A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin Naïve Adults With Type 2 Diabetes
Phase: PHASE3
Conditions: Diabetes, Type 2 Diabetes
Sponsor: Eli Lilly and Company

Protocol I8H-MC-BDCX (b)
A Phase 3, Parallel-Design, Open-Label, Randomized Control Study to Evaluate the Efficacy and 
Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin Naïve 
Adults With Type 2 Diabetes
NCT05362058
Approval Date: 13-May-2022

CONFIDENTIAL 
I8H-MC-BDCX (b) 
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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 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin 
Naïve Adults with Type 2 Diabetes 
Protocol Number: I8H-MC-BDCX 
Amendment Number: b 
Compound: LY3209590 
Brief Title: 
Efficacy and Safety of LY3209590 Compared to Degludec in Adults with Type 2 Diabetes Who 
Are Starting Basal Insulin for the First Time 
Study Phase: 3 
Acronym: QWINT-2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): 
IND: 129390 
EudraCT: 2021-005891-21 
Document ID: VV-CLIN-040206 
Approval Date: Protocol amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
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I8H-MC-BDCX (b) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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I8H-MC-BDCX (b) 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment (a) 
15 Feb 2022 
Original Protocol 
04 Feb 2022 
Amendment [b] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary rationale for the current amendment is to address regulatory feedback regarding 
exclusionary ALT and AST thresholds and rescue medication. These changes are detailed in the 
table below. 
Section no and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Edited the subsections ‘Overall Design’, 
‘Brief Summary’, and ‘Intervention 
Groups and Duration’ 
Correction 
Updated the section to align with the 
changes in the main body of the protocol 
For consistency 
1.2. Schema 
Added a note below the schema as 
follows: During the safety follow-up 
period, CGM device will be worn for 4 
weeks (52 to 56), but device return and 
data download will occur a week later (on 
Week 57). 
For clarity 
1.3.1. Screening Visit 1, Lead-
In Visit 2, and Treatment 
Visits 3-18 
In CGM sensor insertion line, added 
“Participants will be required to replace 
the sensor at designated intervals per the 
investigator instruction. Additional 
unscheduled visits may be needed for 
participants support” under comments 
column 
For clarity 
1.3.2. Treatment Visits 19 to 
31, Early Discontinuation, 
Unscheduled Visits, and 
Safety Follow-up Visits 801 
and 802 
In CGM sensor insertion line, added 
“Participants will be required to replace 
the sensor at designated intervals per the 
investigator instruction. Additional 
unscheduled visits may be needed for 
participants support” under comments 
column 
For clarity 
1.3.2. Treatment Visits 19 to 
31, Early Discontinuation, 
Unscheduled Visits, and 
Safety Follow-up Visits 801 
and 802 
In CGM device return and data download 
line, added “CGM device will be worn for 
4 weeks (52 to 56), but device return and 
data download will occur a week later (on 
Week 57).” 
For clarity 
3. Objectives, Endpoints, and 
Estimands 
Removed “Incidence” from the subgroup 
tertiary objective endpoint of Level 1 and 
composite of Level 2 and 3 hypoglycemia 
events during the treatment period 
Correction 
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I8H-MC-BDCX (b) 
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3. Objectives, Endpoints, and 
Estimands 
Moved the “Evaluation of Immunogenicity 
- Incidence of positive LY3209590 
treatment-emergent anti-drug antibodies” 
under Tertiary Safety Parameters 
For consistency 
3. Objectives, Endpoints, and 
Estimands 
Removed “Potential intrinsic and extrinsic 
factors” under tertiary objective – 
Characterize the PK/PD of LY3209590 
For consistency 
3. Objectives, Endpoints, and 
Estimands 
In Primary estimand subsection, United 
States registration, edited the text in 
primary clinical question of interest to 
clarify “study eligible” participants 
For clarity 
3. Objectives, Endpoints, and 
Estimands 
Edited Treatment regimen estimand 
attributes table  
- Population: added cross reference to 
Section 9.2, and removed other cross 
references 
For clarity 
3. Objectives, Endpoints, and 
Estimands 
In Primary estimand subsection, 
Registration for countries outside the 
United States, edited the text in primary 
clinical question of interest to clarify 
“study eligible” participants 
For clarity 
3. Objectives, Endpoints, and 
Estimands 
Edited Efficacy estimand attributes table  
- Population: added cross reference to 
Section 9.2, and removed other cross 
references 
For clarity 
4.1. Overall Design 
Updated CGM related items to the 
description of the visits 
For clarity and consistency 
4.2. Scientific Rationale for 
Study Design 
Added “of 52 weeks” to Study Duration 
subsection 
For clarity 
5.1. Inclusion Criteria 
In inclusion criterion 3, added “as 
determined by central laboratory” 
For clarity 
5.1. Inclusion Criteria 
In inclusion criterion 4, updated the 
language 
For clarity 
5.1. Inclusion Criteria 
In inclusion criterion 8, added a note “The 
use of personal, non-study CGM device 
will not be allowed 
For clarity 
5.2. Exclusion Criteria 
In exclusion criterion 20, increased AST 
and ALT thresholds from 2.5x ULN to 3x 
ULN 
To address regulatory feedback 
5.2. Exclusion Criteria 
In exclusion criterion 20, updated the 
language of non-alcoholic fatty liver 
disease 
For consistency 
5.2. Exclusion Criteria 
In exclusion criterion 26, added “glimins” 
For clarity 
5.2. Exclusion Criteria 
In exclusion criterion 29, added wording 
“after having signed the ICF” and “after 
receiving at least 1 dose of the study basal 
insulin” 
For clarity 
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6.1.2. Rescue Medicine for 
Management of Severe or 
Persistent Hyperglycemia 
Modified the rescue criteria (timing to 
initiate the rescue therapy) to match the 
program strategy 
To address regulatory feedback 
Modified the language in paragraphs 1 and 
3; moved paragraph 4; and included the 
last two paragraphs 
To address regulatory feedback  
6.3. Measures to minimize 
Bias: Randomization and 
Blinding 
In the Randomization and stratification 
subsection, added “Yes/No” to the use of 
sulfonylurea and GLP-1 RA at 
randomization 
For clarity 
6.5.1.3. LY3209590 Dose 
Adjustment Based on 
Hypoglycemia Events 
Added “over the previous week” to the 
second column heading of the table 
For clarity 
6.5.2.3 LY3209590 Dose 
Adjustment Based on 
Hypoglycemia Events 
Added “over the previous week” to the 
second column heading of the table 
For clarity 
6.7. Treatment of Overdose 
Added “consider holding sulfonylureas if 
clinically appropriate” 
To optimize the overdose 
management guidance 
6.8.3. Antihyperglycemic 
Medications 
In the table showing the conditions for use 
of concomitant antihyperglycemic 
medications, replaced “N” with “See 
Note” in ‘Rescue Therapy’ column for 
‘Non-study basal insulins’ and ‘Insulin 
mixtures’ rows; and added “Note: 
Participants who require a non-study basal 
insulin or insulin mixture as rescue therapy 
must discontinue study basal insulin 
therapy (LY3209590 or insulin degludec). 
The participant will remain in the study 
and follow procedures for the remaining 
study visits”  
For clarity 
6.8.4. Treatment after Study 
Completion 
Added this new section 
To address regulatory feedback  
7.1.2. QTc Stopping Criteria 
Removed the section  
There is no specific QTc stopping 
criteria due to no known or 
suspected safety-related risk with 
insulins or LY3209590 
8.1.1.2. Continuous Glucose 
Monitoring (CGM) Systems 
Updated the section 
To address regulatory feedback 
9. Statistical Considerations  
Replaced “Visit 31 (Week 52)” with 
“Week 52 (Visit 31)”  
For clarity 
9.2. Analyses Sets 
Updated the analysis population/set. 
To meet the anticipated 
requirement for excluding 
inadvertently enrolled participants 
in some countries.  
9.3. Statistical Analyses 
Made updates according to the changes in 
analyses sets. 
As 9.2 and for clarity. 
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10.4.2. Contraception 
Guidance 
Corrected the typo error and added “these 
forms of contraception must be used for 
the duration of the study.” 
Correction 
10.7. Appendix 7. Country-
specific Requirements 
10.7.3. Germany 
Deleted “10.1.3. Informed Consent 
Process” as reference to “legally 
authorized representative,” “legal 
guardian,” “parents” is not mentioned in 
the protocol amendment. 
Correction 
Updated the brief rationale in the table 
10.9. Appendix 9: 
Abbreviations and Definitions 
Added CGM parameters. 
To address regulatory feedback 
Removed ‘FAS’ 
Correction 
Throughout protocol 
Following glucose values in mg/dL, added 
corresponding values in mmol/L. 
For clarity 
Throughout protocol 
Minor editorial and formatting changes  
Minor, therefore, not detailed. 
 
 
 
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I8H-MC-BDCX (b) 
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Table of Contents 
Protocol Amendment Summary of Changes Table ....................................................................3 
1. 
Protocol Summary ........................................................................................................11 
1.1. 
Synopsis ..........................................................................................................................11 
1.2. 
Schema ............................................................................................................................15 
1.3. 
Schedule of Activities (SoA) ..........................................................................................16 
1.3.1. 
Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3-18 ......................................17 
1.3.2. 
Treatment Visits 19 to 31, Early Discontinuation, Unscheduled 
Visits, and Safety Follow-Up Visits 801 and 802...........................................................24 
2. 
Introduction ...................................................................................................................33 
2.1. 
Study Rationale ...............................................................................................................33 
2.2. 
Background .....................................................................................................................33 
2.3. 
Benefit/Risk Assessment ................................................................................................34 
2.3.1. 
Risk Assessment .............................................................................................................34 
2.3.2. 
Benefit Assessment .........................................................................................................35 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................35 
3. 
Objectives, Endpoints, and Estimands .......................................................................36 
4. 
Study Design ..................................................................................................................41 
4.1. 
Overall Design ................................................................................................................41 
4.2. 
Scientific Rationale for Study Design ............................................................................43 
4.3. 
Justification for Dose ......................................................................................................43 
4.4. 
End of Study Definition ..................................................................................................44 
5. 
Study Population ...........................................................................................................45 
5.1. 
Inclusion Criteria ............................................................................................................45 
5.2. 
Exclusion Criteria ...........................................................................................................46 
5.3. 
Lifestyle Considerations .................................................................................................48 
5.4. 
Screen Failures ................................................................................................................49 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................49 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................50 
6.1. 
Study Intervention(s) Administered................................................................................50 
6.1.1. 
Medical Devices..............................................................................................................51 
6.1.2. 
Rescue Medicine for Management of Severe or Persistent 
Hyperglycemia ................................................................................................................51 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................52 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................52 
6.4. 
Study Intervention Compliance ......................................................................................53 
6.5. 
Dose Modification ..........................................................................................................53 
6.5.1. 
LY3209590 Dose Initiation and Adjustment ..................................................................53 
6.5.2. 
Insulin Degludec Dose Initiation and Adjustment ..........................................................55 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................56 
6.7. 
Treatment of Overdose ...................................................................................................56 
6.8. 
Concomitant Therapy .....................................................................................................56 
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6.8.1. 
Medications with Approved Weight Loss Indication .....................................................57 
6.8.2. 
Chronic Systemic Glucocorticoid Medication ................................................................57 
6.8.3. 
Antihyperglycemic Medications .....................................................................................58 
6.8.4. 
Treatment after Study Completion..................................................................................59 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................61 
7.1. 
Discontinuation of Study Intervention ............................................................................61 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................62 
7.1.2. 
Hypersensitivity Reactions .............................................................................................62 
7.1.3. 
Temporary Discontinuation of Study Intervention .........................................................62 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................63 
7.3. 
Lost to Follow up ............................................................................................................64 
8. 
Study Assessments and Procedures.............................................................................65 
8.1. 
Efficacy Assessments .....................................................................................................65 
8.1.1. 
Glucose Monitoring ........................................................................................................65 
8.1.2. 
Patient-Reported Outcomes ............................................................................................67 
8.2. 
Safety Assessments .........................................................................................................70 
8.2.1. 
Physical Examinations ....................................................................................................70 
8.2.2. 
Vital Signs .......................................................................................................................70 
8.2.3. 
Electrocardiograms .........................................................................................................70 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................70 
8.2.5. 
Hepatic Monitoring .........................................................................................................71 
8.2.6. 
Pregnancy Testing ...........................................................................................................73 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................73 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................75 
8.3.2. 
Pregnancy ........................................................................................................................76 
8.3.3. 
Cardiovascular Events ....................................................................................................77 
8.3.4. 
Systemic Hypersensitivity Reactions ..............................................................................77 
8.3.5. 
Injection Site Reactions ..................................................................................................78 
8.3.6. 
Hypoglycemia .................................................................................................................78 
8.4. 
Pharmacokinetics ............................................................................................................79 
8.5. 
Pharmacodynamics .........................................................................................................79 
8.6. 
Genetics ..........................................................................................................................79 
8.7. 
Biomarkers ......................................................................................................................79 
8.8. 
Immunogenicity Assessments.........................................................................................80 
8.9. 
Health Economics ...........................................................................................................80 
9. 
Statistical Considerations .............................................................................................81 
9.1. 
Statistical Hypotheses .....................................................................................................81 
9.1.1. 
Multiplicity Adjustment ..................................................................................................81 
9.2. 
Analyses Sets ..................................................................................................................82 
9.3. 
Statistical Analyses .........................................................................................................82 
9.3.1. 
General Considerations ...................................................................................................82 
9.3.2. 
Primary Endpoint or Estimand Analysis.........................................................................83 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................84 
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I8H-MC-BDCX (b) 
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9.3.4. 
Tertiary Endpoint(s) Analysis .........................................................................................85 
9.3.5. 
Safety Analyses ...............................................................................................................85 
9.3.6. 
Other Analysis ................................................................................................................86 
9.3.7. 
Subgroup Analyses .........................................................................................................87 
9.4. 
Interim Analysis ..............................................................................................................88 
9.5. 
Sample Size Determination ............................................................................................88 
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: Country-specific Requirements ...............................................................114 
10.7.1. Canada...........................................................................................................................114 
10.7.2. Brazil .............................................................................................................................115 
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10.7.3. Germany ........................................................................................................................117 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................122 
10.9. 
Appendix 9: Abbreviations and Definitions .................................................................126 
10.10. 
Appendix 10: Protocol Amendment History ................................................................130 
11. 
References ....................................................................................................................132 
 
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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 as a Weekly Basal Insulin Compared to Insulin Degludec in Insulin 
Naïve Adults with Type 2 Diabetes 
Brief Title: 
Efficacy and Safety of LY3209590 Compared to Degludec in Adults with Type 2 Diabetes Who 
Are Starting Basal Insulin for the First Time 
Regulatory Agency Identifier Number(s): 
IND: 129390 
EudraCT: 2021-005891-21 
Rationale: 
This Phase 3 study will evaluate the efficacy and safety of once-weekly administration of 
LY3209590 on glycemic control compared with daily administration of insulin degludec in 
insulin naïve adult participants with Type 2 diabetes (T2D) who are starting basal insulin therapy 
for the first time. This study will inform the clinical development of LY3209590. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
Demonstrate noninferiority of LY3209590 compared to 
insulin degludec for the treatment of T2D in adults 
Change in HbA1c from baseline to Week 52 
Key Secondary (Multiplicity Adjusted)  
Demonstrate noninferiority of LY3209590 compared to 
insulin degludec for participants using GLP-1 receptor 
agonists 
Change in HbA1c from baseline to Week 52 
Demonstrate noninferiority of LY3209590 compared to 
insulin degludec for participants not using GLP-1 
receptor agonists 
Change in HbA1c from baseline to Week 52 
Demonstrate superiority of LY3209590 compared to 
insulin degludec in selected parameters of glycemic 
control 
 
Change in HbA1c from baseline to Week 52 
 
Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), inclusive, collected during 
the CGM session prior to Week 52 
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Other Secondary 
Compare the effect of LY3209590 to insulin degludec 
in parameters of glycemic control 
 
Change from baseline to Week 26 of HbA1c 
 
Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), inclusive, collected during 
the CGM session prior to Week 26 
 
Change from baseline to Week 26 and Week 52 of 
fasting glucose measured by SMBG 
 
Glucose variability measured during the CGM 
session prior to Weeks 26 and 52 
 
Insulin dose at Weeks 26 and 52 
Compare the effect of LY3209590 to insulin degludec 
on safety endpoints 
 
Incidence and rate of composite of Level 2 and 3 
hypoglycemia events during treatment period 
 
Incidence and rate of composite of Level 2 and 3 
nocturnal hypoglycemia events during treatment 
period 
 
Change from baseline to Weeks 26 and 52 in body 
weight 
 
Measurements collected during CGM sessions 
prior to Weeks 12, 26, and 52 of 
o 
Time in hypoglycemia with glucose  
<70 mg/dL (3.9 mmol/L) 
o 
Time in hypoglycemia with glucose  
<54 mg/dL (3.0 mmol/L), and 
o 
Time in hyperglycemia defined as 
glucose >180 mg/dL (10.0 mmol/L) 
Compare the effect of LY3209590 to insulin degludec 
on patient-reported outcomes questionnaires 
 
Change from baseline to Weeks 26 and 52 of 
o 
TRIM-D 
o 
SF-36, and 
o 
EQ-5D-5L 
Abbreviations: CGM = continuous glucose monitoring; SF-36 = Short Form-36; SMBG = self-monitoring of blood 
glucose; T2D = type 2 diabetes; TRIM-D = Treatment-Related Impact Measure – Diabetes. 
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 degludec administered 
daily, in insulin-naïve adults with T2D who are on stable treatment with 1 to 3 noninsulin 
diabetes medications prior to entering the study. Participants will continue prior stable therapy 
with 1 to 3 allowed noninsulin diabetes medications during the study. 
The study includes a 3-week screening and lead-in period, a 52-week treatment period, and a 
safety follow-up period approximately 5 weeks after the last visit in the treatment period. 
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Brief Summary 
All participants will use a study-provided, blinded continuous-glucose monitoring (CGM) 
system, glucometer, and e-diary to facilitate diabetes and hypoglycemia management and for 
data collection throughout the study.  
The primary outcome is the change in hemoglobin A1c (HbA1c) from baseline at Week 52. 
Study Population: 
In general, participants may take part in the study if they 
 are 18 years of age or older 
 have a diagnosis of T2D 
 are starting basal insulin for the first time 
 have been taking 1 to 3 medication that lowers their blood glucose levels for at least 3 
months prior to screening and are willing to maintain this stable treatment for the 
duration for the study, 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, participants may not take part in the study if they 
 have received these diabetes treatments within 30 days prior to screening 
o glinides 
o glimins 
o pramlintide, 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 888 participants will be randomly assigned to LY3209590 and insulin degludec 
in a 1:1 ratio. With the assumption of 15% dropout at Week 52, approximately 377 and 377 
participants will complete 52 weeks of treatment on LY3209590 and insulin degludec, 
respectively. 
Intervention Groups and Duration: 
Participants who meet entry criteria will be randomly assigned in a 1:1 ratio to LY3209590 or 
insulin degludec basal insulin treatment. LY3209590 will be administered once weekly, and 
insulin degludec will be administered once daily. 
The study treatment period duration is 52 weeks. 
Both LY3209590 and insulin degludec will be administered by subcutaneous injection. 
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Ethical Considerations of Benefit or Risk: 
Considering the data that are available to date from previous clinical studies, and the measures taken 
to ensure the safety of the participants in this study, the potential risks related with LY3209590 are 
justified by the anticipated benefits a participant with T2D may experience in the study. 
Data Monitoring Committee: Yes 
 
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1.2. 
Schema 
 
Abbreviations: CGM = blinded continuous glucose monitoring; V = visit. 
Note: During the safety follow-up period, CGM device will be worn for 4 weeks (52 to 56), but device return and data download will occur a week later (on 
Week 57). 
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1.3. 
Schedule of Activities (SoA) 
Two tables describe the schedule of activities. 
Table 1 (Section 1.3.1) describes procedures for Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3 to 18. 
Table 2 (Section 1.3.2) describes Treatment Visits 19 to 31, 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. 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. 
 
 
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1.3.1. 
 Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3-18 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
T 
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 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
18 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
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 
 
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 
 
 
  
X 
  
X 
 
Vital signs 
X 
X 
X 
X 
X 
  
X 
  
X 
  
 X 
 
 
  
X 
 
X 
 
Include blood pressure and pulse rate. 
Measure 3 times, 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional physical examinations may 
be completed as necessary at 
investigator’s discretion. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
19 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
T 
T = telehealth visit 
F = fasting visit 
12-lead ECG (local) 
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. 
ECGs will be performed prior to 
collection of any blood samples.  
Blinded Continuous Glucose Monitoring 
 
Dispense CGM 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense supplies as needed. 
CGM sensor insertion  
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Participants will be required to replace 
the sensor at designated intervals per the 
investigator instruction. Additional 
unscheduled visits may be needed for 
participants support. 
CGM device return and 
data download 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Participant Education 
 
Diabetes counseling, 
training, and education 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes SMBG, hypoglycemia (see 
Sections 5.3 and 8.3.6).  
After Visit 3, conduct as needed. 
e-diary, glucometer, and 
CGM training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, conduct as needed. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
20 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
T 
T = telehealth visit 
F = fasting visit 
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 
X 
Review entries of BG, hypoglycemia 
events, and insulin dose. If participant is 
not compliant, study personnel will re-
educate the participant on study 
requirements for continued study 
participation. 
Paper Patient-Reported Outcomes 
 
Treatment-Related 
Impact Measure - 
Diabetes  
(TRIM-D) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electronic Patient-reported Outcomes 
 
SF-36 v2 acute 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Tests and Sample Collections 
 
Hematology 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Hemoglobin A1c 
(HbA1c) 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
Clinical chemistry  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
21 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
T 
T = telehealth visit 
F = fasting visit 
Glucose 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect for WOCBP only. 
Urine pregnancy (local) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The result must be available 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 in 
Section 10.4. 
C-Peptide 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR (CKD-EPI)  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
UACR 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacokinetic (PK) 
samples 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Visit 3: collect sample at least 15 min 
after dosing. 
For all other visits, collect at any time 
during the visit. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
22 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
T 
T = telehealth visit 
F = fasting visit 
Immunogenicity (ADA) 
samples 
 
 
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. 
Randomization and Dosing Related Activities 
 
Process visit using 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization using 
IWRS 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
Insulin dose assessment 
or adjustment or 
documentation  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense LY3209590 or 
insulin degludec, and 
related supplies 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Site administers 
LY3209590 or insulin 
degludec  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing and injection 
training 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, conduct as needed. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
23 
Study  
I8H-MC-BDCX 
Table 1 
Screening 
and 
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 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
16 
18 
 
Visit Interval 
Tolerance (days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
T 
F 
T 
 
T 
 
T 
T 
T 
F 
T 
 
T 
T = telehealth visit 
F = fasting visit 
Observe participant 
administer LY3209590 
and insulin degludec 
 
 
 
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 degludec  
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Abbreviations: ADA = antidrug antibody; BG = blood glucose; CGM = continuous glucose monitoring; eGFR (CKD-EPI) = estimated glomerular filtration rate 
(chronic kidney disease epidemiology collaboration); ECG = electrocardiogram; FSH = follicle-stimulating hormone; ICF = informed consent form; IWRS = 
interactive web-response system; SF-36 v2 acute = Short Form-36 Version 2 Health Survey Acute Form; SMBG = self-monitoring of blood glucose; TRIM-D 
= Treatment-Related Impact Measure – Diabetes; UACR = urinary albumin/creatinine ratio; WOCBP = Women of childbearing potential. 
 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
24 
1.3.2. 
Treatment Visits 19 to 31, Early Discontinuation, Unscheduled Visits, and Safety Follow-Up Visits 801 and 802 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
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 
 
Adverse events (AEs) 
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 
Clinical assessment based 
on participant history and 
e-diary entries. 
Physical Evaluation 
 
Weight 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
25 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
Vital signs 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Include blood pressure 
and pulse rate. Measure 3 
times, 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 
 
 
 
 
 
 
X 
X 
 
 
X 
Additional physical 
examinations may be 
completed as necessary at 
investigator’s discretion. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
26 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
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. 
ECGs will be performed 
prior to collection of any 
blood samples.  
Blinded Continuous Glucose Monitoring 
 
CGM sensor insertion  
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Participants will be 
required to replace the 
sensor at designated 
intervals per the 
investigator instruction. 
Additional unscheduled 
visits may be needed for 
participants support. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
27 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
CGM device return and data 
download 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
ED visit: if the ED visit 
occurs during a CGM 
session, the device must 
be returned and data 
downloaded.  
CGM device will be worn 
for 4 weeks (52 to 56), 
but device return and data 
download will occur a 
week later (on Week 57). 
Participant Education 
 
Diabetes counseling, 
training, and education 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct as needed. 
e-diary, glucometer, and 
CGM training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conduct as needed. 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
28 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
Electronic Participant Diary and Blood Glucose Meter 
 
Diary compliance check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review entries of BG, 
hypoglycemia events, and 
insulin dose. If participant 
is not compliant, study 
personnel will re-educate 
the participant on study 
requirements for 
continued study 
participation. 
Dispense ancillary supplies 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Dispense supplies as 
needed. 
Required diary return 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
The diary must be 
returned on the last 
participant visit.  
Electronic Patient-Reported Outcomes 
 
Simplicity Questionnaire 
(SIM-Q) study intervention  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
SF-36 v2® Health Survey 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
29 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
Basal Insulin Experience 
Likelihood of incorporating 
into routine 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
EQ-5D-5L 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Paper Patient-Reported Outcomes 
 
Treatment-Related Impact 
Measure - Diabetes  
(TRIM-D) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Laboratory Tests and Sample Collections 
 
Hematology 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Hemoglobin A1c (HbA1c) 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
Clinical chemistry  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Glucose 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Lipid panel 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Urinalysis  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCX (b) 
30 
Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
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) 
samples 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
Collect sample at any 
time during the visit. 
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.  
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Study  
I8H-MC-BDCX 
Table 2 
Treatment 
 
 
Safety Follow-
Up 
Comments 
Visit Number 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
ED 
UV 
801 
802 
ED = early 
discontinuation 
UV = unscheduled visit 
801, 802 = safety follow-
up 
Weeks from 
Randomization 
20 
22 
23 
24 
25 
26 
28 
32 
36 
42 
48 
50 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
T 
 
T 
T 
T 
F 
T 
T 
F 
T 
 
T 
F 
F 
 
T 
F 
T = telehealth visit  
F = fasting visit  
Stored samples 
 
Exploratory biomarker 
samples  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Dosing related activities 
 
Process visit using IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
X 
X 
 
Insulin dose assessment or 
adjustment or documentation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Dispense LY3209590 or 
insulin degludec, and related 
supplies 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
Dosing and injection training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, review 
conduct as needed. 
Assess dosing compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Participant returns unused 
LY3209590 or insulin 
degludec 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
Assessment for poststudy 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
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Abbreviations: ADA = antidrug antibody; BG = blood glucose; CGM = continuous glucose monitoring; eGFR (CKD-EPI) = estimated glomerular filtration rate 
(chronic kidney disease epidemiology collaboration); ECG = electrocardiogram; IWRS = interactive web-response system; SF-36 v2 acute = Short Form-36 
Version 2 Health Survey Acute Form; TRIM-D = Treatment-Related Impact Measure – Diabetes; UACR = urinary albumin/creatinine ratio; WOCBP = 
Women of childbearing potential. 
 
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2. 
Introduction 
LY3209590 is a long-acting insulin receptor agonist in development for the once-weekly 
treatment of hyperglycemia in patients with T2D and T1D. 
2.1. 
Study Rationale 
This Phase 3 study will evaluate the efficacy and safety of once-weekly administration of 
LY3209590 on glycemic control compared with daily administration of insulin degludec in 
insulin naïve adult participants with T2D who are starting basal insulin therapy for the first time. 
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. 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 with a simple titration regimen could 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. 
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. 
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. 
Phase 1 results 
LY3209590 pharmacokinetics show a low peak-to-trough ratio and extended half-life that 
supports once-weekly dosing. 
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Single-ascending doses of LY3209590 lowered fasting glucose in a dose- and concentration-
dependent manner, with a prolonged time-action profile. 
Overall, LY3209590 was well tolerated in healthy participants and participants with T2D. 
Phase 2 Study BDCL preliminary results 
Study BDCL is a randomized, open-label, comparator-controlled study evaluating the efficacy 
and safety of LY3209590 compared with insulin degludec. Study participants have T2D, are 
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. 
Safety data during 26 weeks of treatment in participants with T2D showed no increased risk of 
safety with LY3209590 compared to degludec. 
LY3209590 was noninferior to degludec for glycemic control as measured by change in HbA1c 
after 26 weeks of treatment.  
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of LY3209590 may be found in the IB, and that of insulin degludec may be found 
in the local product package insert. 
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, or 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 degludec. 
Potential risks for the LY3209590-prefilled pen device are described in the “Instructions for 
Use”.  
Management of Risks 
Sections 5.1, 5.2, 6.1.2, 6.8.1, and 8.3 address known potential risks associated with LY3209590. 
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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 each 
episode of 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. 
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 algorithm used in the study requires consideration and adjustment of insulin dosing 
by the investigator based on participant FBG and hypoglycemia events (see Section 6.5). 
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 also 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. 
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. 
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3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
Demonstrate noninferiority of LY3209590 compared to 
insulin degludec for the treatment of T2D in adults 
Change in HbA1c from baseline to Week 52 
Key Secondary (Multiplicity Adjusted)  
Demonstrate noninferiority of LY3209590 compared to 
insulin degludec for participants using GLP-1 receptor 
agonists 
Change in HbA1c from baseline to Week 52 
Demonstrate noninferiority of LY3209590 compared to 
insulin degludec for participants not using GLP-1 
receptor agonists 
Change in HbA1c from baseline to Week 52 
Demonstrate superiority of LY3209590 compared to 
insulin degludec in selected parameters of glycemic 
control 
 
Change in HbA1c from baseline to Week 52 
 
Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), inclusive, collected during 
the CGM session prior to Week 52 
Other Secondary 
Compare the effect of LY3209590 to insulin degludec 
in parameters of glycemic control 
 
Change from baseline to Week 26 of HbA1c 
 
Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), inclusive, collected during 
the CGM session prior to Week 26 
 
Change from baseline to Weeks 26 and 52 of 
fasting glucose measured by SMBG 
 
Glucose variability measured during the CGM 
session prior to Weeks 26 and 52 
 
Insulin dose at Weeks 26 and 52 
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Compare the effect of LY3209590 to insulin degludec 
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 
 
Measurements collected during CGM sessions 
prior to Weeks 12, 26, and 52 of 
o 
Time in hypoglycemia with glucose  
<70 mg/dL (3.9 mmol/L) 
o 
Time in hypoglycemia with glucose  
<54 mg/dL (3.0 mmol/L) 
o 
Time in hyperglycemia defined as 
glucose >180 mg/dL (10.0 mmol/L) 
Compare the effect of LY3209590 to insulin degludec 
on patient-reported outcomes questionnaires 
 
Change from baseline to Weeks 26 and 52 of 
o 
TRIM-D 
o 
SF-36, and 
o 
EQ-5D-5L 
Tertiary 
Compare the effect of LY3209590 to insulin degludec 
in participants using GLP-1 receptor agonists versus 
participants not using GLP-1 receptor agonists 
 
Rate of Level 1 and composite of Level 2 and 3 
hypoglycemia events during the treatment period 
 
Change from baseline to Weeks 26 and 52 in body 
weight 
 
Insulin dose at Weeks 26 and 52 
 
Measurements collected during CGM sessions 
prior to Weeks 12, 26, and 52 of 
o 
Time in hypoglycemia with glucose  
<70 mg/dL (3.9 mmol/L) 
o 
Time in hypoglycemia with glucose  
<54 mg/dL (3.0 mmol/L) 
o 
Time in hyperglycemia defined as 
glucose >180 mg/dL (10.0 mmol/L), and 
o 
Time in glucose range between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L), 
inclusive 
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Compare the effect of LY3209590 to insulin degludec 
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 of 
fasting serum glucose 
Compare the effect of LY3209590 to insulin degludec 
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 
 
Evaluation of immunogenicity - 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 degludec 
for patient-reported outcomes 
 
SIM-Q and 
 
Frequency of responses to Basal Insulin 
Experience of “likelihood of incorporating into 
routine” 
Abbreviations: CGM = continuous glucose monitoring; GLP-1 = glucagon-like peptide-1; HbA1c = hemoglobin 
A1c; PK/PD = pharmacokinetics/pharmacodynamics; SMBG = self-monitoring of blood glucose; SF-36 = Short 
Form-36 Version 2 Health Survey Acute Form; 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 degludec in HbA1c 
change from baseline after 52 weeks of treatment, in study eligible participants, 
regardless of treatment discontinuation for any reason and regardless of initiation of 
rescue medication? 
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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 degludec in HbA1c 
change from baseline after 52 weeks of treatment, in study eligible participants who 
adhere to the randomized treatment without intercurrent events during the study treatment 
period? 
 
 
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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 estimands for multiplicity-adjusted objectives 
The superiority test in change from baseline to Visit 31 (Week 52) in HbA1c will also be based 
on the primary estimands described above. 
The change from baseline to Visit 31 (Week 52) in HbA1c in the subpopulations of participants 
using or not using GLP-1 receptor agonists will use treatment regimen estimand for US 
registration and efficacy estimand for other countries. 
The time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive measured 
during CGM session prior to Visit 31 (Week 52) will use treatment regimen estimated for US 
registration and efficacy estimand for other countries. 
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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 degludec administered 
daily. 
The study includes a 3-week screening and lead-in period, a 52-week treatment period, and a 
safety follow-up period approximately 5 weeks after the last visit in the treatment period. 
Screening and Lead-In 
Visit 1: 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. 
Visit 2: Lead-In 
Participants will receive their e-diary, glucometer, and the CGM system. 
Participants will receive training on 
 diabetes self-monitoring and management 
 study glucometer 
 CGM 
 electronic study diaries, and 
 study requirements. 
The CGM sensor will be inserted at Visit 2, and participants will be required to wear the sensor 
and insert a new sensor when indicated per the SoA. 
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 
Visit 3 (Week 0): Randomization 
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 administer the first dose of LY3209590 
or insulin degludec,  
 study personnel will download the CGM 
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 participant will continue CGM wear per the SoA, and  
 study personnel complete all visit procedures. 
Participants assigned to insulin degludec will continue daily administration after Visit 3. 
Visit 4 (Week 1) 
Study personnel and participants complete all visit procedures described in the SoA. 
Study personnel will provide dosing training and observe participants administer their second 
dose of LY3209590, or insulin degludec. 
Visit 5 through Visit 31 (Week 2 through Week 52) 
Study personnel and participants complete all visit procedures described in the SoA. 
The participant’s median FBG will be used to titrate basal insulin dose adjustments throughout 
the study based on the study titration algorithm described in Section 6.5.1. 
Participants will collect blinded CGM for  
 4 weeks prior to Visit 7, and the site will download the CGM data at Visit 7 
 4 weeks prior to Visit 15, and the site will download the CGM data at Visit 15 
 4 weeks prior to Visit 24, and the site will download the CGM data at Visit 24; and 
 4 weeks prior to Visit 31, and the site will download the CGM data at Visit 31. 
The investigator or study staff will review participant e-diary compliance for 
 SMBG 
 hypoglycemia events, including related signs and symptoms, and 
 dosing information, including date and time of doses. 
Last study treatment visit: either Visit 31 (Week 52) or ED visit 
Participants should complete all visit procedures in a fasting state. 
Participants will return unused study intervention to the investigative site. 
Assessments for the transition to non-study diabetic treatment after the participant’s last dose 
The investigator will determine a participant’s transition from study treatment to another non-
study diabetic treatment. 
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. 
Participants will collect blinded CGM for 4 weeks following Visit 31, and the site will download 
the CGM data at Visit 802. 
The investigator will follow-up on the participant’s transition from study treatment to another 
non-study diabetic treatment. 
Participants will return study devices at the final study visit. 
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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 compared to insulin degludec. 
The follow-up visit after the last dose is designed to capture any additional safety signals and to 
monitor the transition from study treatment to non-study diabetic treatment. 
Comparator 
Insulin degludec was chosen as the comparator because it is widely accepted as the best-in-class 
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. 
4.3. 
Justification for Dose 
The dosing guidance for starting doses and dose titrations of LY3209590 and insulin degludec 
are derived based on findings from Phase 2 studies and model-based simulations. These data 
informed the development of a titration algorithm to safely and efficiently initiate and guide 
LY3209590 and insulin degludec dose adjustments to achieve the same glycemic goals of FBG 
between 80 and 120 mg/dL (4.4 and 6.6 mmol/L), while minimizing hypoglycemia risk. 
See Section 6.5 for dose modification and titration details. 
LY3209590 
Initial loading dose 
The initial loading dose aims to optimize and accelerate glycemic control by allowing 
participants to reach a steady-state concentration faster. The use of a single one-time-only 
loading dose enables participants to achieve concentrations close to steady state within a few 
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days rather than a period of weeks. This approach minimizes the significant titrations while 
reaching steady state. 
Participants randomly assigned to LY3209590 will receive a single loading dose of 300 U of 
LY3209590, which equals 3 times the starting weekly dose of 100 U. 
This approach is supported by the Phase 2 Study BDCL and PK model-based simulations. 
Starting weekly dose 
The second dose is the starting weekly dose of 100 U, unless hypoglycemia is observed after the 
initial loading dose, requiring a dose reduction. 
Dose Adjustments 
Assessments for dose adjustment will occur from the third dose onwards. Dosing will be 
individualized based on FBG and hypoglycemia events, and adjustments should occur weekly 
from Visits 5 to 15 (Weeks 2 to 12) and then every 4 weeks thereafter. 
Insulin degludec 
Insulin degludec will be titrated to achieve the FBG target using an algorithm that is patterned 
after the well-established Riddle algorithm but modified to balance efficacy and hypoglycemia 
risk for the same FBG targets as LY3209590. 
Starting dose 
The starting dose is 10 U, consistent with the insulin degludec label. 
Dose Adjustments 
Dosing will be individualized based on FBG and hypoglycemia events, and adjustments should 
occur weekly from Visits 4 to 15 (Weeks 1 to 12) and then every 4 weeks thereafter. 
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. 
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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 inclusive, 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%-10.5%, inclusive, as determined by central laboratory at 
screening. 
4. Are on a stable treatment with 1 to 3 antihyperglycemic medication, 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. 
These antihyperglycemic medications are accepted in the study 
 DPP-4 inhibitors 
 SGLT2 inhibitors 
 biguanides, such as metformin 
 alpha-glucosidase inhibitors 
 GLP-1 receptor agonists, oral or injectable 
 sulfonylureas, 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. 
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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 
 use only the glucometer supplied for use in the study, and 
 wear the CGM device as directed, see Section 8.1.1.2. 
Note: The use of personal, non-study CGM device will not be allowed. 
Note: persons with physical limitations who are not able to perform the injections must 
have the assistance of an individual trained to inject the intervention. 
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 applies: 
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 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 
 coronary bypass surgery. 
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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 non-alcoholic fatty liver disease (that is, study participants 
with non-alcoholic fatty liver disease are eligible for participation), and/or have elevated 
liver enzyme measurements, as determined by the central laboratory at screening and as 
indicated below: 
a. Total bilirubin >2x ULN, with the exception of previously diagnosed Gilbert’s 
disease 
b. ALT or serum glutamic pyruvic transaminase >3x ULN 
c. AST or serum glutamic oxaloacetic transaminase >3x ULN, or 
d. 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. 
Exceptions: 
 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 
 glimins 
 pramlintide, 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. 
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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, 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 having signed the ICF or 
any other study investigating LY3209590 after receiving at least 1 dose of the study basal 
insulin. 
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. 
Exceptions: 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. 
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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. 
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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 or 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 degludec will be dispensed at the study visits summarized in SoA. 
Returned LY3209590 or insulin degludec should not be re-dispensed to the participants. 
This table lists the interventions used in this clinical study. 
Intervention Name 
LY3209590 
Insulin degludec 
IMP and NIMP/AxMP 
IMP 
IMP 
Authorized as defined by 
EU Clinical Trial 
Regulationa 
No 
Yes 
Use 
Experimental  
Active comparator  
Type  
Biologic 
Biologic 
Dose Formulation 
Solution 
Solution 
Unit Dose Strength(s) 
500 units/mL 
100 units/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 
Abbreviations: AxMP = auxiliary medicinal product; IMP = Investigational Medicinal Product; NIMP = non-
investigational medicinal product. 
a Study interventions identified as authorized are used in accordance with the terms of their marketing 
authorizations. 
LY3209590 frequency of administration and guidance for missed doses 
LY3209590 should be administered once weekly at approximately the same time and day each 
week. If a dose is missed, it should be administered as soon as possible if at least 3 days (72 
hours) 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. 
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Insulin degludec frequency of administration 
Insulin degludec should be administered daily at approximately the same time each day. 
Anatomical Location of Injections 
For both LY3209590 and insulin degludec, participants should rotate injection sites from one 
injection to the next, even when injecting within the same region. Injections may be administered 
in the abdomen, thigh, arm, or buttock. Refer to the IFU for complete instructions on dose 
administration. 
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 or insulin degludec will be provided as a solution in a prefilled pen injector for the 
administration of either LY3209590 or insulin degludec. 
Instructions for device use are provided in the “Instructions for Use.” 
All Product Complaints, 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. 
6.1.2. 
Rescue Medicine for Management of Severe or Persistent Hyperglycemia 
If a participant develops severe, persistent hyperglycemia after randomization, optimization of 
concomitant antihyperglycemic medication and/or the addition of an allowed agent for rescue 
therapy should be considered after investigator assessment, based on conditions described in this 
table. 
Average of FBG over 2-week period 
Timing of events 
>270 mg/dL (15 mmol/L) 
From Visit 15 until 17 (Week 12 to 16)  
>240 mg/dL (13 mmol/L) 
After Visit 17 until 19 (Week 16 to 20) 
>200 mg/dL (11 mmol/L) 
After Visit 19 until 31 (Week 20 to end of study 
treatment at Week 52) 
First, investigators should confirm participant compliance with the assigned intervention and that 
they do not have an acute condition causing severe hyperglycemia. 
Rescue therapy will begin with dose optimization of the participant’s current concomitant 
antihyperglycemic medications. Then consider the addition of an allowed agent for rescue 
therapy (see Section 6.8.3), if applicable, so the participant is taking up to 3 antihyperglycemic 
medications at effective doses before considering prandial insulin rescue therapy. 
If severe, persistent hyperglycemia is not improving in spite of compliance with the assigned 
therapeutic regimen and optimization of other concomitant glucose-lowering agents, the addition 
of prandial insulin may be considered. 
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Participants who receive rescue therapy for hyperglycemia management should also continue 
administering either LY3209590 or insulin degludec for the remaining period in the study. 
Participants who require a non-study basal insulin or insulin mixture as rescue therapy must 
discontinue study basal insulin therapy (LY3209590 or insulin degludec). The participant will 
remain in the study and follow procedures for the remaining study visits. 
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. 
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 degludec. 
Participants will be stratified based on 
 country 
 HbA1c stratum at Visit 1 (<8% and ≥8%)  
 sulfonylurea use at randomization (Yes/No), and 
 GLP-1 RA use at randomization, regardless of oral or injectable administration (Yes/No). 
Blinding 
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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. 
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 
Dosing will be individualized based on FBG and hypoglycemia events. The FBG target is 80 to 
120 mg/dL (4.4 to 6.6 mmol/L). 
The investigator is responsible for titrating the basal insulin dose using the guidance in Sections 
6.5.1 and 6.5.2. 
6.5.1. 
LY3209590 Dose Initiation and Adjustment 
This section outlines the LY3209590 
 general dosing information by visit 
 dose adjustment guidance based on FBG, and 
 dose adjustment guidance based on hypoglycemia. 
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6.5.1.1. 
LY3209590 General Dosing Information by Visit 
This table provides general dosing information across visits for all participants randomly 
assigned to LY3209590. 
LY3209590 General Dosing Information 
Visit (Week) 
Dose 
Additional dosing instruction 
Visit 3 (Week 0) initial loading 
dose  
300 U  
CAUTION: Do NOT repeat 
administration of the loading dose.  
Visit 4 (Week 1) starting weekly 
dose  
100 U 
If a participant experiences 
hypoglycemia in the previous week, 
then reduce the starting weekly 
dose to 60 U, a 40 U reduction 
based on adjustments for 
hypoglycemia (see Section 6.5.1.3). 
Visits 5-15 (Weeks 2-12) 
Doses will be individualized based 
on FBG and hypoglycemia events 
Dose modifications may occur 
weekly. 
After Visit 15 
Doses will be individualized based 
on FBG and hypoglycemia events 
Dose modifications may occur 
every 4 weeks. 
6.5.1.2. 
LY3209590 Dose Adjustment Based on FBG 
This table provides guidance for dose adjustments based on median FBG from the 3 most 
recently recorded FBG data from the previous week. 
If the participant experienced any documented BG ≤70 mg/dL (≤3.9 mmol/L) in the previous 
week, the dose should not be increased. 
If the median FBG is… 
Then…  
mg/dL 
mmol/L 
<80 
<4.4 
reduce the LY3209590 dose by 20 U. 
80-120 
4.4-6.6 
do not change the dose. 
121-140 
6.7-7.7 
increase the LY3209590 dose by 20 U. 
>140 
>7.7 
increase the LY3209590 dose by 40 U. 
6.5.1.3. 
LY3209590 Dose Adjustment Based on Hypoglycemia Events 
This table provides guidance when hypoglycemia events occur. 
If a participant reports… 
with a blood glucose value of... 
over the previous week 
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) 
___ 
 
 
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6.5.2. 
Insulin Degludec Dose Initiation and Adjustment 
This section outlines the insulin degludec 
 general dosing information by visit 
 dose adjustment guidance based on FBG, and 
 dose adjustment guidance based on hypoglycemia. 
6.5.2.1. 
Insulin Degludec General Dosing Information by Visit 
This table provides general dosing information across visits for all participants randomized to 
insulin degludec. 
Insulin degludec General Dosing Information 
Visit 
Dose 
Additional dosing instruction 
Visit 3 (Week 0) starting dose  
10 U/day  
 
Visits 4-15 (Weeks 1-12) 
Doses will be individualized based 
on FBG and hypoglycemia events 
Dose modifications may occur 
weekly 
After Visit 15 (Week 12) 
Doses will be individualized based 
on FBG and hypoglycemia events  
Dose modifications may occur 
every 4 weeks 
6.5.2.2. 
Insulin Degludec Dose Adjustment Based on FBG 
This table provides guidance for dose adjustments based on median FBG from the 3 most 
recently recorded FBG data from the previous week. 
If the participant experienced any documented hypoglycemia (BG ≤70 mg/dL) (≤3.9 mmol/L) in 
the previous week, the dose should not be increased. 
If the median FBG is… 
Then…  
mg/dL 
mmol/L 
<80 
<4.4 
reduce the dose by 3 U. 
80-120 
4.4-6.6 
do not change the dose. 
121-140 
6.7-7.7 
increase the dose by 3 U. 
>140 
>7.7 
increase the dose by 6 U. 
6.5.2.3. 
Insulin Degludec Dose Adjustment Based on Hypoglycemia Events 
This table provides guidance when hypoglycemia events occur. 
If a participant reports… 
with a blood glucose value of… 
over the previous week 
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 units 
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 
___ 
 
 
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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. 
6.7. 
Treatment of Overdose 
An overdose of LY3209590 or insulin degludec, 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 degludec 
depending on the participant treatment assignment. 
In the event of an overdose, the investigator or treating physician should 
 contact the medical monitor immediately 
 evaluate the participant to determine, in consultation with the medical 
monitor, whether study intervention should be interrupted or whether the dose 
should be reduced 
 consider holding sulfonylureas if clinically appropriate 
 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 
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 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. 
Non-study 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. 
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 or 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. 
 
 
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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 
Non-study 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 
Alpha-glucosidase 
inhibitors 
Y 
Yes, if on 
stable therapy 
90 days prior 
to screening 
N/A 
Y 
Y 
Sulfonylureas 
Y 
Yes, if on 
stable therapy 
90 days prior 
to screening 
N/A 
Y 
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; 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. 
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Note: Participants who require a non-study basal insulin or insulin mixture as rescue therapy must discontinue study 
basal insulin therapy (LY3209590 or insulin degludec). 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. 
6.8.4. 
Treatment after Study Completion 
Study interventions will not be made available to study participants after Visit 31 (Week 52) or 
after the participant’s early discontinuation from study treatment. 
At the last treatment visit (Visit 31 [Week 52] or ED visit), the investigator will determine 
participant’s transition from study treatment to another non-study diabetic treatment. The 
investigator may prescribe a non-study basal insulin for use during the safety follow-up period. 
Participants will continue their concomitant non-insulin antihyperglycemic medications at the 
discretion of the investigator and continue to monitor their FBG and complete the e-diary. 
Study participants treated with LY3209590 transitioning to a non-study basal insulin: 
Study participants will receive the last injection of LY3209590 at Week 52 of the study and can 
begin the transition to the non-study insulin after Visit 31 (Week 52). At Visit 31 (Week 52), the 
investigator will review the instructions for transitioning to the non-study insulin. During this 
transition period, the participant’s FBG should be used to guide dose initiation and adjustment 
for the insulin prescribed for the safety follow-up period. 
No daily basal insulin will be required until the FBG is above 120 mg/dL (6.6 mmol/L) for 2 
consecutive measurements. The prescribed non-study daily basal insulin should be started at a 
dose of 10 units/day and adjusted based on FBG and the investigator judgement in accordance 
with any country-specific label. The initial prescribed dose and any dose adjustments made for 
the non-study insulin during the safety follow-up period should be documented in the eCRF. An 
unscheduled visit in addition to Visit 801 may occur during this time to facilitate the transition to 
the non-study daily basal insulin. 
Since LY3209590 has a half-life of approximately 17 days, a careful titration of the daily basal 
insulin is necessary to prevent hypoglycemia due to overlapping insulin action. Therefore, 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. 
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Study Participants treated with insulin degludec transitioning to a non-study basal insulin: 
Study participants assigned to the insulin degludec treatment arm may transition to a non-study 
basal insulin after Visit 31 (Week 52). The investigator will prescribe the non-study insulin and 
titrate the dose based on FBG and clinical judgement in accordance with the country-specific 
label for the basal insulin. The initial prescribed dose and any dose adjustments made during the 
safety follow-up period will be documented in the eCRF. 
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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 Appendix 1. 
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 diagnosed with an active or untreated malignancy, except for 
successfully treated basal or squamous cell carcinoma 
 the participant did not take insulin degludec 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. 
 
 
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7.1.1. 
Liver Chemistry Stopping Criteria 
The study intervention should be interrupted or discontinued if 1 or more of these conditions 
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 degludec 
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 degludec or 3 consecutive doses 
for LY3209590 at any time during the study. This information should be documented by the 
investigator. 
Guidance when temporary discontinuation of study intervention occurs 
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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, and 
 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 posttreatment 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. 
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7.3. 
Lost to Follow up 
Participants 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. 
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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 
 fasting blood glucose measured by SMBG 
 Level 2 and 3 nocturnal hypoglycemia 
 Level 2 and 3 hypoglycemia events 
 body weight 
 insulin dose 
 CGM measurements 
o time in range between 70 and 180 mg/dL (3.9 and 10 mmol/L), inclusive 
o glucose variability, and 
o time in hyperglycemia or hypoglycemia, and 
 patient-reported outcomes questionnaires 
o TRIM-D 
o SIM-Q 
o SF-36 v2 Health Survey 
o Basal Insulin Experience, and 
o EQ-5D-5L. 
See Section 3 for specific efficacy endpoints. 
See Section 8.3.6 for information related to hypoglycemia and hyperglycemia. 
8.1.1. 
Glucose Monitoring 
Participants must use only the study-provided glucometer during the study. 
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. 
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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 
 
whenever hypoglycemia is experienced or suspected 
 
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. 
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. 
The FBG should be measured upon waking in the morning, prior to food or caloric beverage 
intake. 
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. 
8.1.1.2. 
Continuous Glucose Monitoring (CGM) Systems 
The study-provided CGM system or alternative sponsor-approved glucose monitoring device 
will be used in blinded mode during the study. 
The blinded CGM will not display the sensor glucose readings to the participant or investigator, 
and high and low glucose alerts will not be available to the participant. 
Participants are not allowed to use a personal, non-study CGM device during the study. 
Training and initiation 
Site personnel will dispense CGM supplies and initiate blinded CGM sessions at the times 
specified according to the SoA. Participants will be trained on the CGM system before use and 
will be required to replace the sensor at designated intervals per the investigator instruction. 
Participants are not allowed to connect the transmitter and/or sensor of the CGM system to a 
personal smartphone, smartphone application, or other system. 
CGM data compliance 
At the end of each CGM session, participants will return the CGM system or used sensors to the 
site. Site personnel will upload the CGM data to a vendor-hosted online portal to view data 
capture compliance using the available reports and visualization tools. The compliance threshold 
of 80% for each session is defined as the percentage of actual data versus expected data collected 
during a session. Site personnel will re-educate participants on CGM operation and requirements 
when session compliance is <80%. 
To minimize data loss, the CGM service vendor will review site uploads and notify site users 
and/or site monitor when sessions do not meet the compliance thresholds. CGM compliance 
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reports will also be provided to the Sponsor during the study for review and to determine if 
further mitigation is necessary. 
8.1.2. 
Patient-Reported Outcomes 
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. 
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. SIM-Q 
3. SF-36 v2 Health Survey Acute Form 
4. Basal Insulin Experience: Likelihood of incorporating into routine, and 
5. EQ-5D-5L. 
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. 
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. 
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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 
Each item is scored on a 5-point scale ranging from “Very complex” to “Very simple.” 
8.1.2.3. 
Short Form-36 Version 2 Health Survey Acute Form 
Description of SF-36 v2 
The SF-36 v2 Health Survey Acute form is a participant self-administered measure designed to 
assess these 8 domains 
 Physical Functioning 
 Role Physical 
 Bodily Pain 
 General Health 
 Vitality 
 Social Functioning 
 Role Emotional, and 
 Mental Health. 
The Physical Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Participants answer each item using Likert 3-
point, 5-point, or 6-point scales for the responses. 
Scoring 
Each domain is scored individually, and information from these 8 domains is further aggregated 
into 2 health component summary scores, the Physical Component Summary and Mental 
Component Summary. 
Scoring of each domain and both summary scores are norm based and presented in the form of 
T-scores, with a mean of 50 and standard deviation of 10. 
Higher scores indicate better levels of function and/or better health (Maruish 2011). 
8.1.2.4. 
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.” 
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8.1.2.5. 
EQ-5D-5L 
Description of EQ-5D-5L 
The EQ-5D-5L (EuroQol Research Foundation 2019) is a standardized, 5-item, self-administered 
instrument for use as a measure of health outcome. It provides a simple descriptive health profile 
and a single health state index value that can be used in the clinical and economic evaluation of 
health care as well as population health surveys. 
The EQ-5D-5L assesses 5 dimensions of health 
 mobility 
 self-care 
 usual activities 
 pain or discomfort, and 
 anxiety or depression. 
The 5L version scores each dimension at 5 levels 
 no problems 
 slight problems 
 moderate problems 
 severe problems, and 
 unable to perform or extreme problems. 
A total of 3125 health states are possible. 
Scoring 
The scores on the 5 dimensions can be presented as a health profile or converted to a single 
health state index value. 
The single health state index value can be derived based on a formula that attaches weights to 
each of the levels in each dimension. This index value ranges between less than 0 to 1, where 
negative values are valued as worse than dead, 0 is a health state equivalent to death, and 1 
represents perfect health. 
EQ Visual Analog Scale 
The EQ Visual Analog Scale records the respondent’s self-rated health status on a vertical 
graduated visual analog scale from 0 to 100, where 0 represents the worst imaginable health and 
100 represents the best imaginable health. 
In conjunction with the health state data, this provides a composite picture of the respondent’s 
health status. 
 
 
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8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
Physical examination at screening 
The complete physical examination will include, at a minimum, assessments of these systems 
 cardiovascular 
 respiratory 
 gastrointestinal, and 
 neurologic. 
Height and weight will be measured and recorded. 
Additional assessments include clinical signs and symptoms related to T2D, T2D-related 
illnesses, and injection site reactions. 
8.2.2. 
Vital Signs 
Blood pressure and pulse rate will be measured when specified 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. 
Electrocardiograms 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. 
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. 
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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, as defined in Section 10.2, 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) 
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 
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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 
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 
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 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, or 
 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. 
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 Appendix 3: 
 adverse events (AEs) 
 serious adverse events (SAEs), and 
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 product complaints (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 product complaints, 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. 
 
 
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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 
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 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Product Complaints (PC) 
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 
Product Complaint 
form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint 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 
Product Complaint 
form 
 
a Serious adverse events 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 degludec. 
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. 
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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. 
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 protocol 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. 
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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.  
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 <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 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. 
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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. 
Nocturnal hypoglycemia 
Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, that occurs at 
night and presumably during sleep between midnight and 0600 (6:00 am). 
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. 
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 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. 
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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.  
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. 
Treatment-emergent ADAs are 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. 
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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 degludec on glycemic control as measured by change in HbA1c from baseline to Week 
52 (Visit 31) in participants with T2D who are starting basal insulin for the first time. 
The null hypothesis (H0) is the difference between LY3209590 versus insulin degludec in the 
change from baseline to Week 52 (Visit 31) 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 Hypotheses 
The key secondary objectives (multiplicity adjusted) are to test the hypotheses that LY3209590 
is 
 not inferior to insulin degludec for change in HbA1c from baseline to Week 52 (Visit 31) 
for the subpopulation of participants using GLP-1 receptor agonists 
H0: the difference (LY3209590-insulin degludec) >0.4% 
 not inferior to insulin degludec for change in HbA1c from baseline to Week 52 (Visit 31) 
for the subpopulation of participants not using GLP-1 receptor agonists 
H0: the difference (LY3209590-insulin degludec) >0.4% 
 superior to insulin degludec for change in HbA1c from baseline to Week 52 (Visit 31) 
H0: the difference (LY3209590-insulin degludec) ≥0.0, and 
 superior to insulin degludec with respect to time in glucose range between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) inclusive, collected during the CGM collected session 
prior to Week 52 (Visit 31)  
H0: the difference (LY3209590-insulin degludec) ≤0.0. 
These hypotheses and the primary hypothesis will be tested using a strategy to control the overall 
Type 1 error (see Section 9.1.1). 
9.1.1. 
Multiplicity Adjustment 
A graphical approach (Bretz et al. 2009, 2011) for multiple comparisons will be used to ensure 
the strong control of overall type I error rate for testing the primary and key secondary 
(multiplicity adjusted) objectives. 
The overall significance level (α) will be set to 0.05. The total α will be used for the primary 
objective first, then the α will be allocated and transitioned to other key secondary objectives 
once the primary objective is met. The testing procedure and α allocation will be established 
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according to the clinical importance and statistical power of the endpoints in this study 
population. 
The details of graphical testing scheme will be described in the SAP. 
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 ICF. 
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 
 
all measurement 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 
 
measurement up to the discontinuation of study treatment or 
the initiation of rescue medication. 
Safety Analysis Set (SS) 
The data will include 
 
mITT Population 
 
all measurement 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 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% confidence intervals 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. 
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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 CSR. 
9.3.2. 
Primary Endpoint or Estimand Analysis 
The primary objective is to compare the HbA1c change from baseline to Week 52 between 
LY3209590 and insulin degludec 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, treatment LS mean 
difference (LY3209590 – insulin degludec) in the HbA1c change from baseline to Week 52 
(Visit 31) will be estimated. 
For both estimands, LY3209590 will be declared noninferior to insulin degludec if the upper 
limit of the 2-side 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 the 
following formula: 
HbA1c in mmol/mol = 10.93 * HbA1c in % - 23.5 (http://www.ngsp.org/ifccngsp.asp). 
Treatment regimen estimand 
The treatment regimen estimand will be based on the HbA1c data at baseline and Week 52 (Visit 
31) from 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 31) but have non-missing measures at Week 52 (Visit 31). 
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 31) 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, strata (country, GLP-1 RA treatment at randomization, and SU 
use 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 31) if all participants adhere to the treatment without intercurrent events. 
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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 implicitly in the 
MMRM analysis under the assumption of missing at random. The MMRM model will include 
treatment, strata (country, GLP-1 RA treatment at randomization and SU use 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. 
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. 
9.3.3. 
Secondary Endpoints Analysis 
9.3.3.1. 
Multiplicity-Adjusted Endpoints 
A graphical approach will be used to control the overall type I error for the primary objective and 
testing of key secondary objectives as described in Section 9.1. 
Noninferiority test 
The noninferiority test in change from baseline to Week 52 (Visit 31) in HbA1c for the 
subpopulations will be based on the ANCOVA model for treatment regimen estimand (using data 
from the EAS1) and an MMRM model for efficacy estimand (using data from the EAS2)  
In the ANCOVA model, treatment, strata (country and SU use at randomization), and baseline of 
the dependent variable will be used as covariates. 
The MMRM model will include treatment, strata (country and SU use at randomization), visit 
and treatment-by-visit interaction as fixed effects, and baseline of the dependent variable as a 
covariate. 
For the treatment regimen estimand, the missing data will be imputed by multiple imputation 
with the approach similar to the imputation used for the primary endpoint. 
 
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Superiority test 
The superiority test in change from baseline to Week 52 (Visit 31) in HbA1c will be based on the 
same primary endpoint analysis described above.  
The time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive, 
measured by CGM, will be analyzed using an ANCOVA model for treatment regimen estimand 
and an MMRM model for efficacy estimand. In the ANCOVA model, treatment, strata (country, 
baseline HbA1c stratum [<8.0%, ≥8.0%], GLP-1 RA treatment at randomization, and SU use at 
randomization), and baseline of the dependent variable will be used as covariates. The MMRM 
model will include treatment, strata (country, baseline HbA1c stratum [<8.0%, ≥8.0%], GLP-1 
RA treatment at randomization, and SU use at randomization), visit and treatment-by-visit 
interaction as fixed effects, and baseline of the dependent variable as a covariate. For treatment 
regimen estimand, the missing data will be imputed by multiple imputation with the approach 
similar to the imputation used for the primary endpoint. 
9.3.3.2. 
Other Secondary Endpoints 
Other secondary endpoints include various measures for efficacy, safety, and patient-reported 
outcome questionnaires. 
Efficacy measures and patient-reported questionnaires will be analyzed using the EAS2 unless 
otherwise noted. 
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 
Refer to the SAP for analyses related to tertiary endpoints. 
9.3.5. 
Safety Analyses 
Safety Measures Include 
 treatment exposure 
 AE 
 vital signs 
 weight 
 hypoglycemia 
 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 degludec, 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. 
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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 participant-reported hypoglycemia will be analyzed using data from the e-diary by 
 Level 1 (defined by glucose value ≥54 to <70 mg/dL [≥3.0 to <3.9mmol/L]) 
 Level 2 (defined by glucose <54 mg/dL [<3.0 mmol/L]) 
 Level 3 (severe hypoglycemia), and 
 the composite of Levels 2 and 3. 
The analysis periods of 0-6, 0-12, 0-26, 0-52, 12-26, and 26-52 weeks of treatment will be 
considered. Documented hypoglycemia will be defined as 
 All documented hypoglycemia - episodes for the 24-hour period 
 Non-nocturnal hypoglycemia - episodes during 6 AM to midnight, and 
 Nocturnal hypoglycemia - episodes during midnight to 6 AM.  
The incidence and rate of hypoglycemia will be summarized by treatment and analysis period for 
different types of hypoglycemia. 
For continuous safety variables (for example, laboratory measures, vital signs and weight), 
MMRM or ANCOVA models will be used. For categorical safety variables (for example, 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 described in the SAP. 
9.3.6. 
Other Analysis 
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 and/or concentration and efficacy, and safety as well 
as biomarker endpoints may be characterized. In addition, if population PK and PK/PD models 
can be established, the impact of additional participant factors, such as age, weight, sex, and 
renal function on PK and/or PD parameters, may be examined. Should anti-drug antibody be 
detected from immunogenicity testing, its impact on LY3209590 PK or any relevant PD 
parameters will also be examined. 
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9.3.6.2. 
Evaluation of Immunogenicity 
The baseline anti-LY3209590-antibody (ADA) status (detected or not detected) will be 
summarized by treatment for the participants evaluable for TEADA defined as participants with 
non-missing baseline and at least 1 non-missing postbaseline measurement. 
The number and percentage of participants who are treatment-emergent ADA-positive 
(TEADA+) will be summarized by treatment group. 
The frequency of cross-reactive binding to endogenous insulins may also be summarized for the 
participants with TEADA+. 
The relationship between the presence of TEADA and the safety and efficacy measures may be 
assessed. 
Definition of TEADA+ 
A participant is considered TEADA+ if either treatment-induced ADA or treatment-boosted 
ADA occurs. 
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 ≥2 dilutions (4-fold) of the 
baseline titer.  
9.3.7. 
Subgroup Analyses 
The following outcomes will be analyzed by the subgroups of GLP-1 RA use at randomization: 
 rate of Level 1 hypoglycemia events during Weeks 0 to 26, Weeks 26 to 52, and Weeks 0 to 
52 
 rate of composite of Level 2 and 3 hypoglycemia events during Weeks 0 to 26, Weeks 26 to 
52, and Weeks 0 to 52 
 change from baseline to Week 26 and Week 52 in body weight 
 insulin dose at Week 26 and Week 52 
 measurements collected during CGM sessions collected prior to Weeks 12, 26, and 52 of 
o time in hypoglycemia with glucose <70 mg/dL (3.9 mmol/L)  
o time in hypoglycemia with glucose <54 mg/dL (3.0 mmol/L) 
o time in hyperglycemia defined as glucose >180 mg/dL (10.0 mmol/L), and 
o time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L, 
respectively), inclusive. 
The analyses will evaluate whether the treatment impact is different by the subgroups. The 
models used for these analyses will vary depending on the outcome. Other subgroup analyses 
may be performed as deemed appropriate. 
Details of the modeling will be provided in the SAP. 
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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 888 participants will be randomly assigned to LY3209590 and insulin degludec 
in a 1:1 ratio. With the assumption of 15% dropout at Week 52, approximately 377 and 377 
participants will complete 52 weeks of treatment on LY3209590 and insulin degludec, 
respectively. 
The primary objective of this study is to test the hypothesis that LY3209590 is noninferior to 
insulin degludec on glycemic control as measured by change from baseline to Visit 31 (Week 
52) in HbA1c in participants with T2D who are starting basal insulin for the first time. 754 
completers (377 on LY3209590 and 377 on insulin degludec) will provide an at least 99% 
statistical power to show noninferiority between LY3209590 and insulin degludec using the 
upper limit of a 2-sided 95% confidence interval (LY3209590 – insulin degludec) and these 
assumptions 
 NIM of 0.4% 
 no true difference between treatment groups, and 
 an SD of 1.1%. 
This sample size also has at least 95% statistical power to show noninferiority between 
LY3209590 and insulin degludec using a 0.3% NIM at Week 52. 
The number of participants in each subpopulation of background treatment will be approximately 
50% of the study population with balanced treatment assignment to support the following 
secondary objectives, controlled for Type 1 error: 
To demonstrate noninferiority of LY3209590 to insulin degludec in HbA1c change from 
baseline to Week 52 for the subpopulation of participants using GLP-1 RAs 
To demonstrate noninferiority of LY3209590 to insulin degludec in HbA1c change from 
baseline to Week 52 for the subpopulation of participants not using GLP-1 RAs. 
In each subpopulation, 188 completers for each study intervention will provide an approximately 
90% statistical power to show noninferiority between LY3209590 and insulin degludec using the 
upper limit of a 2-sided 95% confidence interval (LY3209590 – insulin degludec) and these 
assumptions 
 a NIM of 0.4% 
 no true difference between treatment groups, and 
 an SD of 1.1%. 
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The 754 completers will provide 95% statistical power to demonstrate the superiority of 
LY3209590 versus insulin degludec, of change in HbA1c from baseline to 52 weeks, assuming 
an SD of 1.1% and true mean difference is -0.3%, using the alpha of 0.05. 
The 754 completers will provide at least 95% statistical power to show the superiority of the 
percentage of time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive 
during the CGM session prior to Week 52 between LY3209590 and insulin degludec, assuming 
an SD of 18% and true mean difference is 5%, using the alpha of 0.05. 
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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, Investigator Brochure, 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 (CFR), 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 
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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. 
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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 pharmacokinetic 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 case report forms, 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. 
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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 pre-defined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These pre-defined 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 (CTA) 
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. 
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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 (COA) 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 (eCOA) 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 eCOA 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 
product complaint 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. 
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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. 
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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. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in the table below 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. 
 
 
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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  
Very-low-density lipoprotein (VLDL-C) 
  
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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  
  
 
 
 
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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: ADA = anti-drug 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. 
 
 
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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 
International Organization for Standardization 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 
sponsor 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 10.9. 
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 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. 
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 or disorder being studied or expected progression, signs or symptoms of 
the disease or 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. 
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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.  
 
 
 
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10.3.3. 
Definition of Product Complaints 
Product Complaint 
 A product complaint 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 product complaints: 
o deficiencies in labeling information, and 
o use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints 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 they 
have a product complaint or problem with the study intervention so that the situation 
can be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint 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/product complaint 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/product complaint 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 
product complaint information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint 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 product complaints. 
 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.  
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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 adverse event 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 adverse event 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 adverse event 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 pre-defined 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 degludec in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that they have 
reviewed the AE/SAE and have 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. 
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 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
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 
post-mortem 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) 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. 
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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 toward 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, 
IRB/IEC, 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.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Women of childbearing potential (WOCBP) 
Females are considered women of childbearing potential if 
 they have had at least 1 cycle of menses, or 
 they have Tanner 4 breast development. 
Any amount of spotting should be considered menarche. 
Women not of childbearing potential 
Females are considered women not of childbearing potential if 
 they have a congenital anomaly, such as Mullerian agenesis, 
 they are infertile due to surgical sterilization, or 
 they are postmenopausal. 
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, and tubal 
ligation. 
Postmenopausal 
The postmenopausal state should be defined as 
 a woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note 
OR 
 a woman at least 40 years of age and up to 55 years old with an intact uterus, not on 
hormone therapy⸸, 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 
 a woman 55 years of age or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea 
OR 
 a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone 
replacement therapy. 
⸸ Women should not be taking medications during amenorrhea, such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
 
 
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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, and 
 
take pregnancy tests. 
are completely abstinent 
 
they must agree to remain completely abstinent 
are not completely abstinent 
 
they must agree to 
o 
use 1 highly effective method (less than 
1% failure rate) of contraception, or a 
combination of 2 effective methods of 
contraception. 
o 
take pregnancy tests.  
 
these forms of contraception must be used for 
the duration of the study. 
Note on forms of contraception: At least 1 form of contraception must be highly effective, meaning that it has a 
less than 1% failure rate. 
 
Guidance for all men 
No male contraception is required except in compliance with specific local government study 
requirements. 
 
 
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Methods of contraception for women of childbearing potential 
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 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  
 
male or female condoms with spermicide 
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o 
condom with spermicide 
o 
diaphragm with spermicide, or 
o 
female condom with spermicide. 
Note: The barrier method must include use of a 
spermicide (that is, condom with spermicide, 
diaphragm with spermicide, and female condom with 
spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone 
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of above 2, 
cervical mucus, symptothermal) 
 
withdrawal 
 
post coital douche, and 
 
lactational amenorrhea. 
 
 
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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) 
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    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. 
 
 
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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. 
 
 
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10.7. 
Appendix 7: Country-specific Requirements 
10.7.1. 
Canada 
This section describes protocol changes applicable to adult participants at study sites in Canada. 
This table describes the changes and provides a rationale for the changes. 
Protocol Section Number and Name 
Description of the Change 
Brief Rationale 
Inadvertently Enrolled Participants 
New section specific to 
Canada. 
Information on inadvertently 
enrolled participants added per 
Canadian local requirements. 
The revised text described below shows the changes applicable to adult participants at study sites 
in Canada. Deletions are identified by strikethrough format and additions by underlined text. 
Inadvertently Enrolled Participants 
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study intervention 
and safety follow-up should be performed as outlined in the SoA and Section 8.3 of the protocol.  
 
 
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10.7.2. 
Brazil 
This section describes protocol changes applicable to adult participants at study sites in Brazil. 
This table describes the changes and provides a rationale for the changes. 
Protocol Section Number and Name 
Description of the Change 
Brief Rationale 
Section 5.2. Exclusion Criteria 
Exclusion criterion 28 
30 days is changed to 1 year. 
Resolution No. 251 (Brazil 1997). 
The National ERB Brazil 
recommends not having a 
participant enter a new clinical 
study if less than 1 year has elapsed 
since participation in another 
clinical study of an investigational 
drug or device unless there is a 
direct benefit to the research 
participant. 
Section 10.1.12. Sample Retention  
Biological samples will be 
stored for up to 10 years. 
Compliance with Brazilian 
regulation applicable to sample 
storage, resolution CNS 441 (Brazil 
2011). 
Patient Access to Project Benefits 
New section specific to Brazil. 
Clarifies the sponsor responsibilities 
to comply with Resolution CNS 466 
(Brazil 2012) and RDC 38 (Brazil 
2013). 
Section 11. References 
Addition of Brazil-specific 
references 
The references are specific to the 
Brazil-specific requirements. 
The revised text described below shows the changes applicable to adult participants at study sites 
in Brazil. Deletions are identified by strikethrough format and additions by underlined text. 
5.2. 
Exclusion Criteria 
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, 3 months or 5 half-lives, whichever is 
longer, should have passed prior to Visit 1. 
Are currently enrolled in, discontinued, or completed within a period of 1 year, before 
inclusion, from a clinical study involving an investigational intervention or nonapproved 
use of a drug or device, or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study unless there is 
direct benefit to the research subject. A time period of 30 days, as indicated by the 
protocol, must still be followed if a direct benefit to the research participant is identified. 
 
 
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10.1.12. Sample Retention 
In Brazil, the biological samples obtained within this study will be stored for up to 10 years, with 
possibility of renewal under request, followed by appropriate justification and a report with all 
activities developed with the biological samples (CNS 441/2011). The sample and any data 
generated from it can be linked back to the participant only by investigator site personnel. The 
duration allows the sponsor to respond to regulatory requests related to the study intervention. 
Patient Access to the Project Benefits 
In Brazil, at the end of their participation in the study, all participants must have assured access 
to the best proven prophylactic, diagnostic, and therapeutic methods, which may include 
LY3209590 or insulin degludec, identified through the study (CNS 466/2012 and RDC 38/2013). 
11. 
References 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 251/1997 do Conselho Nacional de Saúde/MS: 
Normas de Pesquisa com Novos Fármacos, Medicamentos, Vacinas e Testes Diagnósticos 
Envolvendo Seres Humanos. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 466/2012 do Conselho Nacional da Saúde / 
MS: Diretrizes e Normas Regulamentadoras de Pesquisas Envolvendo Seres Humanos. 
Publicado no Diário Oficial da União em 13 de junho, 2013. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 340/2004 do Conselho Nacional da Saúde/MS: 
Diretrizes para Análise Ética e Tramitação dos Projetos de Pesquisa da Área Temática 
Especial de Genética Humana. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 441/2011 do Conselho Nacional da Saúde / 
MS: Diretrizes para análise ética de projetos de pesquisas que envolvam armazenamento de 
material biológico humano ou uso de material armazenado em pesquisas anteriores. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução-RDC 38/2013 
da Agência Nacional deVigilância Sanitária/MS: Aprova o regulamento para os programas de 
acesso expandido, usocompassivo e fornecimento de medicamento pós-estudo.  
 
 
 
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10.7.3. 
Germany 
This section describes protocol changes applicable to adult participants at study sites in 
Germany. 
This table describes the changes and provides a rationale for the changes. 
Protocol Section Number and Name 
Description of the Change 
Brief Rationale 
7.2. 
Participant 
Discontinuation/Withdraw from the 
Study 
 
8.3. 
Adverse Events, Serious Adverse 
Events, and Product Complaints 
 
 
 
Deleted references to “legally 
authorized representative,” 
“legal guardian,” “parents”. 
The German Drug Law 
(Arzneimittelgesetz – AMG) with 
reference to EU Regulation 
536/2014 requires that adult 
participants act on their own 
behalf and provide their own 
written informed consent. If 
written consent is not possible, 
verbal consent with a witness is 
acceptable. No legal 
representative consent is 
accepted. 
10.8 Appendix 8: Provisions for Changes in 
Study Conduct During Exceptional 
Circumstances 
Replaced references to 
“exceptional circumstances” 
with the “COVID-19 
pandemic”. 
Temporary measures may only be 
used in response to the COVID-
19 pandemic. 
The revised text described below shows the changes applicable to adult participants at study sites 
in Germany. Deletions are identified by strikethrough format and additions by underlined text. 
7.2. 
Participant Discontinuation/Withdraw from the Study 
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 enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
● if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
 
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8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3: 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 Product complaints (PCs) 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
Section 10.8. Appendix 8: Provisions for Changes in Study Conduct During Exceptional 
Circumstances due to the COVID-19 Pandemic 
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 Study disruptions due to the COVID-19 pandemic 
Individual, site, or regional restrictions due to the COVID-19 pandemic 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 during the COVID-19 pandemic 
In an exceptional circumstance, a 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 
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 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances the COVID-19 pandemic 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
To ensure the quality of data and the well-being of participants, it will be ensured that the 
investigator sites and their staff are following GCP principles and are meeting the sponsor 
responsibilities of Section 5 of ICH GCP. Throughout these activities the participant remains 
under the care of the primary investigator. 
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 the COVID-19 pandemic 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 product complaints 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. 
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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 eCRF. 
Lilly Medical should be informed of any labs that meet criteria for temporary or permanent study 
intervention discontinuation. 
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 the COVID-19 pandemic: 
 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 
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interruption due to an exceptional circumstance the COVID-19 pandemic. 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. 
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, Visit 31 (Week 52), 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 the COVID-19 pandemic. 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. 
 
Section 10.10. Appendix 10: Abbreviations and Definitions 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
 
 
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10.8. 
Appendix 8: 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. 
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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 product complaints 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 eCRF. 
Lilly Medical should be informed of any labs that meet criteria for temporary or permanent study 
intervention discontinuation. 
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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. 
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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, Visit 31 (Week 52), 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. 
 
 
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10.9. 
Appendix 9: 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 labelling of the medicinal 
product, which is used as an investigational medicinal product 
authorized AxMP 
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 labelling of the medicinal 
product, which is used as an auxiliary medicinal product 
AxMP 
auxiliary medicinal product. See also NIMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. AxMP does not include investigational medicinal product (IMP) or 
concomitant medications. Concomitant medications are medications unrelated to the 
clinical trial and not relevant for the design of the clinical trial 
CGM 
continuous glucose monitoring; can refer to study procedure or analysis of 
representative CGM derived variables including but not limited to: 
 time in range from 70 to 180 mg/dL (3.9-10 mmol/L) and 70 to 140 mg/dL (3.9-7.7 
mmol/L) 
 time below range from ≥54 mg/dL (3 mmol/L) to <70 mg/dL (3.9 mmol/L), <70 
mg/dl (3.9 mmol/L), and <54 mg/dL (3 mmol/L) 
 time above range from >180 mg/dL (10 mmol/L) to ≤250 mg/dL (13.9 mmol/L) 
and >250 mg/dL (13.9 mmol/L) 
 daily average glucose  
 glucose management indicator  
 between- and within-day glucose variability 
 low blood glucose index, high blood glucose index; blood glucose risk indicator; 
and 
 ambulatory glucose profiles with interquartile ranges. 
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 
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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 
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 
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 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
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 
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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 
IRB 
Institutional Review Boards 
IWRS 
interactive web-response system 
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 
NIMP 
non-investigational medicinal product 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. 
See AxMP.  
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 
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PT-INR 
prothrombin time, INR 
QTc 
corrected QT interval 
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 
SU 
sulphonylureas 
T1D 
Type 1 diabetes 
T2D 
Type 2 diabetes 
TEADA 
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 
 
 
 
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10.10. 
Appendix 10: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]: (15 Feb 2022) 
This amendment is considered to be nonsubstantial.Overall Rationale for the Amendment 
The overall rationale for the changes implemented in the protocol amendment is to update the 
insulin degludec dose adjustments so that it will more closely reflect those for LY3209590. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Visit and Week numbers were 
changed and an additional row 
was added to the table to indicate 
that insulin degludec dose 
adjustments may occur every 4 
weeks after Week 12 (Visit 15) 
Table was modified to reflect the 
changes in insulin degludec dose 
adjustments 
Section 1.2 Schema 
Added “CGM Visits” to Safety 
Follow-Up section 
Correction-this section was 
missing in original schema 
Section 1.3.1 
Schedule of 
Activities 
Demographics comment-replaced 
“gender” with “sex” 
Preferred terminology 
Section 1.3.1 and 
1.3.2 Schedule of 
Activities 
Added the following text to ECG 
comment-“ECGs will be 
performed prior to collection of 
any blood samples” 
For clarification 
Section 4.3 
Justification for Dose 
Text was changed to indicate that 
insulin degludec dose adjustments 
should occur weekly from Visits 
4 to 15 (Weeks 1 to 12) and then 
every 4 weeks thereafter.  
The text was modified to be 
consistent with LY3209590 dose 
adjustments 
Section 6.1 Study 
Intervention(s) 
Administered 
Added the following text to 
Anatomical Location of 
Injections –“ Injections may be 
administered in the abdomen, 
thigh, arm, or buttock. Refer to 
the IFU for complete instructions 
on dose administration. 
Anatomical location of insulin 
injections added to address FDA 
feedback to include acceptable 
anatomical locations for insulin 
administration in the protocol 
Section 6.5.1.2 
LY3209590 Dose 
Adjustment Based on 
FBG 
Addition of the following 
sentence: 
“If the participant experienced 
any documented BG ≤70 mg/dL 
(≤3.9 mmol/L) in the previous 
To emphasize that, in the 
occurrence of a hypoglycemia 
event <70, insulin doses should 
not increase 
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week, the dose should not be 
increased” 
Section 6.5.2.1 
Insulin Degludec 
General Dosing 
Information by Visit 
Visit and Week numbers were 
changed and an additional row 
was added to the table to indicate 
that insulin degludec dose 
adjustments may occur every 4 
weeks after Week 12 (Visit 15) 
Table was modified to reflect the 
changes in insulin degludec dose 
adjustments 
Section 6.5.2.2 
Insulin Degludec 
Dose Adjustment 
Based on FBG 
Addition of the following 
sentence: 
“If the participant experienced 
any documented BG ≤70 mg/dL 
(≤3.9 mmol/L) in the previous 
week, the dose should not be 
increased” 
To emphasize that, in the 
occurrence of a hypoglycemia 
event <70, insulin doses should 
not increase 
Section 9.3.6.1 
Pharmacokinetic and 
Pharmacodynamic 
Analyses 
Replaced “gender” with “sex” 
Preferred terminology 
Throughout 
Minor editorial revisions 
Minor, therefore, have not been 
summarized 
 
 
 
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11. 
References 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective multiple 
test procedures. Statist Med. 2009;28:586-604. https://doi.org/10.1002/sim.3495. 
Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison procedures 
using weighted Bonferroni, Simes, or parametric tests. Biomet J. 2011;53(6):894-913. 
https://onlinelibrary.wiley.com/doi/pdf/10.1002/bimj.201000239. 
EuroQol Research Foundation. EQ-5D-5L user guide, version 3.0. Updated September 2019. 
Accessed 01 February 2022. https://euroqol.org/publications/user-guides. 
Maruish ME, editor. User’s Manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality 
Metric Incorporated; 2011. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley; 1987. 
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