; SMBG = self-monitoring of blood glucose; UACR = 
urinary albumin/creatinine ratio; UV = unscheduled visit. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
31 
2. 
Introduction  
LY3209590 is a long-acting insulin receptor agonist in development for the once-weekly 
treatment of hyperglycemia in people with T2D and T1D. 
2.1. 
Study Rationale  
This Phase 3 study will evaluate the efficacy and safety of LY3209590 administered weekly as a 
fixed dose escalation compared with daily administration of insulin glargine in insulin-naïve 
adult participants with T2D who are starting basal insulin therapy for the first time.  The fixed 
dose escalation is a simplified dose escalation scheme using 4 set doses of 100 U, 150 U, 250 U, 
and 400 U of LY3209590, with treat-to-target dose adjustments after at least 4 weeks at each 
step to achieve the glycemic goals of FBG between 80 and 130 mg/dL. 
This study will inform the clinical development of LY3209590. 
2.2. 
Background  
Current state of diabetes care  
Most people with diabetes are not achieving glycemic targets. For example, only about one 
quarter of patients with T2D on insulin and only about 30% of patients with T1D achieve the 
target glycated HbA1c of 7% and 7.5%, respectively (Blonde et al. 2019; UK National Diabetes 
Audit 2017). 
Treatment complexity, fear of hypoglycemia, delays in insulin initiation and intensification, and 
suboptimal dosing may pose challenges to diabetes care. There is a need to overcome barriers to 
dose optimization with basal insulins that provide simple dosing algorithms, rapid achievement 
of glycemic targets, and a predictable profile with low likelihood of contributing to 
hypoglycemia. 
Potential for improved treatment regimens and compliance 
Once-weekly insulin using a fixed dose escalation could reduce treatment complexity, result in 
earlier adoption of insulin therapy that may improve treatment compliance, and lead to better 
real-world patient outcomes. Weekly insulins with a lower peak-to-trough profile during the 
week and a nearly flat insulin profile could also reduce within-day glucose variability and result 
in more consistent and predictable glycemic control (Heise 2021). 
LY3209590  
LY3209590 is a novel insulin receptor agonist that is in development as a once-weekly basal 
insulin for the treatment of hyperglycemia in patients with T2D and T1D. LY3209590 has the 
potential to decrease patient burden, overcome barriers to initiation of insulin therapy, and may 
improve glycemic control and quality of life for these patients. 
A detailed description of the chemistry, pharmacology, nonclinical and clinical efficacy, and 
safety of LY3209590 is provided in the IB. 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
32 
Summary of clinical results 
A total of 5 clinical studies, in healthy participants and participants with T2D, have been 
completed to assess the PK/PD, safety, and efficacy of LY3209590. The results thus far support 
continued development of LY3209590 as a treatment for diabetes mellitus.  
Pharmacokinetic and pharmacodynamic results  
Single-ascending doses of LY3209590 lowered fasting glucose in a dose- and concentration-
dependent manner, with a prolonged time-action profile.  
After multiple ascending doses over 6 weeks, maximum concentration and weekly area under the 
concentration curve (AUC) increased proportionally with dose.  
LY3209590 pharmacokinetics show a low peak-to-trough ratio and extended half-life that 
supports once-weekly dosing.  
Phase 2 clinical study results 
Available results from Phase 2 studies I8H-MC-BDCM, I8H-MC-BDCL, and I8H-MC-BDCP 
reflect the potential advantage of having a more stable insulin exposure and less glycemic 
variability with a long-acting insulin receptor agonist like LY3209590. All studies were open-
label and degludec was the active comparator.  
The choice of study population in this study is supported by available efficacy and safety data 
from Study BDCL, conducted in insulin-naïve participants with T2D.  
Phase 2 Study BDCL results 
Study BDCL was a randomized, open-label, comparator-controlled, treat-to-target study 
evaluating the efficacy and safety of LY3209590 compared with insulin degludec. Study 
participants had T2D, were insulin naïve, and treated with a stable dose of metformin, alone or in 
combination with a stable dose of a DPP-4 inhibitor and/or an SGLT2 inhibitor, for at least 3 
months prior to screening. 
Participants randomly assigned to LY3209590 achieved very good glycemic control during 26 
weeks of treatment. LY3209590 demonstrated noninferiority versus degludec for HbA1c change 
from baseline with both treatment groups achieving a mean HbA1c <7% at study endpoint and 
participants spending on average more than 75% of their glucose Time in Range70-180.  
In this open-label study, there was a low occurrence of hypoglycemia and reported TEAEs were 
similar during treatment with LY3209590 compared with degludec. In general, the observed 
safety data were consistent with expectations for insulin in this population. LY3209590 was well 
tolerated, and no safety findings emerged from the study that would prevent further clinical 
development.  
 
2.3. 
Benefit/Risk Assessment  
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of LY3209590 may be found in the IB and that of insulin glargine may be found in the local 
product package insert.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
33 
2.3.1. 
Risk Assessment  
Potential risks for this study 
The potential risks associated with LY3209590 include 
 hypoglycemia 
 hyperglycemia 
 hypersensitivity reaction 
 injection-site reactions, for example, injection-site rash, erythema, pruritus, or 
lipohypertrophy 
 immunogenicity, and 
 cardiovascular risks. 
It is expected that the known risks would be similar to other insulins. 
Safety data available to date suggest that there is no increased risk to participants’ safety with 
LY3209590 treatment compared to insulin glargine. 
Use of a standard fixed dose escalation for insulin dose adjustment is novel and, to date, 
untested. 
Management of risks 
Sections 5.1, 5.2, 6.1.2, and 8.3 address known potential risks associated with LY3209590. 
Protocol risk management measures 
Participant education for hypoglycemia 
After signing informed consent, all participants will be educated about signs and symptoms of 
hypoglycemia, how to treat hypoglycemia, and how to collect appropriate information for 
hypoglycemia. Hypoglycemia may be identified by spontaneous reporting of symptoms from 
participants, whether confirmed or unconfirmed by simultaneous glucose values, or by blood 
glucose samples collected between study visits. 
Monitoring of participant blood glucose levels 
Each participant will have a study-provided glucometer that will wirelessly transfer participant 
SMBG to their study-provided e-diary. Participants should use the glucometer whenever 
hypoglycemia is experienced or suspected and check glucose values. The use of personal 
glucometer or continuous glucose monitoring is not permitted. 
A web-interface and reporting system will be available for use by study personnel to view 
participant e-diary entries, including SMBG, insulin doses, and hypoglycemia information 
throughout the study. Automated alerts will be transmitted to the investigator any time the 
participant reports a potential severe episode of hypoglycemia, defined as requiring assistance 
due to neurological impairment, in the e-diary. 
Dose modification and rescue therapy 
The dosing regimen used in the study requires the investigator to adjust the insulin dose based on 
participant FBG and hypoglycemia events (see Section 6.5). The justification for the treat-to-
target dosing regimen is detailed in Section 4.3. As modifications of the basal insulin dose may 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
34 
be influenced by other clinical circumstances or safety considerations known to the investigator, 
the investigator may prescribe a dose other than the regimen recommended dose. If the 
investigator prescribes a dose other than the regimen recommended dose, the investigator is 
responsible for documenting the clinical rationale for the prescribed dose. 
Participants will be monitored for persistent, severe hyperglycemia and will receive rescue 
therapy if this should occur (see Section 6.1.2).  
2.3.2. Benefit Assessment  
Participants may benefit by receiving personal health information, routine safety assessments, 
and frequent engagement with health care providers during the study, which provide 
opportunities for coaching and support. 
Participants may benefit from the improvement of glycemic control promoted by basal insulin. 
The weekly administration of LY3209590 has the potential to offer a more consistent glycemic 
control, while the fixed dose escalation regimen may represent a simple way to initiate insulin 
treatment for the first time. 
2.3.3. Overall Benefit Risk Conclusion  
Considering the clinical data to date and measures taken to minimize risk for the participants in this 
study, the potential risks identified in association with LY3209590 are justified by the anticipated 
benefits that may be afforded to insulin-naïve participants with T2D. 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
35 
3. 
Objectives, Endpoints, and Estimands  
Objectives 
Endpoints 
Primary 
Demonstrate noninferiority of LY3209590 compared to 
insulin glargine for the treatment of T2D in adults 
Change in HbA1c from baseline to Week 52 
Key Secondary (Gated)  
Demonstrate superiority of LY3209590 compared to 
insulin glargine  
Change in HbA1c from baseline to Week 52 
Other Secondary 
Compare the effect of LY3209590 to insulin glargine 
in parameters of glycemic control 
 
Change from baseline to Week 26 for HbA1c 
 
Change from baseline to Weeks 16, 26, and 52 for 
fasting glucose measured by SMBG 
 
Insulin dose at Weeks 16, 26, and 52 
Compare the effect of LY3209590 to insulin glargine 
on safety endpoints 
 
Incidence and rate of composite of Level 2 and 3 
hypoglycemia events during the treatment period 
 
Incidence and rate of composite of Level 2 and 3 
nocturnal hypoglycemia events during the 
treatment period 
 
Change from baseline to Weeks 26 and 52 in body 
weight  
Compare the effect of LY3209590 to insulin glargine 
on patient-reported outcomes questionnaires 
 
Change from baseline to Weeks 26 and 52 for  
o 
TRIM-D, and  
o 
DTSQ 
 
Treatment experience at Weeks 26 and 52 for  
o 
DID-EQ, and  
o 
SIM-Q.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
36 
Tertiary 
Compare the effect of LY3209590 to insulin glargine 
for efficacy parameters 
 
Percentage of participants at Week 52 achieving 
o 
HbA1c <7% 
o 
HbA1c <7% without nocturnal 
hypoglycemia, and 
o 
HbA1c ≤6.5% without hypoglycemia 
 
Change from baseline to Weeks 26 and 52 for 
fasting serum glucose 
Evaluate the percentage of participants receiving 
LY3209590 that require a transition to the LY3209590 
prefilled pen 
 
Percentage of participants that require transition to 
the LY3209590 prefilled pen at Weeks 26 and 52 
Evaluate the percentage of participants at each fixed 
LY3209590 dose level 
 
Percentage of participants at each fixed dose level 
at Weeks 26 and 52 
Compare the effect of LY3209590 to insulin glargine 
for safety parameters 
 
Incidence and rate of Level 2 hypoglycemia events 
during treatment period 
 
Incidence and rate of Level 3 hypoglycemia events 
during treatment period 
 
Incidence of positive LY3209590 treatment-
emergent antidrug antibodies 
Characterize the PK/PD of LY3209590 
 
LY3209590 PK and concentration-response 
relationships to key safety and efficacy measures  
Compare the effect of LY3209590 to insulin glargine 
on patient-reported outcomes questionnaires 
Frequency of responses to Basal Insulin Experience of 
“likelihood of incorporating into routine” 
Abbreviations: HbA1c = hemoglobin A1c; DID-EQ = Diabetes Injection Device Experience Questionnaire; 
DTSQ = Diabetes Treatment Satisfaction Questionnaire; PK/PD = pharmacokinetics/pharmacodynamics; SMBG 
= self-monitoring of blood glucose; SIM-Q = Simplicity Questionnaire; T2D = type 2 diabetes; TRIM-D = 
Treatment-Related Impact Measure – Diabetes. 
Primary estimand 
United States registration 
The primary clinical question of interest is 
What is the treatment difference between LY3209590 and insulin glargine in HbA1c 
change from baseline to Week 52, in study eligible participants, regardless of treatment 
discontinuation for any reason and regardless of initiation of rescue medication? 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
37 
Treatment regimen estimand attributes 
This table describes the treatment regimen estimand attributes. 
Treatment Regimen Estimand Attribute 
Description 
Population 
Targeted study population. See Section 9.2 for details. 
Endpoint  
HbA1c change from baseline to Week 52. 
Remaining intercurrent events 
None. The 2 intercurrent events, treatment 
discontinuation for any reason and initiation of rescue 
medication, are both addressed by the treatment 
condition of interest attribute. 
Treatment condition  
The randomized treatment regardless of treatment 
discontinuation and use of rescue medications. 
Population-level summary  
Difference in mean changes between treatment 
conditions. 
Rationale for the treatment regimen estimand 
The treatment regimen estimand estimates how participants with T2D are treated in clinical 
practice and considers both efficacy and safety. 
Registration for countries outside the United States 
The primary clinical question of interest is 
What is the treatment difference between LY3209590 and insulin glargine in HbA1c 
change from baseline to Week 52, in study eligible participants who adhere to the 
randomized treatment without intercurrent events during the study treatment period? 
Efficacy estimand attributes 
This table describes the efficacy estimand attributes. 
Efficacy Regimen Estimand Attribute 
Description 
Population 
Targeted study population. See Section 9.2 for details.  
Endpoint  
HbA1c change from baseline to Week 52. 
Remaining intercurrent events 
None. The 2 intercurrent events, treatment 
discontinuation for any reason and initiation of rescue 
medication, are both handled by the hypothetical 
strategy, for example, the potential outcome for those 
participants if the intercurrent events have not occurred 
will be estimated. 
Treatment condition  
The randomized treatment. 
Population-level summary  
Difference in mean changes between treatment 
conditions. 
Rationale for the efficacy estimand 
The efficacy estimand supports the interpretation of the treatment effect as participants adhere to 
study treatment and free from the confounding effect of rescue medications. 
Secondary estimand for gated objective 
The superiority test in change from baseline to Visit 33 (Week 52) in HbA1c will also be based 
on the primary estimands described above. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
38 
4. 
Study Design  
4.1. 
Overall Design  
This is a Phase 3, parallel-design, open-label, randomized control study to evaluate the efficacy 
and safety of LY3209590 administered once-weekly compared to insulin glargine administered 
daily in adult participants with T2D that are insulin naïve.  
The study includes a 3-week screening and lead-in period, a 52-week treatment period, and a 5-
week safety follow-up period after the last visit in the treatment period. 
Participants will be randomly assigned to receive daily insulin glargine or weekly insulin 
LY3209590.  
Participants randomly assigned to insulin glargine 
Participants randomly assigned to insulin glargine will start on 10 U/day and will have weekly 
dose adjustments based on FBG and hypoglycemia events (see Section 6.5.2). 
Participants randomly assigned to receive LY3209590 
Participants randomly assigned to receive LY3209590 will be on a fixed dose escalation for at 
least the first 16 weeks of the study. Participants will start LY3209590 on a fixed dose of 100 U 
per week and will escalate the LY3209590 dose every 4 weeks as required to the set doses of 
150, 250, and 400 U per week. Treat-to-target dose adjustments will be based on FBG of 80 to 
130 mg/dL (4.4-7.2 mmol/L) and hypoglycemia events (see Section 6.5).  
Dose administration will be via a fixed dose autoinjector.   
After Week 16, if a participant who has received the fixed dose of 400 U per week for at least 4 
weeks has median FBG levels >130 mg/dL, then the investigator should transition the participant 
to titratable doses using a prefilled pen. This will provide more dosing flexibility and allow dose 
titrations above 400 U per week.  
If a participant transitions from the fixed dose autoinjector to a prefilled pen, they must continue 
using the prefilled pen for the remainder of the study. 
Screening and Lead-In 
Screening 
Interested participants will sign the appropriate informed consent document(s) prior to initiating 
any procedures. 
The investigator will review medical history, symptoms, risk factors, and other inclusion and 
exclusion criteria prior to any diagnostic procedures. If the participant is eligible after this 
review, then the site will perform the diagnostic procedures to confirm eligibility. 
Lead-In 
Participants will receive their glucometer and electronic study diary and receive training on 
 diabetes self-monitoring and management 
 electronic study diaries, and 
 study requirements. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
39 
Starting with Visit 2, participants must measure their FBG levels each day when possible or at a 
minimum 3 times per week. 
Participants will continue their current diabetes therapy until randomization. 
Treatment period 
Weeks 0-16 (Visits 3-18) 
This is the general flow for Visit 3 
 study personnel confirm enrollment criteria 
 participants are randomly assigned to an intervention group 
 study personnel complete baseline procedures and sample collection 
 study personnel will provide dosing training and the participant receives the first dose of 
LY3209590 or insulin glargine, and 
 study personnel complete all visit procedures. 
Participants assigned to LY3209590 will receive the fixed weekly dose delivered by an 
autoinjector, and participants assigned to insulin glargine will use daily titratable doses delivered 
by prefilled pen. Weeks 0-15 cover the first 16 doses for those assigned to LY3209590.   
See Section 6.5 for detailed dosing information for LY3209590 and insulin glargine. 
Week 1 (Visits 4 and 5) 
Visit 4 – telehealth visit 
Study personnel should review FBG and hypoglycemia events from the previous week to 
confirm the appropriate dose. 
For participants assigned to LY3209590, study personnel will confirm the participant administers 
their second dose on that day and the timing of their second dose.  
Participants should record the date and time of the second dose in the e-diary. 
Study personnel will schedule Visit 5, 3(±1) days after Visit 4 (and the second dose of 
LY3209590 or daily dose of insulin glargine) in order to collect a PK sample at the appropriate 
time. A sample will be collected for participants on LY3209590 and insulin glargine. 
Visit 5 – on-site clinic visit. Note: Visit 5 and Visit 6 cannot be scheduled on the same day. 
Study personnel will complete all visit procedures per the SoA.  
Weeks 16-52 (Visits 18-33) 
Participants assigned to LY3209590 will remain on their fixed dose according to the dosing 
instructions in Section 6.5.1.  
During Weeks 16-52, if a participant is receiving the fixed dose of 400 U/week for at least 4 
weeks and they have a median FBG >130 mg/dL for the previous week, the investigator should 
transition the participant to a prefilled pen, which will provide more dosing flexibility for higher 
doses. See Section 6.5.1 for details. 
If a participant changes from the autoinjector to the prefilled pen, they will complete additional 
procedures per the SoA at the time of change and administer the first dose at the site.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
40 
Last study treatment visit: either Week 52 (Visit 33) or ED visit 
Assessments for the transition to nonstudy diabetic treatment after the participant’s last dose 
The investigator will determine a participant’s transition from study treatment to another 
nonstudy diabetic treatment (see Section 6.9). 
Participants will continue their concomitant antihyperglycemic medications at the discretion of 
the investigator. 
Safety follow-up visits 801 and 802 
Study personnel and participants complete all visit procedures described in the SoA. 
The investigator will follow-up on the participant’s transition from study treatment to another 
nonstudy diabetic treatment (see Section 6.9). 
Participants will return study devices at the final study visit. 
4.2. 
Scientific Rationale for Study Design  
Primary endpoint 
The primary efficacy measurement is HbA1c, a widely used measure of glycemic control that 
reflects a cumulative history of glucose levels in the preceding 2 to 3 months. 
Overall design 
Blinding 
This is an open-label study. Investigators, participants, and study-site personnel will be 
unblinded to the assigned treatment. To eliminate potential biases, designated members of the 
Lilly study team will remain blinded throughout the study (see Section 6.3). Only a minimum 
number of Lilly personnel will see the randomization table and treatment assignments before the 
study is complete. 
Study duration 
The treatment duration of 52 weeks is a reasonable time frame to observe the effects of 
LY3209590 as a fixed dose escalation compared to insulin glargine. 
The follow-up visits after the last dose are designed to capture any additional safety signals and 
to monitor the transition from study treatment to nonstudy diabetic treatment. 
Comparator 
Insulin glargine was chosen as the comparator because it is a widely used basal insulin. 
Collection of race and ethnicity data 
In this study, collection of demographic information includes ethnicity (where permissible) and 
race. The scientific rationale is based on the need to assess variable response in safety or efficacy 
based on race or ethnicity. This question can be answered only if all the relevant data are 
collected.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
41 
4.3. 
Justification for Dose  
The dosing guidance for starting doses and dose modifications of LY3209590 and insulin 
glargine are derived based on findings from Phase 2 studies and PK/PD model-based 
simulations. The uniquely flat PK profile is a key property of LY3209590. Both modeling-
simulation and the Phase 2 results support no need for frequent dose adjustments with a low risk 
of hypoglycemia in insulin-naive T2D.   
These data informed the development of a treat-to-target dose escalation scheme using 4 fixed 
doses of 100 U, 150 U, 250 U and 400 U, to safely and efficiently initiate and guide LY3209590 
dose adjustments to achieve the glycemic goals of FBG between 80 and 130 mg/dL, while 
minimizing hypoglycemia risk. 
The potential benefits of the fixed dose escalation regimen administered by an autoinjector are  
 the ease of use for people nervous about starting injection therapy, and  
 a viable first step in overcoming insulin initiation and titration inertia for people with 
T2D who are starting basal insulin for the first time.  
LY3209590 starting dose 
To determine the appropriate starting dose for the autoinjector, simulations were performed 
using a wide range of starting doses. A starting dose of 100 U was selected because it showed 
similar or lower hypoglycemia rates compared to insulin degludec and resulted in a very low 
drop-out rate as a result of hypoglycemia (<5%). Importantly, this starting dose is consistent with 
the actual average mean weekly starting dose of ~ 97 U in Study BDCL, after correction for the 
loading dose. 
Fixed dose escalation  
Iterative simulations were conducted to determine the remaining 3 fixed doses to achieve the best 
balance between glycemic control and the percentage of participants achieving glycemic targets 
in the given dose range. In all simulation iterations, the occurrence of hypoglycemia was low and 
glycemic targets were achieved with slight variations in the percentage of participants 
successfully managed within a given dose escalation range. Based on review of the simulation 
outputs, inputs from medical experts, as well as data analytics on real-world insulin usage, the 
final recommended 4 fixed LY3209590 doses are 100 U, 150 U, 250 U, and 400 U. 
See Section 6.5 for dose modification and titration details.  
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last scheduled procedure shown in the SoA. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
42 
5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Are ≥18 years of age, at screening, or older per local regulations. 
Type of participant and disease characteristics 
2. Have a diagnosis of T2D according to the World Health Organization criteria. 
3. Have an HbA1c of 7.0% to 10.0%, inclusive, determined by the central laboratory at 
screening. 
4. Are on a stable treatment with 1 to 3 antihyperglycemic medication(s) for at least 3 
months prior to screening, and willing to continue the stable treatment for the duration of 
the study. All therapies must be used at stable doses and in accordance with the 
corresponding local product label. 
Up to 3 of these antihyperglycemic medications are acceptable 
 DPP-4 inhibitors 
 SGLT2 inhibitors 
 biguanides, such as metformin 
 alpha-glucosidase inhibitors 
 GLP-1 receptor agonists, oral or injectable, or 
 thiazolidinediones. 
5. Are insulin naïve. 
Exceptions: 
 short-term insulin treatment for a maximum of 14 days, prior to screening, and 
 prior insulin treatment for gestational diabetes. 
Weight 
6. Have a body mass index ≤45 kg/m2. 
Contraceptive or barrier requirements 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
7. Male participants: no male contraception required except in compliance with specific 
local government requirements. 
Female participants: for the contraception requirements of this protocol, see Section 10.4. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
43 
Study procedures 
8. Are reliable and willing to make themselves available for the duration of the study and 
are willing and able to follow study procedures as required, such as 
 self-inject intervention 
 store and take provided study interventions as directed 
 maintain an electronic study diary, and 
 use only the glucose monitoring device supplied for use in the study. 
Note a): persons with physical limitations who are not able to perform the injections must 
have the assistance of an individual trained to inject the intervention. 
Note b): The use of personal glucometer or continuous glucose monitoring device is not 
permitted. 
Informed consent 
9. Are capable of giving signed informed consent as described in Section 10.1.3, which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
Other inclusions 
10. Have usual wake and sleep patterns, such that midnight to 0600 hours will reliably reflect 
a usual sleeping pattern. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
11. Have a diagnosis of T1D, latent autoimmune diabetes, or specific type of diabetes other 
than T2D, for example, monogenic diabetes, diseases of the exocrine pancreas, or drug-
induced or chemical-induced diabetes. 
12. Have a history of >1 episode of ketoacidosis or hyperosmolar state or coma requiring 
hospitalization within 6 months prior to screening. 
13. Have had severe hypoglycemia episodes within 6 months prior to screening. 
14. Have a history of renal transplantation, are currently receiving renal dialysis, or have an 
estimated glomerular filtration rate <20 mL/min/1.73 m2 as calculated by the Chronic 
Kidney Disease-Epidemiology equation, determined by the central laboratory at 
screening. 
15. Have had a blood transfusion or severe blood loss within 90 days prior to screening. 
16. Have known hemoglobinopathy, hemolytic anemia or sickle cell anemia, or any other 
traits of hemoglobin abnormalities known to interfere with the measurement of HbA1c. 
17. Have had New York Heart Association Class IV heart failure or any of these 
cardiovascular conditions within 3 months prior to screening 
 acute myocardial infarction 
 cerebrovascular accident (stroke), or 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
44 
 coronary bypass surgery. 
18. Have had gastric bypass (bariatric) surgery, restrictive bariatric surgery, for example Lap-
Band, or sleeve gastrectomy within 1 year prior to screening. 
19. Have had a significant weight gain or loss within 3 months prior to screening, for 
example, ≥5%. 
20. Have acute or chronic hepatitis, cirrhosis, or obvious clinical signs or symptoms of any 
other liver disease (except nonalcoholic fatty liver disease, which is allowed), or have 
elevated liver enzyme measurements, determined by the central laboratory at screening, 
of the following 
 total bilirubin >2x ULN, except for participants previously diagnosed with 
Gilbert’s syndrome 
 ALT or serum glutamic pyruvic transaminase >3x ULN 
 AST or serum glutamic oxaloacetic transaminase >3x ULN, or 
 ALP >2.5x ULN.  
21. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy within 5 years prior to screening. 
Exception: Basal cell or squamous cell skin cancer. 
22. Are at increased risk for developing cancer or a recurrence of cancer. 
23. Have a history of or current significant psychiatric disorders considered clinically 
significant, in the opinion of the investigator. 
24. Have a history or presence of an underlying disease, or surgical, physical, or medical 
condition that, in the opinion of the investigator, would potentially affect participant 
safety within the study or interfere with the interpretation of data. 
25.  Have a known hypersensitivity or allergy to any of the study interventions or their 
excipients. 
Prior or concomitant therapy 
26. Have received these diabetes treatments within 30 days prior to screening 
 glinides 
 pramlintide 
 sulphonylureas 
 Dual GIP/GLP-1 RA (for example, tirzepatide), or 
 insulin or any insulin containing product. 
27. Are receiving or received systemic glucocorticoid therapy for >14 days within the month 
before screening. 
Exceptions: 
 replacement therapy for adrenal insufficiency 
 topical, intraocular, intranasal, or inhaled preparations, or 
 intra-articular injection. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
45 
Prior or concurrent clinical study experience 
28. Are currently enrolled or have participated within the last 30 days in a clinical study 
involving an investigational intervention or any other type of medical research judged not 
to be scientifically or medically compatible with this study. If the previous investigational 
intervention has a long half-life, then 3 months or 5 half-lives, whichever is longer, 
should have passed prior to Visit 1. 
29. Have previously completed or withdrawn from this study after signing the ICF or any 
other study investigating LY3209590 after receiving at least 1 dose of study intervention. 
Other exclusions 
30. Have hypoglycemia unawareness in the opinion of the investigator. 
31. Are women who test positive for pregnancy or intend to become pregnant. 
32. Are women who are lactating or breastfeeding. 
33. Have evidence of any substance use disorder of any severity defined by the Diagnostic 
and Statistical Manual of Mental Disorders-5, within 6 months prior to screening. 
Exception: nicotine or caffeine. 
34. Are Lilly employees or are employees of any third party involved in the study who 
require exclusion of their employees. 
35. 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. 
36. Are unsuitable for inclusion in the study in the opinion of the investigator. 
5.3. 
Lifestyle Considerations  
Diabetes management counseling 
Qualified study personnel 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. Diabetes self-management counseling may be reviewed 
throughout the study, as needed. 
Dietary and exercise considerations 
Study participants should generally follow a healthy meal plan and continue their usual exercise 
habits throughout the course of the study. 
Dietary and exercise restrictions 
Study participants should not initiate an intensive diet or 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. 
Blood donation 
Study participants should not donate blood or blood products during the study or for 4 weeks 
following their last study visit. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
46 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.  
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened.  
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable to this study. All entry criteria must be met within the specified 
intervals in the SoA. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
47 
6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.  
Investigators and other study personnel are expected to treat 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 or national standards of care for diabetes, the investigators 
should follow current published standards of care from the American Diabetes Association.  
6.1. 
Study Intervention(s) Administered  
LY3209590 and insulin glargine will be dispensed at the study visits summarized in SoA. 
Returned LY3209590 or insulin glargine should not be re-dispensed to the participants. 
This table lists the interventions used in this clinical study. 
Intervention 
Name 
LY3209590 
Insulin glargine 
Dose 
Formulation 
Solution 
Solution 
Unit Dose 
Strength(s) 
 
Autoinjector fixed dose 
strengths 
 
100 U/0.5 mL 
 
150 U/0.5 mL 
 
250 U/0.5 mL 
 
400 U/0.5 mL 
Prefilled pen for variable 
doses (>400 U) 
500 U/mL 
Prefilled pen 
100 U/mL 
Dosage Level(s) 
Individualized dosing 
(see Section 6.5.1) 
Individualized dosing 
(see Section 6.5.2) 
Frequency of 
Administration 
Once weekly  
Once daily 
Route of 
Administration 
Subcutaneous 
Subcutaneous 
Authorized as 
defined by EU 
Clinical Trial 
Regulationa 
No 
Yes 
a Study interventions identified as authorized are used in accordance with the terms of their marketing 
authorizations. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
48 
LY3209590 dosing information 
See Section 6.5.1 for dose initiation and guidance for dose adjustments. 
LY3209590 frequency of administration and guidance for missed doses 
LY3209590 should be administered once weekly at approximately the same time and day each 
week.  
Missed doses 
If a dose is missed, it should be administered as soon as possible if at least 3 days remain until 
the next scheduled dose. If less than 3 days remain before the next scheduled dose, skip the 
missed dose and administer the next dose on the regularly scheduled day. 
In each case, participants can then resume their regular once-weekly dosing schedule. 
The day of weekly administration can be changed, if necessary, only if the last dose has been 
administered at least 3 days earlier. 
If 2 consecutive doses are missed, contact the sponsor. 
Insulin glargine dosing information 
See Section 6.5.1 for dose initiation and guidance for dose adjustments. 
Insulin glargine frequency of administration 
Insulin glargine should be administered daily at approximately the same time each day. 
Anatomical location of injections 
Acceptable locations for injection include the abdomen, thigh, arm, or buttock.   
For both LY3209590 and insulin glargine, participants should rotate injection sites from one 
injection to the next, even when injecting within the same region. 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Medical Devices  
LY3209590 will be provided as a drug/device combination product with either a single dose 
autoinjector or a prefilled pen for the administration of LY3209590. All participants randomly 
assigned to receive LY3209590 will use autoinjectors for at least the first 15 weeks of the study 
but may transition to a prefilled pen if doses >400 U per week are required from Week 16 
onwards.  
Insulin glargine will be provided as a solution in a prefilled pen. 
Instructions for device will be provided. 
All PCs or device deficiencies, including malfunction, use error and inadequate labeling, shall be 
documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3.1) and appropriately managed by the sponsor.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
49 
6.1.2. 
Rescue Medicine for Management of Severe or Persistent Hyperglycemia  
The investigator should follow this general guidance if a participant develops severe, persistent 
hyperglycemia during the study. 
If a participant develops severe, persistent hyperglycemia after Week 16, additional 
antihyperglycemic medication should be considered after investigator assessment, based on 
conditions described in this table. 
Average of fasting blood glucose over 2-week period 
Timing of events 
>270 mg/dL (15 mmol/L) 
Weeks 16 to 20  
(from Visit 18 until Visit 22)  
>240 mg/dL (13 mmol/L) 
Weeks 20 to 26  
(after Visit 22 until Visit 25) 
>200 mg/dL (11 mmol/L) 
Weeks 26 to 52  
(after Visit 25 until Visit 33) 
Note: Rescue medicine may start at Week 12 in the rare instance that a participant had a dose reduction due to 
hypoglycemia but subsequently has severe or persistent hyperglycemia and meets the average of FBG 
>200 mg/dL over a 2-week period.  
Before changing the dose of concomitant medications or introducing any new treatments as 
rescue therapy, investigators should first confirm participant compliance with the assigned 
intervention, LY3209590 or insulin glargine, and ensure that the participant does not have an 
acute condition causing severe hyperglycemia. 
Next, investigators should optimize the participant’s concomitant antihyperglycemic medications 
or consider the addition of allowed concomitant antihyperglycemic medications (see Section 
6.8.3), if applicable, so the participant is taking up to 3 antihyperglycemic medications at 
effective doses before considering rescue therapy with insulin. Investigators should report any 
changes in dose for the concomitant antihyperglycemic medications that are in response to 
meeting the rescue criteria, as rescue therapy in the CRF.  
The investigator should ensure that the participant met the criteria for severe or persistent 
hyperglycemia before initiating rescue medicine and document this in the source files. 
If severe, persistent hyperglycemia is not improving despite compliance with the assigned 
therapeutic regimen and optimization of other concomitant glucose-lowering agents, the addition 
of prandial insulin may be considered.  
Participants who receive rescue therapy for hyperglycemia management should also continue 
administering either LY3209590 or insulin glargine for the remaining period in the study.   
If a participant is transitioning to a prefilled pen, investigators should  
 ensure that the transition does not occur at the same time as initiation of rescue therapy, 
and  
 wait for at least 4 weeks after the first dose with the LY3209590 prefilled pen.  
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
50 
6.2. 
Preparation, Handling, Storage, and Accountability  
The investigator or designee must confirm appropriate storage conditions have been maintained 
during transit for all study intervention received and any discrepancies are reported and resolved 
before use of the study intervention. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. All study intervention 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 study personnel. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.  
Participant responsibilities 
In-use storage conditions are expected to be followed according to the instructions for use 
provided by the sponsor. Study participants will be trained on the proper storage and handling of 
the study intervention.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
Randomization and stratification 
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, the login information and directions for the IWRS will be provided 
to each site. 
Participants will be randomly assigned in an 1:1 ratio to LY3209590:insulin glargine. 
Participants will be stratified based on 
 country 
 HbA1c stratum at Visit 1 (<8% and ≥8%), and  
 GLP-1 RA use at randomization, regardless of oral or injectable administration, 
(Yes/No). 
Blinding 
This is an open-label study. Investigators and participants will be unblinded to the assigned 
treatment groups. 
The Lilly study team members who are closely involved in data interpretation and analysis 
planning will remain blinded throughout the course of the study. Only a minimum number of 
Lilly personnel will see the randomization table and treatment assignments before the study is 
complete. 
The investigator should make every effort to preserve the blinding when contacting the Lilly 
study team members, including the Lilly clinical research physician or scientist. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
51 
Unblinded reviews 
External committees reviewing unblinded data during the study are described in Section 10.1.5. 
An early PK/PD unblinded transfer may also be conducted. Only a small group of personnel can be 
unblinded to the data for the potential PK/PD analysis and must keep information confidential until 
the planned unblinding of the trial. 
6.4. 
Study Intervention Compliance  
Participants are responsible for entering the date of their daily or weekly insulin dose and dose 
amount in their e-diary. 
The investigator or trained designee will assess treatment compliance at each visit based on 
review of the participant glycemic control, e-diary completion, and adherence to prescribed dose 
and study procedures. 
If a participant is considered poorly compliant with their study procedures, for example, missed 
visits or specific diagnostic tests, they will be retrained as needed by designated study personnel.  
6.5. 
Dose Modification  
The investigator is responsible for titrating the basal insulin dose using the guidance in the SoA, 
Sections 6.5.1 and 6.5.2 and their clinical judgment. 
General insulin dose adjustment considerations 
Fasting blood glucose  
Dosing will be individualized based on FBG and hypoglycemia events.  
The FBG treat-to-target is 80 to 130 mg/dL (4.4 to 7.2 mmol/L), inclusive.   
Use the median FBG for dose adjustment and follow this guidance: 
 Determine the median FBG from the 3 most recently recorded FBG readings from the 7-
day period prior to the site visit.   
 If only 2 FBG measurements are available, use the lower of the readings for the dose 
assessment. 
 If only 1 FBG measurement is available, the investigator determines if a dose change is 
necessary.  
Investigators are expected to follow the dosing regimen for the protocol. However, modifications 
of the basal insulin dose may be influenced by other clinical circumstances or safety 
considerations known to the investigator. If the investigator prescribes a dose other than the 
regimen recommended dose, the investigator is responsible for documenting the clinical rationale 
for the prescribed dose. 
When considering any dose adjustments (in either treatment group), the investigator will also 
review whether the participant experienced any documented episodes of hypoglycemia. If the 
participant experienced any documented BG ≤70 mg/dL (≤3.9 mmol/L) in the previous week, 
the basal insulin dose should not be increased.  
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
52 
Hypoglycemia 
A participant’s dose may be decreased based on hypoglycemia at any time during the study 
(Sections 6.5.1 and 6.5.2). 
Do not increase the study intervention dose if hypoglycemia (BG ≤70 mg/dL) is reported in the 
week prior to the assessment. 
Although hypoglycemia criteria for dose reduction are specified in the tables for each treatment 
in Sections 6.5.1 and 6.5.2, it is important for the investigator to rule out any other contributing 
factors, such as increased physical activity or illness, which may cause an unusual occurrence of 
hypoglycemia. In these circumstances, the decision to reduce the dose is at the discretion of the 
investigator.  
Study participants will be instructed to check their BG, when they experience signs and 
symptoms suggestive of hypoglycemia, and to administer appropriate treatment for when BG 
≤70 mg/dL (3.9 mmol/L). They will be instructed to recheck BG levels 15 minutes following 
treatment of hypoglycemia and repeat treatment and BG recheck after another 15 minutes until 
the BG level has returned to the target range of 80-130 mg/dL (4.4-6.6 mmol/L) (CDC 2021). 
Instructions will be provided for clinical management of participants who experience frequent or 
repeated hypoglycemia. As necessary, additional instruction/education may be provided to 
participants by investigative staff, including increased BG monitoring, treatment adjustments, or 
other approaches (for example, behavioral interventions and lifestyle modification) to mitigate 
hypoglycemia frequency or severity. 
6.5.1. 
LY3209590 Dose Initiation and Adjustment  
This section outlines the LY3209590 
 general dosing information  
 dose adjustments guidance based on FBG, and 
 dose adjustment guidance based on hypoglycemia. 
6.5.1.1. 
General LY3209590 Dosing Information  
Starting dose 
The starting dose for LY3209590 occurs on Week 0 at Visit 3, and is 100 U, administered once-
weekly, using a single dose autoinjector. 
Dose escalations for Week 4 up to Week 16 (Visits 8-18)  
The investigator should make every effort to follow the fixed dose escalation regimen to achieve 
a treat-to-target FBG of 80 to130 mg/dL during the first 16 weeks using the fixed dose levels of 
150 U, 250 U, and 400 U, administered once-weekly by single dose autoinjectors.  
Assessments for potential dose adjustment will occur every 4 weeks based on a participant’s 
median FBG and hypoglycemia events.  
Participants will maintain a dose level for 4 weeks until the next assessment for potential dose 
increase. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
53 
Dose escalations after Week 16 
Assessments for potential dose adjustment may occur at each visit and at least every 4 weeks.  
If a participant has a fixed dose (autoinjector) escalation after Week 16, they must remain on that 
dose for 4 weeks before an assessment for further dose escalation. 
If, at Week 16 or after, a participant… 
Then… 
 
has been on the fixed dose of 400 U/week for at 
least 4 weeks  
 
has a median FBG >130 mg/dL for the previous 
week, AND 
 
has not met hypoglycemia criteria described in 
Section 6.5.1.3. 
the investigator should transition the participant to a 
variable dose delivered by the prefilled pen.  
Note: The prefilled pen provides more dosing 
flexibility and allows dose titration above 400 U/week.  
If a participant transitions from the fixed dose autoinjector to the prefilled pen, the first dose 
administration with the prefilled pen will be administered at the site.  
If a participant transitions from the fixed dose autoinjector to a prefilled pen, they must continue 
using the prefilled pen for the remainder of the study.  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
54 
 
LY3209590 dose escalation schema 
 
Abbreviations: AI = autoinjector; FBG = fasting blood glucose; U = units. 
1At 4 weeks, 8 weeks, 12 weeks, 16 weeks, and per visit schedule thereafter. 
2Participant must remain on the autoinjector dose for 4 weeks before next assessment for dose escalation. 
380-130 mg/dL. 
4Participants who transition to the prefilled pen must continue to use this device for the remainder of the study. 
 
Details for dose reduction in response to hypoglycemia are given in Section 6.5.1.3. 
 
 
 
Scheduled FBG 
assessment for 
dose escalation1,2
Remain on current 
AI dose
At target FBG3
Above target FBG3
Reassess after 4 wks
Received 400 U/wk for ≥ 4 
wks and above target FBG3
Start dose 
100 U AI
Dose increase to  
next step up 150 U, 
250 U or 400 U AI
Transition to 
Prefilled pen for 
doses > 400 U/wk4
Wks 0-16 and per visit 
schedule thereafter
Wks 16-52
Received 400 U/wk for ≥4 
wks and at target FBG3
Scheduled FBG 
assessment for 
dose escalation1,2
At target FBG3
Above target FBG3
Remain on 400 U 
AI 
Flexible doses 
adjusted per protocol
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
55 
6.5.1.2. 
LY3209590 Dose Adjustments Based on Fasting Blood Glucose  
Dose adjustments for participants on a fixed dose administered by the autoinjector 
Assessments for potential dose adjustment will occur every 4 weeks. 
This table provides guidance for dose adjustments if the participant is on a fixed dose 
administered by a single dose autoinjector.   
If the median FBG is… 
And… 
Then…  
<80 mg/dL 
<4.4 mmol/L 
the participant has not 
met hypoglycemia 
criteria described in 
Section 6.5.1.3 
 do not change the dose. 
 make recommendations to the participant to 
reduce hypoglycemia risk or occurrence, for 
example  
o  more frequent BG monitoring  
o  consider behavioral interventions and 
lifestyle modifications. 
80-130 mg/dL 
(target) 
4.4-7.2 
mmol/L 
---- 
do not change the dose. 
>130 mg/dL 
>7.3 mmol/L 
---- 
increase the LY3209590 dose to the next higher 
single dose autoinjector dose level.  
>130 mg/dL at or 
after Week 16 
>7.3 mmol/L 
at or after 
Week 16 
the participant 
 has been on a fixed 
dose of 400 U/week 
for at least 4 weeks, 
and  
 has not met 
hypoglycemia 
criteria described in 
Section 6.5.1.3. 
the investigator should transition the participant 
to a prefilled pen with variable dose capabilities 
above 400 U/week. 
Dose adjustment for participants on a variable dose administered by a prefilled pen 
If a participant transitions from the single dose autoinjector to a prefilled pen, they must continue 
using the prefilled pen for the remainder of the study. 
Assessments for potential dose adjustment may occur weekly or at least every 4 weeks. 
This table provides guidance for dose adjustments if the participant is transitioning to or using 
the prefilled pen. 
If the median FBG is… 
Then…  
<80 mg/dL 
<4.4 mmol/L 
reduce the LY3209590 dose by 20 U. 
80-130 mg/dL (target) 
4.4-7.2 mmol/L 
do not change the dose. 
131-140 mg/dL 
7.3-7.7 mmol/L 
increase the LY3209590 dose by 20 U. 
>140 mg/dL 
>7.7 mmol/L 
increase the LY3209590 dose by 40 U. 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
56 
6.5.1.3. 
LY3209590 Dose Adjustments Based on Hypoglycemia Events  
Guidance for participants receiving 100 U LY3209590 
If a participant is receiving a 100 U LY3209590 dose and experiences hypoglycemia, the 
investigator will  
 rule out any other contributing factors, such as increased physical activity or illness, 
which may cause an unusual occurrence of hypoglycemia, and  
 discontinue intervention if participant meets dose reduction criteria due to hypoglycemia. 
General guidance 
If a participant experiences any hypoglycemia event (BG ≤70 mg/dL) in the previous week and 
their FBG is >130 mg/dL at the next dose assessment time point, the investigator should not 
increase the dose. In this situation, the only time the investigator should increase the dose is if 
they determine that it was an unusual occurrence of hypoglycemia that was explained by other 
contributing factors, such as increased physical activity or illness. 
Dose adjustments for participants on a fixed dose administered by the autoinjector 
This table provides guidance for dose adjustments based on hypoglycemia events. 
If a participant using the 
autoinjector reports… 
With a blood glucose value of... 
Then… 
≥3 hypoglycemic events 
≤70 mg/dL (3.9 mmol/L) 
reduce the LY3209590 dose to the 
next lower autoinjector dose level. 
≥1 hypoglycemic event 
<54 mg/dL (3.0 mmol/L) 
≥1 nocturnal hypoglycemic event 
≤70 mg/dL (3.9 mmol/L) 
any confirmed severe hypoglycemia 
(neurological impairment confirmed 
by investigator) 
___ 
If the autoinjector dose is reduced due to hypoglycemia, the participant should remain on the 
lower dose for the remainder of the study, unless a further dose decrease is required due to 
hypoglycemia.   
Dose adjustment for participants on a variable dose administered by a prefilled pen 
This table provides guidance for dose adjustments based on hypoglycemia events.  
If a participant using a prefilled 
pen reports… 
with a blood glucose value of... 
then… 
≥3 hypoglycemic events 
≤70 mg/dL (3.9 mmol/L) 
reduce the LY3209590 dose by 40 U. 
≥1 hypoglycemic event 
<54 mg/dL (3.0 mmol/L) 
≥1 nocturnal hypoglycemic event 
≤70 mg/dL (3.9 mmol/L) 
Any confirmed severe 
hypoglycemia 
(neurological impairment confirmed 
by investigator) 
___ 
6.5.2. 
Insulin Glargine Dose Initiation and Adjustment  
This section outlines the insulin glargine 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
57 
 general dosing information  
 dose adjustment guidance based on FBG, and 
 dose adjustment guidance based on hypoglycemia. 
6.5.2.1. 
General Insulin Glargine Dosing Information  
All insulin glargine doses will be administered using a prefilled pen.  
The starting dose for insulin glargine occurs on Week 0 at Visit 3. 
The starting dose for insulin glargine is 10 U/day.   
The investigator will use an individualized flexible dose approach throughout the study with 
weekly assessments for potential dose adjustment during the 52 weeks of treatment.   
6.5.2.2. 
Insulin Glargine Dose Adjustments According to Fasting Blood Glucose  
This table provides guidance for dose adjustments based on median FBG recorded during the 
previous week.  
If the median FBG is… 
Then…  
<80 mg/dL 
<4.4 mmol/L 
reduce the dose by 3 U. 
80-130 mg/dL (target) 
4.4-7.2 mmol/L 
do not change the dose. 
131-140 mg/dL 
7.3-7.7 mmol/L 
increase the dose by 3 U. 
>140 mg/dL 
>7.7 mmol/L 
increase the dose by 6 U. 
6.5.2.3. 
Insulin Glargine Dose Adjustments According to Hypoglycemia Events  
A participant’s dose may be decreased based on hypoglycemia at any time during the study. 
Dose adjustments for participants receiving insulin glargine 
This table provides guidance for dose adjustments based on hypoglycemia events. 
If a participant reports… 
With a blood glucose value 
of… 
Then… 
≥3 hypoglycemic events 
≤70 mg/dL (3.9 mmol/L) 
reduce the dose by 2 to 6 U. 
 
Dose reductions of 2 or 4 U may 
occur every 3 days to achieve a 
weekly 6 U reduction as clinically 
indicated. 
≥1 hypoglycemic event  
<54 mg/dL (3.0 mmol/L) 
≥1 nocturnal hypoglycemic event  
≤70 mg/dL (3.9 mmol/L) 
any confirmed severe hypoglycemia 
(neurological impairment confirmed by 
investigator) 
___ 
 
6.6. 
Continued Access to Study Intervention after the End of the Study  
The sponsor will not provide participants with any ongoing supplies of study intervention after 
they have completed the study treatment period or permanently discontinued the study 
intervention. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
58 
6.7. 
Treatment of Overdose  
An overdose of LY3209590 or insulin glargine, defined as a dangerously large amount of insulin 
compared to the protocol-prescribed dose, will be reported as per Section 10.3.1. In the event of 
an overdose, refer to the IB for LY3209590 or product label for insulin glargine depending on 
the participant treatment assignment. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
59 
In the event of an overdose, the investigator or treating physician should: 
 contact the medical monitor immediately 
 consider holding non-insulin diabetes medications, if clinically appropriate 
 evaluate the participant to determine, in consultation with the medical 
monitor, whether study intervention should be interrupted or whether the dose 
should be reduced 
 closely monitor the participant for any AE or SAE and laboratory abnormality 
until study intervention no longer has a clinical effect, and 
 obtain a plasma sample for PK analysis if the participant is assigned to 
LY3209590. 
 
6.8. 
Concomitant Therapy  
Concomitant therapy regimens 
All participants should maintain their usual medication regimens for concomitant conditions or 
diseases throughout the study, unless those medications are specifically excluded in the protocol 
(see Section 5.2). 
Participants taking concomitant medications should be on stable dosages at the time of screening 
and should remain at stable dosages throughout the study, unless changes need to be made 
because of an AE or rescue therapy (see Section 6.1.2). 
Acceptable non-insulin diabetes treatments are described in Section 6.8.3. 
Changing concomitant therapy 
Participants should consult with authorized study personnel before taking any new medications 
during the study, except when initiated for treatment of medical emergencies. Authorized study 
personnel should consult the sponsor’s medical monitor if there are any questions about 
concomitant therapies during the study. 
Concomitant therapy data collection 
For therapy that the participant is receiving at the time of enrollment or receives during the 
study, including over-the-counter medications, authorized study personnel should collect 
 the name of medication, vaccine, or therapy 
 the reason for use, and 
 dates of administration, including start and end dates. 
For diabetes and lipid-modifying medications, collect dosage information including dose and 
frequency. 
Nonstudy medications taken by study participants who have signed informed consent, but are not 
randomly assigned, will not be reported unless an SAE or AE occurs that the investigator believes 
may have been caused by a study procedure. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
60 
6.8.1. 
Medications with Approved Weight Loss Indication  
Allowed usage of weight loss medication during the study 
A participant may use a medication that promotes weight loss if they are on stable therapy 90 
days prior to screening. 
Allowed medications include, but are not limited to 
 over-the-counter medications, including food supplements that promote weight loss 
 liraglutide 3.0 mg 
 orlistat 
 sibutramine 
 mazindol 
 phentermine 
 lorcaserin 
 phentermine and topiramate combination 
 naltrexone or bupropion, or 
 semaglutide injection 2.4 mg. 
Prohibited usage of weight loss medication during the study 
After screening, no prescription or over-the-counter medications that promote weight loss may 
be initiated or changes in dosage allowed. 
6.8.2. 
Chronic Systemic Glucocorticoid Medication  
Chronic systemic glucocorticoid therapy is allowed for no more than two 14-consecutive day 
periods during study treatment period. Each period must be at least 30 days apart. 
This restriction does not apply to glucocorticoid therapy used as replacement therapy for adrenal 
insufficiency, or topical, intraocular, intranasal, inhaled preparations, and intra-articular 
injections. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
61 
6.8.3. 
Antihyperglycemic Medications  
This table shows the conditions for use of concomitant antihyperglycemic medications. 
Drug Class 
Use during Screening or 
Lead-In 
Conditions for Use after Randomization 
 
Y = yes, if on stable therapy 
90 days prior to screening. 
N = No 
During 
Treatment 
Period 
Acute 
Therapy 
Treatment 
for up to 14 
days 
Rescue 
Therapy  
During 
Safety 
Follow-
Up 
Period 
GLP-1 RAs 
Y 
Yes, if on 
stable therapy 
90 days prior 
to screening 
N/A 
Y 
Y 
DPP-4 inhibitors 
Y 
N/A 
Y 
Y 
SGLT2 inhibitors 
Y 
N/A 
Y 
Y 
Nonstudy basal 
insulins 
N 
N 
Yes, only if 
study basal 
insulin is 
temporarily 
discontinued 
See Note 
Y 
Insulin mixtures 
N 
N 
Yes, only if 
study basal 
insulin is 
discontinued 
See Note 
Y 
Prandial insulin 
N 
N 
Y 
Y 
Y 
Meglitinides 
N 
N 
N/A 
N 
Y 
Dual GIP/GLP-1 RAs 
(for example, 
tirzepatide) 
N 
N 
N/A 
N 
Y 
Alpha-glucosidase 
inhibitors 
Y 
Yes, if on 
stable therapy 
90 days prior 
to screening 
N/A 
Y 
Y 
Sulfonylureas 
N 
N 
N/A 
N 
Y 
Thiazolidinediones 
Y 
Yes, if on 
stable therapy 
90 days prior 
to screening 
N/A 
Y 
Y 
Metformina 
Y 
Yes, if on 
stable therapy 
90 days prior 
to screening 
N/A 
Yes, if the 
dose is below 
maximum 
approved dose 
per country-
specific label 
Y 
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GIP = glucose dependent insulinotropic peptide; GLP-1 RA = 
glucagon-like peptide-1 receptor agonist; N = no; N/A   not applicable; SGLT2 = sodium-glucose cotransporter 2; Y 
= yes. 
a Switching metformin manufacturer is allowed if the dosage is the same. Changing to a metformin formulation with 
a different action profile (that is, from short-acting to long-acting metformin) is not permitted.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
62 
Note: Participants who require a nonstudy basal insulin or insulin mixture as rescue therapy must first discontinue 
study intervention (LY3209590 or insulin glargine). The participant will remain in the study and follow procedures 
for the remaining study visits. 
Dose adjustments of allowable non-insulin antihyperglycemic medications are permitted after 
randomization under the following circumstances: 
 situations that require short-term treatment interruption consistent 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 estimated glomerular filtration rate 
 in the case of increased hypoglycemia risk during the treatment period (as described in 
Section 8.3.6) 
 a dose increases as part of rescue therapy, and 
 for safety reasons at the discretion of the investigator. 
Any changes in dose should be documented.  
6.9. 
Nonstudy Treatment after the End of the Study  
The investigator will assess each participant to determine the need to transition to a nonstudy 
treatment for T2D at visits described in the SoA. Unscheduled visits, in addition to those 
described in the SoA, may occur during this time to facilitate the transition. 
The participant’s FBG and other clinical factors should be used to guide dose initiation and 
adjustment in accordance with the country-specific label.  
A daily basal insulin is not required until the FBG is above 120 mg/dL for 2 consecutive 
measurements.  
If a nonstudy daily basal insulin is required, start the dose at 10 U/day and adjust based on FBG 
and investigator judgment in accordance with any country-specific label.  
Study participants treated with LY3209590 
Since LY3209590 has a half-life of approximately 17 days, a careful titration of any new anti-
hyperglycemic treatment will be necessary to prevent hypoglycemia due to overlapping action. 
The investigator should consider titrating the daily insulin to reach 50% of the required daily 
dose at approximately 2 weeks and 80% at approximately 4 weeks. 
Study participants treated with insulin glargine 
Study participants assigned to insulin glargine will transition to a nonstudy treatment after Visit 
33. The investigator will prescribe the nonstudy treatment and titrate the dose based on their 
clinical judgment in accordance with the country-specific label.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
63 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.9. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits, as 
shown in the SoA.  
Participants who stop the study intervention permanently may receive another glucose-lowering 
medication. The new glucose-lowering medication will be recorded on the CRF for 
antihyperglycemic medications. 
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study 
 the participant requests to discontinue study intervention 
 the participant is receiving a 100 U dose and needs a dose reduction 
 the participant is diagnosed with an active or untreated malignancy, except for 
successfully treated basal or squamous cell carcinoma 
 the participant did not take insulin glargine for more than 21 consecutive days or 
missed more than 3 consecutive doses of LY3209590 at any time during the study, or 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
64 
7.1.1. 
Liver Chemistry Stopping Criteria  
The study intervention should be interrupted or discontinued if 1 or more of these conditions 
described in this table occur. 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for intervention interruption or 
discontinuation decisions rather than TBL 
>2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL >2x ULN  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for intervention interruption or 
discontinuation decisions rather than TBL 
>2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) 
 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited, non-intervention etiology is identified. 
7.1.2. 
Hypersensitivity Reactions  
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the sponsor’s designated medical monitor should be notified. 
If the investigator is uncertain about whether a systemic hypersensitivity reaction has occurred 
and whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor.  
7.1.3. 
Temporary Discontinuation of Study Intervention  
Criteria for temporary discontinuation of LY3209590 or insulin glargine 
The investigator may temporarily interrupt study treatment, due to an AE, clinically significant 
laboratory value, hospital visits, travel, or shortage of study treatment supply. 
This will be allowed for up to 21 consecutive days for insulin glargine or 3 consecutive doses for 
LY3209590 at any time during the study. This information should be documented by the 
investigator. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
65 
Guidance when temporary discontinuation of study intervention occurs 
Every effort should be made by the investigator to maintain participants in the study and to 
restart study intervention promptly, as soon as it is safe to do so. 
Participants will continue their study visits and follow-up according to the SoA. 
Participants should resume the dose prescribed before the temporary dosing interruption at the 
discretion of the investigator. 
Recording temporary discontinuation of study intervention 
The dates of study intervention interruption and restart must be documented in source documents 
and entered on the CRF. 
Participant noncompliance should not be recorded as interruption of study intervention on the 
CRF.  
7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study 
 at any time at the participant’s own request 
 at the request of the participant’s designee (for example, parents or legal 
guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
 if the participant is diagnosed with any type of diabetes mellitus other than 
T2D  
 if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically 
or medically compatible with this study, or 
 if the participant, for any reason, requires treatment with a therapeutic agent 
that is prohibited by the protocol and has been demonstrated to be effective 
for treatment of the study indication. In this case, discontinuation from the 
study occurs prior to introduction of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and post-treatment follow-up, as shown in the SoA.  
If the participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
If a participant withdraws from the study, the participant may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
66 
7.3. 
Lost to Follow up  
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. Site personnel or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
67 
8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
8.1. 
Efficacy Assessments  
Efficacy will be measured by 
 HbA1c 
 FBG  
 insulin dose, and 
 patient-reported outcomes questionnaires 
o TRIM-D 
o DTSQ-status 
o DTSQ-change 
o SIM-Q 
o DID-EQ, and 
o Basal Insulin Experience. 
See Section 3 for specific efficacy endpoints. 
8.1.1. 
Glucose Monitoring  
Participants must use only the study-provided glucometer during the study. The use of personal 
glucometer or continuous glucose monitoring is not permitted. 
8.1.1.1. 
Self-Monitoring of Blood Glucose (SMBG)  
Glucometer for participant use during the study 
Participants will receive a sponsor-approved glucometer and related testing supplies for use 
during the study. 
Site personnel will train the participant on correct use of the glucometer for self-monitoring 
blood glucose and reporting of hypoglycemia data in the e-diary. 
Participants should use the glucometer 
 
for the 6-point profile 
 
whenever hypoglycemia is experienced or suspected 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
68 
 
Note: If BG values are <80 mg/dL but not below <70 mg/dL (that is, defined as 
hypoglycemia), recommend to the participant that they monitor their BG more frequently to 
prevent hypoglycemia. This is particularly relevant to participants receiving LY3209590 via 
the autoinjector, where dose cannot be adjusted precisely to meet glycemic requirements. 
 
when there is awareness of increased risk related to changes in dietary intake, physical 
activity, or inadvertent or atypical insulin dosing 
 
to check for hyperglycemic events, or 
 
as directed by the investigator. 
Performing a 6-point profile 
Participants will receive instructions to perform SMBG 6-point profiles over a 24-hour period on 
2 nonconsecutive days during the 7-day period prior to visits shown in the SoA. 
The 6-point profile consists of pre-meal and 2-hour postprandial SMBG measurements for the 
morning, midday, and evening meals during 1 day. 
Pre-meal measurements should be taken before the participant begins eating the meal. 
When to measure fasting blood glucose (FBG) during the study 
Site personnel will train the participant to measure FBG daily when possible, and a minimum of 
3 times per week using the study-provided glucometer. 
Participants should not eat or drink anything but water for a minimum of 8 hours before 
measuring their FBG. 
Participants should measure FBG upon waking in the morning after fasting overnight.   
Glucometer data transfer 
The study-provided glucometer will wirelessly transmit blood glucose measurements to the 
participant’s e-diary. Site personnel will be able to view SMBG data that have been transmitted 
to the e-diary through a web-based portal as well as any reported events of hypoglycemia. 
8.1.2. 
Patient-Reported Outcomes  
To ensure balance between participants assigned to LY3209590 or insulin glargine, all 
participants will complete the questionnaires.  
The self-administered questionnaires will be translated into the native language of the region and 
administered at the site during the designated visits in the SoA. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
69 
Order of administering the questionnaires during the visit 
If the participant is not adversely affected by their fasting condition, the questionnaires should be 
completed before the participant has discussed their medical condition or progress in the study 
with the investigator or study personnel. 
Preferred administration order of these questionnaires is: 
1. TRIM-D  
2. DTSQ 
3. SIM-Q 
4. DID-EQ, and 
5. Basal Insulin Experience: Likelihood of incorporating into routine.  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
70 
8.1.2.1. 
Treatment-Related Impact Measure – Diabetes (TRIM-D)  
Description of TRIM-D 
The TRIM-D is a participant self-administered instrument, which assesses the impact of diabetes 
treatment on participants’ functioning and well-being across available diabetes treatments. 
Participants assess their experience “over the past 2 weeks.” 
The TRIM-D assesses 5 domains of impact. 
Domain 
Number of items per domain 
Treatment Burden 
6 
Daily Life 
5 
Diabetes Management 
5 
Compliance 
4 
Psychological Health 
8 
Scoring 
Each of the 28 items is assessed on a 5-point scale, where higher scores indicate a better health 
state. 
8.1.2.2. 
Diabetes Treatment Satisfaction Questionnaire – Status Version (DTSQ-s)  
Description of DTSQ-s 
The DTSQ-s (Bradley and Lewis 1990; Bradley 1999) is a diabetes-specific patient-reported 
outcome instrument that assesses the overall treatment satisfaction and perceived frequency of 
hyperglycemia and hypoglycemia. It is appropriate for use in both T1D and T2D. 
The DTSQ-s consists of 8 items that assess treatment satisfaction as well as concerns about 
hyperglycemia and hypoglycemia over the past few weeks, prior to the visit.  
Scoring for DTSQ-s 
Each item is rated on a 7-point Likert scale.  
Items 1, 4, 5-7, and 8 are rated from 0 (very dissatisfied) to 6 (very satisfied) and can be summed 
up to produce a treatment satisfaction score.   
Items 2 and 3 evaluate the perceived frequency of hyperglycemia and hypoglycemia and are 
rated from 0 (none of the time) to 6 (most of the time).  
8.1.2.3. 
Diabetes Treatment Satisfaction Questionnaire – Change Version (DTSQ-c)  
Description of DTSQ-c 
The DTSQ-c (Bradley 1999) was designed to overcome potential ceiling effects in the status 
version.   
The DTSQ-c has the same 8 items as the status version but is reworded slightly to measure the 
change in treatment satisfaction rather than absolute treatment satisfaction. 
Scoring for DTSQ-c 
Each item is scored on a scale of -3 to +3.   
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
71 
For items 2 and 3, representing perceived frequency of hyperglycemia, and perceived frequency 
of hypoglycemia, the lower the score represents better the perception. 
For the remaining items  
 the higher the score represents the greater the improvement in treatment satisfaction 
 the lower the score represents the greater the deterioration in treatment satisfaction, and 
 a score of 0 represents no change.  
8.1.2.4. 
Simplicity of Diabetes Treatment Questionnaire (SIM-Q) Single Medication 
Status Version  
Description of SIM-Q 
The SIM-Q is a brief 10-item measure developed to assess the simplicity and complexity of 
treatment for T2D. This version of the instrument assesses the simplicity and complexity of a 
single medication. The participant responses should consider only the assigned study 
intervention. 
In this study, only the last 2 questions of the SIM-Q will be completed 
 “How simple or complex is your medication treatment for diabetes?” and 
 “Overall, how simple or complex is it to manage your diabetes, including medication, 
checking your blood glucose levels, diet, and any other aspects of diabetes treatment?” 
Scoring for SIM-Q 
Each item is scored on a 5-point scale ranging from “Very complex” to “Very simple.”  
8.1.2.5. 
Diabetes Injection Device Experience Questionnaire (DID-EQ) Version 1.0  
Description of DID-EQ 
The DID-EQ (Matza et al. 2018) is a self-administered, 10-item questionnaire designed to assess 
participants’ perceptions of non-insulin diabetes injection delivery systems for T2D.  
Scoring for DID-EQ 
Each item is rated on a 4-point scale with higher scores indicating more positive perceptions of 
the injection device.  
Items 1 to 7 focus on specific characteristics of non-insulin injection device, and these 7 items 
comprise the Device Characteristics subscale.  
In addition, there are 3 global items:  
 Item 8 assessing overall satisfaction  
 Item 9 ease of use, and  
 Item 10 convenience of non-insulin injection devices.  
These 3 global items are each scored separately.  
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
72 
8.1.2.6. 
Basal Insulin Experience: Likelihood of Incorporating into Routine  
Description of questionnaire 
The Basal Insulin Experience: Likelihood of incorporating into routine is a self-reported scale 
consisting of a single question to understand the participant’s likelihood of incorporating their 
study insulin into their diabetes management routine. 
Scoring 
The question is rated on a 5-point scale with responses ranging from “very unlikely” to “very 
likely.”  
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
The complete physical examination will include, at a minimum, assessments of these systems: 
 cardiovascular 
 respiratory 
 gastrointestinal, and 
 neurologic. 
Additional assessments include clinical signs and symptoms related to T2D, T2D-related 
illnesses, and injection-site reactions. 
Height and Weight 
Height and weight will be measured as outlined in the SoA. 
8.2.2. 
Vital Signs  
Blood pressure and pulse rate will be measured as outlined in the SoA and as clinically indicated. 
Additional vital signs may be measured during study visits if warranted, as determined by the 
investigator. 
8.2.3. 
Electrocardiograms  
Local and single 12-lead ECG will be obtained as outlined in the SoA. 
ECGs will initially be interpreted by the investigator or qualified designee at the site as soon 
after the time of ECG collection as possible, and ideally while the participant is still present, to 
determine whether the participant meets entry criteria and for immediate participant 
management, should any clinically relevant findings be identified. 
The investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document their review of the ECG printed at the time of 
evaluation. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
73 
8.2.4. 
Clinical Safety Laboratory Tests  
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. 
The laboratory results must be retained with source documents unless a Source Document 
Agreement or comparable document cites an electronic location that accommodates the expected 
retention duration. 
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 5 weeks after the last dose of intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
If such values do not return to normal or baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments must be conducted in accordance with the SoA, 
standard collection requirements, and laboratory manual. 
If laboratory values from non-protocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator, for example, SAE or AE or dose 
modification, then report the information as an AE. 
8.2.5. 
Hepatic Monitoring  
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests, including ALT, AST, ALP, TBL, direct bilirubin, GGT, and creatine kinase, 
should be repeated within 48 to 72 hours to confirm the abnormality and to determine if it is 
increasing or decreasing, if 1 or more of these conditions occur. This table shows when to repeat 
laboratory tests. 
If a participant with baseline results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants with Gilbert’s 
syndrome) 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
74 
What to do if the abnormal condition persists or worsens 
If the abnormal liver test result persists or worsens, clinical and laboratory monitoring, and 
evaluation for possible causes of abnormal liver tests should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including 
 symptoms 
 recent illnesses, for example, heart failure, systemic infection, hypotension, or seizures 
 recent travel 
 history of concomitant medications, including over-the-counter, herbal and dietary 
supplements, and 
 history of alcohol drinking and other substance abuse. 
Frequency of monitoring 
Initially, monitoring of symptoms and liver tests should be done 1 to 3 times weekly, based on 
the participant’s clinical condition and liver test results. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. 
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return to 
approximate baseline levels. 
Comprehensive hepatic evaluation 
When to perform a comprehensive evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of the conditions in this table occur. 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs or symptomsa, or 
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs or symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s syndrome)  
a 
Hepatic signs or symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, 
rash, and/or eosinophilia >5%. 
What a comprehensive evaluation should include 
At a minimum, this evaluation should include 
 physical examination and a thorough medical history, as outlined above 
 tests for 
o PT-INR 
o viral hepatitis A, B, C, or E, and 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
75 
o autoimmune hepatitis, and 
 an abdominal imaging study, for example, ultrasound or computed tomography scan. 
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for 
 hepatitis D virus 
 cytomegalovirus 
 Epstein-Barr virus 
 acetaminophen levels 
 acetaminophen protein adducts 
 urine toxicology screen 
 Wilson’s disease 
 blood alcohol levels 
 urinary ethyl glucuronide, and 
 blood phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a hepatologist or 
gastroenterologist consultation, magnetic resonance cholangiopancreatography, endoscopic 
retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
Collect additional hepatic safety data collection in the hepatic safety CRFs if a participant 
develops 
 a hepatic event considered to be an SAE 
 discontinues study intervention due to a hepatic event, or 
 has changes in laboratory results described in this table. 
If a participant with 
baseline results of...  
develops the following elevations… 
Then… 
Elevated serum ALT 
Collect additional hepatic safety data in 
the hepatic safety CRF. 
ALT <1.5x ULN 
ALT to ≥5x ULN on 2 or more 
consecutive blood tests 
ALT ≥1.5x ULN 
ALT ≥3x baseline on 2 or more 
consecutive blood tests 
Elevated TBL 
TBL <1.5x ULN 
TBL ≥2x ULN, except for participants 
with Gilbert’s syndrome 
TBL ≥1.5x ULN 
TBL ≥2x baseline  
Elevated ALP 
ALP <1.5x ULN 
ALP ≥2x ULN on 2 or more consecutive 
blood tests 
ALP ≥1.5x ULN 
ALP to ≥2x baseline on 2 or more 
consecutive blood tests 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
76 
See Section 10.5 for hepatic laboratory tests. 
8.2.6. 
Pregnancy Testing  
Pregnancy testing will occur as outlined in the SoA. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected as outlined in Sections 8.3.1 and 8.3.2.  
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3: 
 AEs 
 SAEs, and 
 PCs. 
These events will be reported by the participant or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits or contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
For PCs, the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Section 10.3. 
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Adverse Event (AE) 
AE 
Signing of 
the informed 
consent form 
(ICF) 
The last 
safety follow-
up visit 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
77 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Serious Adverse Event (SAE) 
SAE and SAE 
updates 
prior to start of 
study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
SAE and SAE 
updates 
after start of 
study 
intervention 
Start of 
intervention 
The last 
safety follow-
up visit 
Within 24 hours of 
awareness 
SAE CRF  
SAE paper 
form 
SAEa  
after study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
90 days after 
the last dose 
Within 24 hours  
(see Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Product Complaints (PCs) 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
78 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
a SAEs should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive LY3209590 or insulin glargine. 
After learning of a pregnancy in the female partner of a study participant, the investigator will 
obtain a consent to release information from the pregnant female partner directly, and within 24 
hours after obtaining this consent will record pregnancy information on the appropriate form and 
submit it to the sponsor. 
The female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant’s 
pregnancy. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
79 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
gestational age, fetal status (presence or absence of anomalies), or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
A spontaneous abortion (occurring at <20 weeks’ gestational age) or still birth (occurring at ≥20 
weeks’ gestational age) is always considered to be an SAE and will be reported as such. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in Section 8.3.1. While the 
investigator is not obligated to actively seek this information in former study participants, they 
may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. If the participant is discontinued from the study, follow the standard 
discontinuation process and continue directly to the follow-up phase. The follow-up on the 
pregnancy outcome should continue independent of intervention or study discontinuation. 
8.3.3. 
Cardiovascular Events  
A blinded external Clinical Event Committee will adjudicate potential cerebrocardiovascular 
events in a consistent and unbiased manner. 
Events include 
 death 
 myocardial infarction 
 coronary revascularization procedure 
 hospitalization for unstable angina 
 hospitalization for heart failure, and 
 stroke or transient ischemic attack. 
8.3.4. Systemic Hypersensitivity Reactions  
Many drugs, including biologic agents, carry the risk of systemic hypersensitivity reactions. If 
such a reaction occurs, additional data should be provided to the sponsor in the designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
80 
8.3.5. 
Injection-Site Reactions  
Symptoms and signs of a local injection-site reaction may include erythema, induration, pain, 
pruritus, lipodystrophy, and edema. 
If an injection-site reaction is reported by a participant or study personnel, additional information 
about this reaction will be collected in the CRF. 
8.3.6. 
Hypoglycemia  
Participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia and how to treat hypoglycemia. Hypoglycemia events entered into the participant e-
diary will be available for review through a web-based portal that can be accessed by designated 
investigative site personnel at any time. 
Hypoglycemia classification and definitions 
Level 1 
Glucose ≥54 mg/dL (3.0 mmol/L) to <70 mg/dL (3.9 mmol/L)  
Level 1 hypoglycemia can alert a person to take action such as treatment with fast-acting 
carbohydrates. Providers should continue to counsel participants to treat hypoglycemia at this 
glucose alert value. 
Level 2 
Glucose <54 mg/dL (3.0 mmol/L) 
Level 2 hypoglycemia is also referred to as documented or blood glucose-confirmed 
hypoglycemia. The glucose threshold is clinically relevant regardless of the presence or absence 
of symptoms of hypoglycemia. 
Level 3 Severe 
A severe hypoglycemic event is characterized by altered mental or physical status requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions for the treatment of hypoglycemia. 
The determination of an episode of severe hypoglycemia is made by the investigator based on 
the medical need of the participant to have required assistance and is not predicated on the report 
of a participant simply having received assistance. 
Examples of severe hypoglycemia in adults are 
 altered mental status and the inability to assist in their own care 
 semiconscious or unconscious, or 
 coma with or without seizures. 
Glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of glucose concentration to normal is considered sufficient 
evidence that the event was induced by a low glucose concentration. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
81 
Nocturnal hypoglycemia 
Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, that occurs at 
night and presumably during sleep between midnight and 0600 hours. 
Reporting of severe hypoglycemic events 
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE CRF and report it to Lilly as an SAE. 
The investigator should also determine if repeated or prolonged episodes of hypoglycemia 
occurred prior to the severe event. 
8.4. 
Pharmacokinetics  
At the visits and times specified in the SoA, blood samples will be collected for all participants, 
regardless of whether participants transition to prefilled pen during the study. Only samples from 
participants assigned to treatment with LY3209590 will be analyzed for drug concentration. 
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. 
Bioanalytical 
Samples will be analyzed at a laboratory designated by the sponsor and stored at a facility 
designated by the sponsor. Concentrations of LY3209590 will be assayed using a validated 
bioanalytical method. 
Sample retention is described in Section 10.1.12.  
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are described as part of the efficacy assessments in Section 8.1. 
8.6. 
Genetics  
Genetics are not evaluated in this study. 
8.7. 
Biomarkers  
Serum and plasma samples will be used for exploratory biomarker research, where local 
regulations allow. See Clinical Laboratory Tests in Section 10.2, and the SoA for sample 
collection information. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3209590 pathways associated with T2D, mechanisms of action of LY3209590 or research 
methods, or in validating diagnostic tools or assay(s) related to T2D. 
Samples may be used for research to develop methods, assays, prognostics, and/or companion 
diagnostics related to the intervention target, disease state, pathways associated with disease, 
and/or the mechanism of action of the study intervention. 
Sample retention is described in Section 10.1.12.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
82 
8.8. 
Immunogenicity Assessments  
At the visits and times specified in the SoA, venous blood samples from all study participants 
will be collected to determine antibody production against LY3209590. Antibodies may be 
further characterized for cross-reactive binding to endogenous insulin. 
To interpret the results of immunogenicity, a corresponding venous blood sample will be 
collected at the same visits to determine the concentrations of LY3209590 (PK sample). At 
Visit 3, the sample for immunogenicity should be taken before dosing and the PK sample for 
LY3209590 after dosing. 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
TE ADA is defined in Section 9.3.6.2. 
Immunogenicity will be assessed by a validated assay designed to detect and characterize ADA in the 
presence of LY3209590 at a laboratory approved by the sponsor. 
Sample retention is described in Section 10.1.12. 
8.9. 
Health Economics  
Health economics parameters are not evaluated in this study. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
83 
9. 
Statistical Considerations  
The first version of the SAP will be finalized prior to the first participant visit, and it will include 
a more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses  
Primary Hypothesis 
The primary objective of this study is to test the hypothesis that LY3209590 is not inferior to 
insulin glargine on glycemic control as measured by change in HbA1c from baseline to Week 52 
(Visit 33) in participants with T2D who are starting basal insulin for the first time. 
The null hypothesis (H0) is the difference between LY3209590 versus insulin glargine in the 
change from baseline to Week 52 (Visit 33) in HbA1c is greater than the NIM. 
The NIMs of 0.4% and 0.3% will both be tested to meet regulatory requirements. The 2-sided 
95% CI will be used for testing the noninferiority. 
Secondary Hypothesis 
The key secondary (gated) objective is to test the hypothesis that LY3209590 is superior to 
insulin glargine for change from baseline to Week 52 (Visit 33) in HbA1c. 
H0: the difference (LY3209590-insulin glargine) ≥0.0. 
A gatekeeper approach (Westfall and Krishen 2001) will be used to control for type I error for 
the primary and gated secondary objective. 
9.2. 
Analyses Sets  
This table defines the populations for the purpose of analysis. 
Analysis Populations or Datasets 
Description 
Entered Population 
All participants who sign the informed consent form. 
Randomized Population 
All randomized participants. Participants will be analyzed according to 
the treatment they were assigned. 
Modified Intent-to-Treat (mITT) 
Population 
All randomized participants who took at least 1 dose of study treatment. 
Participants will be analyzed according to the treatment they were 
assigned. 
Efficacy Analysis Set 1 (EAS1) for 
treatment regimen estimand 
The data will include  
 
mITT Population excluding participants discontinuing the 
study treatment due to inadvertent enrollment, and 
 
all measurements regardless of the use of study treatment or 
rescue medications.  
Efficacy Analysis Set 2 (EAS2) for 
efficacy estimand 
The data will include 
 
mITT Population excluding participants discontinuing the 
study treatment due to inadvertent enrollment, and 
 
measurements up to the discontinuation of study treatment or 
the initiation of rescue medication. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
84 
Safety Analysis Set (SS) 
The data will include 
 
mITT Population, and 
 
all measurements regardless of the use of study treatment or 
rescue medications. 
 
9.3. 
Statistical Analyses  
9.3.1. General Considerations  
Statistical analysis of this study will be the responsibility of Lilly or its designees.  
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 changes to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or the final clinical study report. Additional exploratory analyses of data will be 
conducted as deemed appropriate. 
Unless otherwise stated, the efficacy analyses will be conducted on either EAS1 or EAS2, and 
the safety analyses will be conducted on the SS. All tests of treatment effects will be conducted 
at a 2-sided alpha level of 0.05 and 2-sided 95% CIs will be calculated. 
Unless otherwise stated, the other secondary and tertiary efficacy measures will be analyzed 
using the data up to the discontinuation of study treatment (EAS2), defined by the date of last 
study dose +10 days or the initiation of rescue medication, whichever is earlier. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final clinical study report. 
 
9.3.2. 
Primary Endpoint or Estimand Analysis  
The primary objective is to compare the HbA1c change from baseline to Week 52 (Visit 33) 
between LY3209590 and insulin glargine and will be based on either of these 2 estimands: 
treatment regimen estimand for registration in the United States, and 
efficacy estimand for registration in other countries. 
The 2-sided 95% CI of the LS mean for individual treatment groups and treatment LS mean 
difference for the HbA1c change from baseline to Week 52 (Visit 33) will be estimated. 
For both estimands, LY3209590 will be declared noninferior to insulin glargine if the upper limit 
of the 2-sided 95% CI for the LS mean difference in the HbA1c change from baseline is below 
NIM (+0.4% or +0.3% for different regulatory requirements). 
The HbA1c is reported in unit of % and will be converted to the unit of mmol/mol using this 
formula: 
HbA1c in mmol/mol = 10.93 * HbA1c in % - 23.5 (NGSP, 2010). 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
85 
Treatment regimen estimand 
The treatment regimen estimand will be based on the HbA1c data at baseline and Week 52 (Visit 
33) for the EAS1, regardless of the use of study intervention or rescue medications. 
Missing measures 
Missing measures at the primary endpoint will be imputed using multiple imputation by the 
retrieved dropout approach. The retrieved dropout participants are those who discontinue study 
intervention prior to Week 52 (Visit 33) but have non-missing measures at Week 52 (Visit 33). 
If there are only a limited number of retrieved participants that leads to a failure in performing 
the multiple imputation analysis, such as the model cannot converge, or the number of retrieved 
dropout participants is small, the missing HbA1c at Week 52 (Visit 33) will be imputed by 
return-to-baseline multiple imputations. 
Analysis model 
After the imputation, the observed and imputed data will be analyzed by the ANCOVA. The 
model will include treatment (LY3209590 and insulin glargine), strata (country, GLP-1 RA 
treatment at randomization), and baseline value of the dependent variable. The statistical 
inference will be based on the multiple imputation framework by Rubin (1987). 
Efficacy estimand 
The efficacy estimand is the treatment difference in the change of HbA1c from baseline to Week 
52 (Visit 33) if all participants adhere to the treatment without intercurrent events. 
The HbA1c collected at all planned postbaseline visits from the EAS2 will be used in the 
analysis. 
Missing measures 
There may be missing values due to the early discontinuation of study treatment or use of rescue 
medication. 
Analysis model 
The MMRM model will be used, and the missing values will be handled in the MMRM analysis 
under the assumption of missing at random. The MMRM model will include treatment 
(LY3209590 and insulin glargine), strata (country, GLP-1 RA treatment at randomization), visit 
and treatment-by-visit interaction as fixed effects, and baseline of the dependent variable as a 
covariate. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom for the MMRM models. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
86 
An unstructured covariance structure will be used to model the within-participant errors. If this 
structure fails to converge, the following covariance structures 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. 
Change in LY3209590 administration device, from autoinjector to prefilled pen, will not be 
considered as an intercurrent event. Thus, the 2 estimands described above will include all 
participants who received LY3209590 study treatment irrespective of the administration device. 
9.3.3. 
Secondary Endpoint(s) Analysis  
9.3.3.1. 
Gated Endpoints  
The superiority test in change from baseline to Week 52 (Visit 33) in HbA1c will be conducted if 
LY3209590 was declared noninferior to insulin glargine for the primary endpoint analysis.  
Superiority test 
The superiority test in change from baseline to Week 52 (Visit 33) in HbA1c will be based on the 
same primary endpoint analysis described above.  
9.3.3.2. 
Other Secondary Endpoints  
Other secondary endpoints include various measures for efficacy, safety, and patient-reported 
outcome questionnaires. 
Unless otherwise stated, efficacy measures and patient-reported questionnaires will be analyzed 
using the EAS2. 
Safety measures will be analyzed using the SS regardless of treatment discontinuation and use of 
rescue medications. 
Analysis details will be provided in the SAP.  
9.3.4. 
Tertiary Endpoint(s) Analysis  
Analyses for tertiary endpoints will be provided in the SAP. 
9.3.5. 
Safety Analyses  
Safety measures include 
 treatment exposure 
 AE 
 vital signs 
 weight 
 hypoglycemia 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
87 
 laboratory measures, and 
 immunogenicity. 
All safety analyses will be based on the SS. 
Events that are newly reported after the first dose of LY3209590 or insulin glargine, or reported 
to worsen in severity from baseline, will be considered TEAEs. The Medical Dictionary for 
Regulatory Activities (MedDRA) lowest level term will be used in the treatment-emergent 
assessment. The maximum severity for each lowest level term during the baseline period will be 
used as baseline severity. 
Summary statistics will be provided for incidence of 
 TEAEs 
 SAEs 
 study discontinuation due to AEs 
 intervention discontinuation due to AEs, and 
 deaths. 
Hypoglycemia analysis 
The analysis periods of 0-16, 0-26, 0-52, 16-26, and 26-52 weeks of treatment will be 
considered.  
The participant-reported hypoglycemia will be analyzed using data from the e-diary by 
 Level 1 (glucose ≥54 to <70 mg/dL) 
 Level 2 (glucose <54 mg/dL) 
 Level 3 (severe), and 
 the composite of Levels 2 and 3. 
This table gives definitions for documented hypoglycemia events. 
Documented hypoglycemia 
Definition 
All documented hypoglycemia  
episodes for the 24-hour period 
Non-nocturnal hypoglycemia   
episodes during 0600 hours to midnight 
Nocturnal hypoglycemia   
episodes during midnight to 0600 hours  
The incidence and rate of hypoglycemia will be summarized by treatment and analysis period for 
different types of hypoglycemia. 
For continuous safety variables, such as laboratory measures, vital signs and weight, MMRM or 
ANCOVA models will be used.  
For categorical safety variables, such as AEs, incidence of hypoglycemia, and treatment-
emergent abnormal laboratory measurements, either Fisher’s exact test or logistic regression will 
be used for treatment comparison. 
Further details for assessing all safety measures will be provided in the SAP.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
88 
9.3.6. 
Other Analyses  
9.3.6.1. 
Pharmacokinetic and 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 dose, concentration, formulations and device, efficacy, 
safety and biomarker endpoints may be characterized.  
The impact of additional participant factors, such as age, weight, gender, and renal function on 
PK and/or PD parameters may be examined, if deemed necessary.  
If ADA is detected from immunogenicity testing, its impact on LY3209590 PK or any relevant 
PD parameters will be examined. 
9.3.6.2. 
Evaluation of Immunogenicity  
The baseline ADA status, as detected or not detected, against LY3209590, will be summarized 
by treatment for the participants evaluable for TE ADA, defined as participants with non-missing 
baseline and at least 1 non-missing postbaseline measurement. 
Definition of TE ADA 
A participant is considered TE ADA positive (TE ADA+) if either treatment-induced ADA or 
treatment-boosted ADA occur. 
Treatment-induced ADA is defined as the participant having a baseline status of ADA Not 
Present and at least 1 postbaseline status of ADA Present with titer ≥2-fold (1 dilution) of the 
minimum required dilution (1:20). 
Treatment-boosted ADA is defined as the participant having a baseline status of ADA Present 
and at least 1 postbaseline status of ADA Present with the titer being ≥4-fold (2 dilutions) of the 
baseline titer.  
Immunogenicity analyses 
The baseline LY3209590 ADA status, as detected or not detected, will be summarized by 
treatment for the participants evaluable for TE ADA.  
The number and percentage of participants who are TE ADA positive (TE ADA+) will be 
summarized by treatment group. 
The frequency of cross-reactive binding to endogenous insulins may be summarized for the 
participants who are TE ADA+. 
The relationship between the presence of TE ADA and the safety and efficacy measures may be 
assessed.  
9.3.7. 
Sensitivity Analyses  
Sensitivity analyses will be conducted excluding the data after the change to LY3209590 
titratable dosing with a prefilled pen to compare the HbA1c change from baseline to Week 52 
(Visit 33) between LY3209590 with the fixed dose regimen and insulin glargine.   
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
89 
Analyses details will be provided in the SAP. 
9.4. 
Interim Analysis  
A program level-safety review using selected efficacy and safety data will be conducted on a 
periodic basis across all ongoing Phase 3 clinical trials evaluating LY3209590. The analysis will 
be performed using the unblinded data and be reviewed by the DMC consisting of experienced 
members external to Lilly (Section 10.1.5). 
Study team personnel will remain blinded. Detailed information for the data review and the 
unblinding are specified in the DMC charter or a separate unblinding plan document. 
9.5. 
Sample Size Determination  
Approximately 670 participants will be randomly assigned to LY3209590 and insulin glargine in 
a 1:1 ratio.  
With the assumption of 15% dropout at Week 52 (Visit 33), approximately 284 participants on 
LY3209590 and 284 participants on insulin glargine will complete 52 weeks of treatment.  
The number of completers will provide at least 99% statistical power to show noninferiority 
between LY3209590 and insulin glargine using the upper limit of a 2-sided 95% CI and these 
assumptions 
 NIM of 0.4% 
 no true difference between treatment groups, and 
 an SD of 1.1%. 
This sample size has at least 90% statistical power to show noninferiority between LY3209590 
and insulin glargine using a 0.3% NIM at Week 52 (Visit 33). 
The number of completers will provide 90% statistical power to show superiority between 
LY3209590 and insulin glargine for change in HbA1c from baseline to Week 52 (Visit 33), 
assuming an SD of 1.1% and true mean difference of -0.3%, and alpha of 0.05. 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
90 
10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o International Organization for Standardization (ISO) 14155, and  
o Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (for example, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and approved 
by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies, if 
applicable, and all other applicable local regulations, and 
o Reporting significant issues related to participant safety, participant rights, or data 
integrity. 
Investigator sites are compensated for participation in the study as detailed in the clinical trial 
agreement. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
91 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
Regulations 50, local regulations, ICH guidelines, privacy and data protection requirements, 
where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant and is kept on file. 
10.1.4. 
Data Protection  
Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets, 
or tissue samples that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that the participant’s personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor has processes in place to ensure data protection, information security, and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach. 
10.1.5. 
Committees Structure  
10.1.5.1. Internal Safety Review Team  
Participant safety will be continuously monitored by the sponsor’s internal safety review team, 
which includes safety signal detection at any time during the study. 
All safety data collected will be summarized and reviewed by the sponsor’s internal safety 
review team for agreement of next steps. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
92 
10.1.5.2. Clinical Event Committee for Adjudication of Events  
A blinded Clinical Event Committee, external to Lilly, will adjudicate all deaths and 
cerebrocardiovascular events. The committee will include physicians external to Lilly with 
cardiology expertise. 
10.1.5.3. Data Monitoring Committee  
An independent, external DMC will be responsible for reviewing unblinded data during the 
study. 
The committee will include, at a minimum, a medical physician with appropriate expertise and a 
statistician. 
Access to the unblinded data will be limited to the DMC and the external Statistical Analysis 
Center statisticians who are providing the analysis of the data. These statisticians will be 
independent from the study team. The study team will not have access to the unblinded data. 
Only the DMC is authorized to evaluate unblinded interim analyses. 
Details about the membership, purpose, responsibilities, and operation will be included in the 
DMC charter. 
10.1.6. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
Data and documents, including the study protocol, SAP, clinical study report, and blank or 
annotated CRFs, will be provided in a secure data-sharing environment for up to 2 years per 
proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
93 
10.1.7. 
Data Quality Assurance  
Investigator responsibilities 
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically, for example, laboratory data. 
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Data monitoring and management 
Quality tolerance limits will be predefined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These predefined parameters will be 
monitored during the study and important excursions from the quality tolerance limits and 
remedial actions taken will be summarized in the clinical study report. 
Monitoring details describing strategy (for example, risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals, for example, 
contract research organizations. 
Study monitors will perform ongoing source data verification to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the clinical trial agreement unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
In addition, sponsor or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site. The study may be audited by sponsor or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
94 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
Electronic data capture system 
An EDC system will be used in this study for the collection of CRF 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 CRF. 
Additionally, clinical outcome assessment data, participant-focused outcome instrument, and 
other data will be collected by the participant, caregiver, or authorized study personnel, using a 
paper source document and will be transcribed by the authorized study personnel into the EDC 
system via direct data captured in the EDC system and will serve as the source documentation. 
Additionally, electronic clinical outcome assessment data (participant-focused outcome 
instrument) will be directly recorded by the participant or study personnel, into an instrument, for 
example, hand-held smart phone or tablet. The electronic clinical outcome assessment data will 
serve as the source documentation, and the investigator does not maintain a separate written or 
electronic record of these data. 
Data storage and access 
Data collected via the sponsor-provided data capture systems will be stored at third parties. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture systems. Prior to decommissioning, the investigator will 
receive or access 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 reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global PC 
management system. 
10.1.8. 
Source Documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on or entered in the CRF and are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definition of what constitutes source data can be found in 10.1.7. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
95 
10.1.9. 
Study and Site Start and Closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to 
 study termination 
o discontinuation of further study intervention development 
 site termination 
o failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
o inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, or 
o total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
96 
10.1.12. 
Sample Retention  
Sample retention 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. 
Sample Type 
Custodian 
Maximum Retention Period after Last Patient Visita 
Exploratory biomarkers  
Sponsor or designee 
15 years 
Pharmacokinetic 
Sponsor or designee 
1 year 
Immunogenicity  
Sponsor or designee 
15 years 
a 
Sample retention periods may differ dependent upon local regulations. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
97 
10.2. 
Appendix 2: Clinical Laboratory Tests  
The clinical laboratory tests will be performed by the Lilly-designated laboratory or by the local 
laboratory as specified in the table below. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded. 
In circumstances where the sponsor approves local laboratory testing in lieu of central laboratory 
testing (in the table below), the local laboratory must be qualified in accordance with applicable 
local regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
98 
 
Clinical Laboratory Tests  
Comments 
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs - red blood cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs - white blood cells)  
  
Differential 
  
Percent and absolute count of: 
  Neutrophils, segmented 
  
  Lymphocytes 
  
  Monocytes 
  
  Eosinophils 
  
  Basophils 
  
Platelets 
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
Alanine aminotransferase (ALT) 
  
Aspartate aminotransferase (AST) 
  
Gamma-glutamyl transferase (GGT) 
  
Blood urea nitrogen (BUN) 
  
Creatinine  
  
Uric acid 
  
Total protein 
  
Albumin 
  
Calcium 
  
Phosphorus 
  
Glucose  
Fasting or random (Refer to SoA) 
Cholesterol  
  
Triglycerides 
  
Lipid Panel 
Assayed by Lilly-designated laboratory  
High-density lipoprotein (HDL) 
  
Low-density lipoprotein (LDL-C) 
This value will be calculated. If triglycerides >400 mg/dL, 
the direct LDL will be assayed  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
99 
Very-low-density lipoprotein (VLDL-C) 
  
Urinalysis 
Assayed by Lilly-designated laboratory 
Specific gravity 
  
pH 
  
Protein 
  
Glucose 
  
Ketones 
  
Bilirubin 
  
Urobilinogen 
  
Blood 
  
Nitrite 
  
Urine leukocyte esterase 
  
Microscopic examination of sediment 
  
Hormones (female) 
  
Serum pregnancy  
Assayed by Lilly-designated laboratory  
Urine pregnancy 
Evaluated locally  
Follicle-stimulating hormone (FSH)  
Assayed by Lilly-designated laboratory. Performed as 
needed to confirm participant’s postmenopausal status 
Urine Chemistry 
Assayed by Lilly-designated laboratory 
Albumin 
 
Creatinine 
 
Calculations 
Generated by Lilly-designated laboratory 
eGFR (CKD-EPI)  
  
Urinary albumin/creatinine ratio (UACR) 
  
Pharmacokinetic Samples  
LY3209590 concentration 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites 
Additional Testing 
Assayed by Lilly-designated laboratory  
C-Peptide 
  
HbA1c 
  
Glucose 
Fasting per SoA 
Exploratory Biomarker Storage Samples 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites 
Serum 
  
Plasma (EDTA) 
  
Immunogenicity Samples 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites 
Anti-LY3209590 antibodies  
  
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
100 
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event  
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory test results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection, 
ideally prior to the next dose after the event, to assess post-event return-to-baseline values. 
Timing 
Sample Type 
Laboratory Testa 
Collect from 30 min to 4 hr after 
the start of the event. 
Note: The optimal collection time 
is from 1 to 2 hr after the start of 
event. 
Serum 
Total tryptase 
Serum 
Complements (C3, C3a, and C5a) 
Serum 
Cytokine panel (IL-6, IL‐1β, IL‐10, or any cytokine 
panel that includes these 3 cytokines)  
Collect samples on the same day as 
the event. 
If samples were already collected 
per the SoA on the same day as the 
event, then duplicate samples are 
not collected. 
Note: The optimal collection time 
is up to 12 hr after the start of the 
event. 
Serum 
LY3209590 ADAs 
Plasma 
LY3209590 concentration 
Abbreviations: ADAs = antidrug antibodies; IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
Information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
101 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting  
 The definitions and procedures detailed in this appendix are in accordance with ISO 
14155. 
 Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list of 
study-related medical devices. 
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This 
definition includes events related to the investigational medical device or comparator 
and events related to the procedures involved except for events in users or other 
persons, which only include events related to investigational devices.  
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, and vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. See definitions in Section 10.8. 
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
102 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy and appendectomy): the 
condition that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
103 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs. 
f. 
Other situations 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
g. Results in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
104 
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, 
the following are also PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected in order to ensure 
the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and PC 
information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
105 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.  
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB for LY3209590 and the Product Information 
for insulin glargine in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
106 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
postmortem findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on an SAE paper form (see next 
section) or to the sponsor by telephone. 
 Contacts for SAE reporting can be found in site training documents.  
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in site training documents. 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
107 
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
 Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRBs/IECs, and investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements.   
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
108 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of childbearing 
potential (WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Women not of 
childbearing potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 
have a congenital anomaly such as Müllerian agenesis  
 
are infertile due to surgical sterilization, or  
 
are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-
oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman: 
 
at any age at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, confirmed by operative note; or  
 
aged at least 40 years and up to 55 years with an intact uterus, not on 
hormone therapya, who has had cessation of menses for at least 12 
consecutive months without an alternative medical cause, AND with a 
follicle-stimulating hormone >40 mIU/mL; or  
 
55 years or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or 
 
aged at least 55 years with a diagnosis of menopause prior to starting 
hormone replacement therapy. 
 
a Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, SERMs, 
or chemotherapy that could induce transient amenorrhea. 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
109 
10.4.2. 
Contraception Guidance  
Guidance for women of childbearing potential 
This outlines the rules for WOCBP to ensure they do not become pregnant during the study. 
If, as part of their preferred and usual lifestyle, 
WOCBP… 
Then… 
are in a same-sex relationship 
they must stay in same-sex relationships without sexual 
relationships with males. 
are completely abstinent 
they must agree to remain completely abstinent 
are not completely abstinent 
they must agree to 
 
use 1 highly effective method of 
contraception, or a combination of 2 effective 
methods of contraception, and 
 
pregnancy testing.  
Participants must have a negative serum pregnancy test 
at screening followed by a negative urine result within 
24 hours prior to first dose of intervention. See the SoA 
for testing requirements. 
Note on forms of contraception: The methods of contraception must be used for the duration of the study.  
 
Guidance for all men 
No male contraception is required except in compliance with specific local government study 
requirements. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
110 
Methods of contraception for women of childbearing potential 
Methods 
Examples 
Highly effective contraception (less than 1% failure 
rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 pounds or 
90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices. 
Effective contraception 
 
cervical sponges 
 
barrier method with use of a spermicide 
o 
male or female condom with spermicide, 
or 
o 
diaphragm with spermicide 
Note: The barrier method must include use of a 
spermicide to be considered effective. 
Ineffective forms of contraception whether used alone 
or in any combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature 
method, cervical mucus, or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea. 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
111 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic Evaluation Testing 
See Section 8.2.5 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
112 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a 
    HBV DNAb 
Anti-actin antibodyc 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNAb 
    EBV DNAb 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNAb 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody 
    HEV RNAb 
    HSV (Type 1 and 2) DNAb 
Microbiologyd 
Liver kidney microsomal Type 1 (LKM-1) antibody 
Culture: 
 
    Blood 
 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Reflex or confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
113 
10.6. 
Appendix 6: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting  
Refer to Appendix 3 for definitions and procedures for recording, evaluating, follow-up, and 
reporting of all events.  
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
114 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local ERBs, regulatory bodies, and any other relevant local authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific requirements in which notification is 
required, for example, upon implementation and suspension of changes. All approvals and 
notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
115 
The following changes in study conduct will not be considered protocol deviations: 
Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments according to the SoA, if written approval is provided by the 
sponsor. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor. 
Other alternative locations: Laboratory draws may be done at an alternate location in exceptional 
circumstances, if written approval is provided by the sponsor. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing, except for HbA1c 
and serum glucose testing. Lilly-designated laboratory testing must be retained for HbA1c and 
serum glucose. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Obtain local labs for safety hematology, chemistry, hormone panel, and urinalysis, when 
applicable, per the SoA. Safety labs should be obtained as specified in the SoA. 
All labs will be reviewed by the investigators. Sign and date review of local labs per normal 
process and follow-up with the participant as needed. Results will not be recorded in the CRF. 
Lilly Medical should be informed of any labs that meet criteria for temporary or permanent study 
intervention discontinuation. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
116 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken. 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site, for example, 
participant’s home, the investigator, sponsor, or both, should ensure oversight of the 
shipping process to ensure accountability and product quality, that is, storage 
conditions maintained and intact packaging upon receipt. 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening or the lead-in visits are valid for a maximum of 24 days. The following rules will be 
applied for active, nonrandomized participants whose participation in the study must be paused 
due to exceptional circumstances: 
 If screening is paused for less than 24 days from the signing of the ICF to the 
randomization visit, the participant will proceed to the next study visit per the usual 
SoA, provided that the randomization visit is conducted within 30 days from first 
screening. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 24 days from signing of the ICF to the 
randomization visit, the participant must be discontinued because of screening 
interruption due to an exceptional circumstance. This is documented as a screen 
failure in the CRF. The participant can reconsent and be rescreened as a new 
participant. The screening procedures per the usual SoA should be followed, starting 
at the screening visit to ensure participant eligibility by the randomization visit. 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
117 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
The primary endpoint visit, Week 52 (Visit 33), should be completed per original schedule 
whenever possible and safe to do so. However, the visit windows should be within ±7 days 
relative to the target visit date. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
118 
10.8. 
Appendix 8: Abbreviations and Definitions  
 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
antidrug antibody 
AE 
adverse event 
ANCOVA 
analysis of covariance 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labeling of the medicinal product, 
which is used as an investigational medicinal product 
CI 
confidence interval 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system 
compliance 
Adherence to all study-related, good clinical practice, and applicable regulatory 
requirements 
CRF 
case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the sponsor for each trial 
participant 
DID-EQ 
Diabetes Injection Device Experience Questionnaire 
DMC 
data monitoring committee; a data-monitoring committee is a group of independent 
scientists who are appointed to monitor the safety and scientific integrity of a human 
research intervention and to make recommendations to the sponsor regarding the 
stopping of a study for efficacy, or for harms, or for futility. The composition of the 
committee is dependent upon the scientific skills and knowledge required for 
monitoring the particular study 
DPP-4 
dipeptidyl peptidase-4 
Device deficiencies 
equivalent to product complaint 
DTSQ-c 
Diabetes Treatment Satisfaction Questionnaire - Change Version 
DTSQ-s 
Diabetes Treatment Satisfaction Questionnaire-Status Version 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
119 
ED 
early discontinuation 
EDC 
electronic data capture 
eGFR (CKD-EPI) 
estimated glomerular filtration rate (chronic kidney disease epidemiology 
collaboration) 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives 
ERB 
Ethical Review Board 
FBG 
fasting blood glucose 
GCP 
good clinical practice 
GLP-1 
glucagon-like peptide-1 
GLP-1 RA 
GLP-1 receptor agonist 
HbA1c 
hemoglobin A1c 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product  
A medicinal product, which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
See also “investigational product.” 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created or locked 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. See also “IMP”. 
IRB 
Institutional Review Board 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
120 
IWRS 
interactive web-response system 
LS 
least squares 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involves a failure to uphold 1 or more 
of the 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, and at the right time. 
In addition to the core 5 rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling (for example, Summary of Product Characteristics, IB, local 
label, and protocol), or 
• shared use of cartridges, prefilled pens, or both. 
misuse 
use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MMRM 
mixed-model repeated measures 
NIM 
noninferiority margin 
participant 
equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK/PD 
pharmacokinetics/pharmacodynamics 
PT-INR 
prothrombin time, INR 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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 
SGLT2 
sodium-glucose cotransporter 2 
SIM-Q 
Simplicity of Diabetes Treatment Questionnaire 
SMBG 
self-monitoring of blood glucose 
T1D 
Type 1 diabetes 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
121 
T2D 
Type 2 diabetes 
TE ADA 
treatment-emergent ADA 
TEAE 
treatment-emergent adverse event: an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment 
TRIM-D 
Treatment-Related Impact Measure – Diabetes 
WOCBP 
women of childbearing potential 
 
 
 
Approved on 31 May 2023 GMT

CONFIDENTIAL 
I8H-MC-BDCW (a) 
122 
11. 
References  
Blonde L, Brunton SA, Chava P, et al. Achievement of target A1C <7.0% (<53 mmol/mol) by U.S. 
type 2 diabetes patients treated with basal insulin in both randomized controlled trials and clinical 
practice. Diabetes. 2019;32(2):93-103. https://doi.org/10.2337/ds17-0082 
Bradley C, Lewis KS. Measures of psychological well-being and treatment satisfaction developed 
from the responses of people with tablet-treated diabetes. Diabet Med. 1990;7(5):445-451. 
https://doi.org/10.1111/j.1464-5491.1990.tb01421.x 
Bradley C. Diabetes Treatment Satisfaction Questionnaire: Change version for use alongside 
status version provides appropriate solution where ceiling effects occur. Diabetes Care. 
1999;22(3):530-532. https://doi.org/10.2337/diacare.22.3.530 
CDC 2021. How to treat low blood sugar (hypoglycemia). Published 2021. Accessed May 02, 2023. 
https://www.cdc.gov/diabetes/basics/low-blood-sugar-treatment.html  
Heise T. The future of insulin therapy. Diabetes Res Clin Pract. 2021;175:108820. 
https://doi.org/10.1016/j.diabres.2021.108820 
Matza LS, Boye KS, Stewart KD, et al. Development of the Diabetes Injection Device 
Experience Questionnaire (DID-EQ) and Diabetes Injection Device Preference Questionnaire 
(DID-PQ). J Patient Rep Outcomes. 2018;2:43. https://doi.org/10.1186/s41687-018-0068-z 
[NGSP]. Harmonizing Hemoglobin A1c Testing. IFCC Standardization of HbA1c. Published 
2010. Accessed May 16, 2022. https://ngsp.org/index.asp 
Rubin DB. Multiple imputation for nonresponse in surveys. John Wiley & Sons Inc.;1987. 
UK National Diabetes Audit 2017. National Diabetes Audit 2016-2017 Short Report, Care 
Processes and Treatment Targets. NHS Digital. Published November 10, 2017. Accessed 
May 02, 2023. https://digital.nhs.uk/data-and-information/publications/statistical/national-
diabetes-audit/national-diabetes-audit-report-1-care-processes-and-treatment-targets-2016-17 
Westfall PH, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple testing 
procedures. J Stat Plan Inference. 2001;99(1):25-40. https://doi.org/10.1016/S0378-
3758(01)00077-5 
Approved on 31 May 2023 GMT

Signature Page for VV-CLIN-109083 v1.0
Signature Page for VV-CLIN-109083 v1.0
Approval
irector
30-May-2023 18:51:05 GMT+0000
Approval
31-May-2023 16:39:47 GMT+0000
Approved on 31 May 2023 GMT
PPD
PPD