A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Trial to Evaluate the Efficacy and Safety of LY3209590 Compared With Insulin Degludec in Participants With Type 2 Diabetes Currently Treated With Basal Insulin (QWINT-3)
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Protocol I8H-MC-BDCU (b) 
A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Trial to Evaluate the Efficacy and Safety of 
LY3209590 Compared With Insulin Degludec in Participants With Type 2 Diabetes Currently Treated With Basal 
Insulin (QWINT-3)
NCT05275400
Approval Date: 13-May-2022

CONFIDENTIAL 
I8H-MC-BDCU(b) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of insulin efsitora alfa (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, Multicenter, Randomized, Parallel-Design, Open-Label Trial to Evaluate the Efficacy 
and Safety of LY3209590 Compared with Insulin Degludec in Participants with Type 2 Diabetes 
Currently Treated with Basal Insulin (QWINT-3) 
Protocol Number: I8H-MC-BDCU(b) 
Amendment Number: b 
Compound: LY3209590 
Brief Title: 
Efficacy and Safety of the Once-Weekly Basal Insulin LY3209590 Therapy Compared with 
Daily Insulin Degludec in Adults with Type 2 Diabetes Treated with Basal Insulin 
Study Phase: Phase 3 
Acronym: QWINT-3 (Once-Weekly Insulin Therapy) 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers 
IND: 129390 
EudraCT: 2021-002569-16 
Document ID: VV-CLIN-045582 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
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I8H-MC-BDCU(b) 
 
2 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
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I8H-MC-BDCU(b) 
 
3 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment a 
28-JAN-2022 
Original Protocol 
08-NOV-2021 
Amendment [b] 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the 
● safety or the rights of the study participants 
Overall Rationale for the Amendment: 
The primary rationale for the current amendment is to address regulatory feedback regarding 
exclusionary ALT and AST thresholds and include specific details for participants who enter the 
study and use personal CGM. These changes are detailed in the table below. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3.2. SoA for the 
Treatment Period (V23-
V37), ET, UV, and 
Safety Follow-Up Period 
(801-802) 
Added a Note “Visit 3 (Week 0) should occur 
11-17 days after Visit 2.” 
For clarity 
Edited the footnote of CGM Visits: removed “to 
ensure adequate data collection” and added 
“During the study blinded CGM sessions, only 
the study CGM device may be worn. 
Participants who routinely use personal 
CGM/FGM at study entry may not wear a 
personal CGM/FGM during the study required 
blinded CGM sessions.” 
To address regulatory feedback 
3. Objectives, Endpoints, 
and Estimands 
In Primary estimand subsection, US 
registration, edited the text in primary clinical 
question of interest to clarify “study-eligible” 
participants 
For clarity 
Edited treatment regimen estimand attributes 
- Population: added cross reference to Section 
9.2 
In Primary estimand subsection, Registration 
for other countries, edited the text in primary 
clinical question of interest to clarify “study-
eligible” participants 
Edited efficacy estimand attributes 
- Population: added cross reference to Section 
9.2 
5.1. Inclusion Criteria 
In inclusion criterion 4, added “as determined 
by central laboratory” 
For clarity 
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4 
Section # and Name 
Description of Change 
Brief Rationale 
In inclusion criterion 5, added trademark name 
for insulin detemir 
In inclusion criterion 8, added “Note: 
Participants who are already using CGM or 
FGM at study entry will be allowed to continue 
to use their personal CGM/FGM during the 
study when not wearing the study CGM. 
Participants must use the study-provided 
glucometer for all FBG values and any other 
BG values reported during the study” 
For clarity and to address 
regulatory feedback 
In inclusion criterion 8, added “not wear a 
personal CGM/FGM during the study blinded 
CGM assessments” and “not initiate the use of 
personal CGM/FGM if not already routinely 
using CGM/FGM at study entry”  
5.2. Exclusion Criteria 
In exclusion criterion 20, added wording “after 
having signed the ICF” and “after receiving at 
least 1 dose of the study basal insulin” 
For clarity 
In exclusion criterion 25, increased AST and 
ALT thresholds from 2.5x ULN to 3x ULN 
To address regulatory request  
6.1.3. General Insulin 
Dose Considerations for 
Both Treatment Groups 
Under “Insulin Dose Titration and Dose 
Maintenance”, modified “Visit 6 (Week 3)” to 
“Visit 5 (Week 2)” 
Correction 
6.8. Concomitant 
Therapy 
Under “Criteria for Use of Concomitant 
Medications” table, replaced “N/A” 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 
Removed all the trademark names from 
footnote “a” 
For consistency 
6.8.1. Rescue Therapy 
for Management of 
Participants with Severe / 
Persistent Hyperglycemia 
during the Treatment 
Period 
Removed paragraph 2 and added “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” 
To address regulatory feedback 
Removed the last paragraph and added 
“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” 
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5 
Section # and Name 
Description of Change 
Brief Rationale 
8.1.5.2. CGM 
Monitoring 
Updated the section 
To address regulatory feedback 
8.4. Pharmacokinetics 
Added “Bioanalytical” subsection 
Correction 
8.7. Biomarkers 
Removed the last paragraph 
Correction 
9. Statistical 
Considerations 
Replaced “Visit 22 (Week 26)” with “Week 26 
(Visit 22)”; “Visit 37 (Week 78)” with “Week 
78 (Visit 37) 
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 
10.2. Appendix 2: 
Clinical Laboratory Tests 
In Glucose line of Clinical Chemistry, added 
“Fasting or random (refer to SoA)”; and deleted 
in Glucose line of Urinalysis. 
Correction 
Added Glucose under Additional Testing 
For clarity 
10.4.2. Females 
Corrected the typographical error and added 
“These forms of contraception must be used for 
the duration of the study.” 
Correction 
10.8. Appendix 8: 
Abbreviations and 
Definitions 
Added CGM parameters. 
To address regulatory feedback 
Added “EAS – efficacy analysis set,” “FGM – 
flash glucose monitoring”, “IFU – instructions 
for Use,” and “SS – safety analysis set”. 
To provide definition of terms 
Moved FSH abbreviation as per the alphabetical 
order 
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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Table of Contents 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
1.3.1. 
SoA for the Screening/Lead In Period I (V1-V2) and Treatment 
Period II (V3-V22) ..........................................................................................................14 
1.3.2. 
SoA for the Treatment Period (V23-V37), ET, UV, and Safety 
Follow-Up Period (801-802)...........................................................................................21 
2. 
Introduction ...................................................................................................................29 
2.1. 
Study Rationale ...............................................................................................................29 
2.2. 
Background .....................................................................................................................29 
2.3. 
Benefit/Risk Assessment ................................................................................................30 
2.3.1. 
Protocol Risk Mitigation Factors ....................................................................................31 
3. 
Objectives, Endpoints, and Estimands .......................................................................32 
4. 
Study Design ..................................................................................................................35 
4.1. 
Overall Design ................................................................................................................35 
4.1.1. 
Design Outline ................................................................................................................35 
4.2. 
Scientific Rationale for Study Design ............................................................................37 
4.3. 
Justification for Dose ......................................................................................................38 
4.4. 
End of Study Definition ..................................................................................................39 
5. 
Study Population ...........................................................................................................40 
5.1. 
Inclusion Criteria ............................................................................................................40 
5.2. 
Exclusion Criteria ...........................................................................................................41 
5.3. 
Lifestyle Considerations .................................................................................................43 
5.4. 
Screen Failures ................................................................................................................44 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................44 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................45 
6.1. 
Study Intervention(s) Administered................................................................................45 
6.1.1. 
Medical Devices..............................................................................................................46 
6.1.2. 
LY3209590 and Insulin Degludec Dosing .....................................................................46 
6.1.3. 
General Insulin Dose Considerations for Both Treatment Groups .................................46 
6.1.4. 
LY3209590 Dose Initiation and Modification ................................................................47 
6.1.5. 
Insulin degludec Dose Initiation and Modification ........................................................50 
6.1.6. 
Management of Hypoglycemia .......................................................................................51 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................52 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................53 
6.4. 
Study Intervention Compliance ......................................................................................53 
6.5. 
Dose Modification ..........................................................................................................53 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................54 
6.7. 
Treatment of Overdose ...................................................................................................54 
6.8. 
Concomitant Therapy .....................................................................................................54 
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6.8.1. 
Rescue Therapy for Management of Participants with Severe / 
Persistent Hyperglycemia during the Treatment Period .................................................56 
6.8.2. 
Concomitant Antihyperglycemia Medication .................................................................57 
6.8.3. 
Medications that Promote Weight Loss ..........................................................................57 
6.8.4. 
Systemic Glucocorticoids ...............................................................................................57 
6.8.5. 
Treatment after the End of the Study ..............................................................................57 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................59 
7.1. 
Discontinuation of Study Intervention ............................................................................59 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................60 
7.1.2. 
Temporary Interruption of Study Treatment...................................................................60 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................61 
7.3. 
Lost to Follow-Up ...........................................................................................................61 
8. 
Study Assessments and Procedures.............................................................................62 
8.1. 
Efficacy Assessments .....................................................................................................62 
8.1.1. 
Primary Efficacy Measure ..............................................................................................62 
8.1.2. 
Key Secondary Efficacy Measures .................................................................................62 
8.1.3. 
Other Secondary Measures .............................................................................................62 
8.1.4. 
Other Efficacy Measures.................................................................................................62 
8.1.5. 
Additional Information on Efficacy and Health Outcomes 
Measures .........................................................................................................................63 
8.2. 
Safety Assessments .........................................................................................................67 
8.2.1. 
Physical Examinations ....................................................................................................67 
8.2.2. 
Vital Signs .......................................................................................................................67 
8.2.3. 
Electrocardiograms .........................................................................................................68 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................68 
8.2.5. 
Hepatic Safety Monitoring ..............................................................................................69 
8.2.6. 
Pregnancy Monitoring ....................................................................................................69 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................69 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................70 
8.3.2. 
Pregnancy ........................................................................................................................72 
8.3.3. 
Hypoglycemia .................................................................................................................73 
8.3.4. 
Systemic Hypersensitivity Reactions ..............................................................................74 
8.3.5. 
Injection site reactions ....................................................................................................74 
8.3.6. 
Adjudicated events: Cerebrocardiovascular Events........................................................74 
8.4. 
Pharmacokinetics ............................................................................................................74 
8.5. 
Pharmacodynamics .........................................................................................................75 
8.6. 
Genetics ..........................................................................................................................75 
8.7. 
Biomarkers ......................................................................................................................75 
8.8. 
Immunogenicity Assessments.........................................................................................75 
8.9. 
Health Economics ...........................................................................................................75 
9. 
Statistical Considerations .............................................................................................76 
9.1. 
Statistical Hypotheses .....................................................................................................76 
9.2. 
Analyses Sets ..................................................................................................................77 
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I8H-MC-BDCU(b) 
 
8 
9.3. 
Statistical Analyses .........................................................................................................77 
9.3.1. 
General Considerations ...................................................................................................77 
9.3.2. 
Primary Endpoint/Estimand Analysis .............................................................................78 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................79 
9.3.4. 
Tertiary Endpoint(s) Analysis .........................................................................................79 
9.3.5. 
Safety Analyses ...............................................................................................................80 
9.3.6. 
Other Analyses ................................................................................................................80 
9.4. 
Interim Analysis ..............................................................................................................81 
9.5. 
Sample Size Determination ............................................................................................81 
10. 
Supporting Documentation and Operational Considerations ..................................83 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................83 
10.1.1. Regulatory and Ethical Considerations ...........................................................................83 
10.1.2. Financial Disclosure........................................................................................................83 
10.1.3. Informed Consent Process ..............................................................................................84 
10.1.4. Data Protection................................................................................................................84 
10.1.5. Committees Structure......................................................................................................85 
10.1.6. Dissemination of Clinical Study Data.............................................................................85 
10.1.7. Data Quality Assurance ..................................................................................................86 
10.1.8. Source Documents ..........................................................................................................87 
10.1.9. Study and Site Start and Closure ....................................................................................88 
10.1.10. Publication Policy ...........................................................................................................88 
10.1.11. Investigator Information .................................................................................................88 
10.1.12. Sample Retention ............................................................................................................88 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................90 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................92 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting ...........................................................................................................94 
10.3.1. Definition of AE .............................................................................................................94 
10.3.2. Definition of SAE ...........................................................................................................95 
10.3.3. Definition of Product Complaints ...................................................................................96 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................97 
10.3.5. Reporting of SAEs ..........................................................................................................99 
10.3.6. Regulatory Reporting Requirements ...............................................................................99 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ........................................................100 
10.4.1. Definitions.....................................................................................................................100 
10.4.2. Females .........................................................................................................................101 
10.4.3. Males .............................................................................................................................102 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments ..................................................................................................................103 
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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 .........................................................................107 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................108 
10.8. 
Appendix 8: Abbreviations and Definitions .................................................................113 
10.9. 
Appendix 9: Protocol Amendment History ..................................................................118 
11. 
References ....................................................................................................................132 
 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Trial to Evaluate the Efficacy 
and Safety of LY3209590 Compared with Insulin Degludec in Participants with Type 2 Diabetes 
Currently Treated with Basal Insulin (QWINT-3). 
Brief Title: 
Efficacy and Safety of the Once-Weekly Basal Insulin LY3209590 Therapy Compared with 
Daily Insulin Degludec in Adults with Type 2 Diabetes Treated with Basal Insulin 
Rationale: 
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. It was designed as a 
divalent (dimer) insulin receptor agonist consisting of a single-chain insulin analog (comprised 
of an insulin B-chain analog, a short peptide linker, and an insulin A-chain analog) fused to a 
second peptide linker that is fused to an unmodified human IgG2 Fc domain. LY3209590 has a 
mean half-life of approximately 17 days and a peak-to-trough PK profile of 1.14. The low peak-
to-trough ratio and extended half-life of LY3209590 support once-weekly dosing and have the 
potential to decrease patient burden, overcome barriers to initiation of basal insulin therapy, and 
may improve glycemic control and quality of life for patients with T2D compared to other basal 
insulins that require daily administration. 
The Phase 2 Study I8H-MC-BDCM (BDCM) demonstrated that following 32 weeks of 
treatment, LY3209590 effectively and safely improved glycemic control, comparable to insulin 
degludec, in participants with T2D treated with basal insulin with or without other allowed non-
insulin lowering medications. The risk of all documented and nocturnal hypoglycemia (with 
blood glucose ≤70 mg/dL [3.9 mmol/L]) was statistically significantly lower (20% to 40%) for 
both LY groups compared to insulin degludec consistent with higher fasting glucose values 
observed with LY3209590. The reported treatment-emergent SAEs were balanced across the 3 
treatment groups. Results of Study BDCM therefore support continued development of 
LY3209590 as a treatment for diabetes mellitus. 
The objective of this Phase 3 study (I8H-MC-BDCU [BDCU]) is to evaluate the efficacy and 
safety of LY3209590 as a weekly basal insulin compared to insulin degludec (daily basal insulin) 
using target FBG values of 80–120 mg/dL (4.4-6.6 mmol/L) in participants with T2D currently 
treated with basal insulin. 
 
 
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11 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
 
To investigate the hypothesis that 
LY3209590 is noninferior to the 
comparator (insulin degludec) on 
glycemic control in study participants 
with T2D currently on basal insulin 
 
Change from baseline in HbA1c at Week 26 
Key Secondary (Multiplicity Adjusted) 
 
 
To demonstrate LY3209590 is superior 
to insulin degludec in the selected 
parameters of glycemic control 
 
Change from baseline in HbA1c at Week 26 
 
The event rate of participant-reported clinically 
significant nocturnal hypoglycemia (<54 mg/dL 
[3.0 mmol/L] or severe) during treatment phase up to 
Week 78 
 
Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L) inclusive measured during the 
CGM session prior to Week 26 
Abbreviations: CGM = continuous glucose monitoring; dL = deciliter; HbA1c = hemoglobin A1c; mg = milligrams; 
T2D = Type 2 Diabetes. 
Note: Other Secondary Objectives and Endpoints are listed in Section 3. 
Overall Design 
Brief Summary: 
Study BDCU is a Phase 3, multicenter, randomized, open-label, comparator-controlled study to 
evaluate the efficacy and safety of once-weekly basal insulin (LY3209590) compared to insulin 
degludec in participants with T2D treated with basal insulin. The study consists of a 3-week 
screening/lead-in period, a 78-week treatment period, and a 5-week safety follow-up period. The 
primary outcome is the change from baseline in HbA1c at Week 26. 
Study details include 
● The study duration will be up to 86 weeks. 
● The treatment duration will be up to 78 weeks. 
Number of Participants: 
Approximately 1341 participants will enter the study such that 939 evaluable participants will be 
randomly assigned in a 2:1 ratio to study drug with 626 participants in the LY3209590 group and 
313 participants in the insulin degludec group. 
Intervention Groups and Duration: 
Participants who meet entry criteria will be randomly assigned in a 2:1 (LY3209590:insulin 
degludec) ratio to the following treatment groups: 
 LY3209590: once-weekly administration, and 
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12 
 Insulin degludec: once-daily administration. 
The total duration of study participation for each participant, including screening and the 
posttreatment follow-up periods, is approximately 86 weeks, across the following study periods: 
 Study Period I: Screening and Lead-In Period, 3 weeks 
 Study Period II: Treatment Period, 78 weeks, and 
 Study Period III: Safety Follow-Up Period, 5 weeks. 
Data Monitoring Committee: Yes 
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1.2. 
Schema 
 
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14 
1.3. 
Schedule of Activities (SoA) 
The SoA described below should be followed for all participants enrolled in Study BDCU. However, for those participants whose 
participation in this study is affected by exceptional circumstances, such as pandemics or natural disasters, please refer to Section 10.7 
for additional guidance. 
1.3.1. 
SoA for the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Informed consent  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
Inclusion/exclusion 
criteria, review and 
confirm 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review lab results and 
confirm I/E criteria 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
Preexisting conditions 
and medical history, 
including relevant 
surgical history 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
Prespecified medical 
history (indication and 
history of interest) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
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15 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Prior treatments for 
indication 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
Substance use 
(recreational drugs, 
alcohol, caffeine, tobacco 
use)  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 10.3 
Physical Evaluation 
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
Weight 
X 
X 
X 
X 
X 
  
X 
  
X 
  
 X 
 
X 
  
X  
 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
  
X 
  
X 
  
 X 
 
X 
  
 X 
 
X 
 
X 
See Section 8.2.2 
Physical examination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
X 
Additional physical 
examinations may be 
completed as necessary 
at PI discretion 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
16 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Hypoglycemia events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG (local) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.3 
Blinded Continuous Glucose Monitoring 
CGM sensor insertion 
and training 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Dispense CGM supplies 
as needed 
CGM device return and 
data download 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Participant Education  
Diabetes counseling, 
SMBG, hypoglycemia 
training/education 
  
X 
X 
  
  
  
  
  
  
  
  
  
 
  
  
 
  
 
 
Includes diabetes 
counseling, SMBG, 
hypoglycemia (see 
Sections 5.3, 8.3.3). 
After V3, review as 
needed 
Participant Diary (Electronic) and BG Meter  
Dispense e-diary, 
glucometer, complete 
training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense ancillary 
supplies as needed 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
17 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Diary compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review FBG, 
hypoglycemia events, 
insulin dose 
Patient-Reported Outcomes (Paper)  
Treatment-Related Impact 
Measure - Diabetes 
(TRIM-D) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Patient-Reported Outcomes (Electronic)  
Diabetes Treatment 
Satisfaction 
Questionnaire – Status 
(DTSQs) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes Treatment 
Satisfaction 
Questionnaire-Change 
(DTSQc) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
EQ-5D-5L 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Simplicity Questionnaire 
(SIM-Q) – Daily Basal 
Insulin 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
18 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Simplicity Questionnaire 
(SIM-Q) study 
intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Basal Insulin Experience: 
Preference  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Basal Insulin Experience: 
Likelihood of 
Incorporating into 
Routine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Tests and Sample Collections  
Hematology 
X 
  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
 
  
 
X 
 
Hemoglobin A1c 
(HbA1c) 
X 
  
X 
  
 X 
  
X 
  
  
  
  
  
X 
  
X  
 
 
 
X 
 
Clinical chemistry  
X 
  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
 
  
 
X 
 
Glucose 
  
  
 
  
  
  
X 
  
  
  
  
  
 
  
  
 
  
 
 
 
Lipid panel 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
X 
 
Serum pregnancy 
X 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
Collect for WOCBP only 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
19 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Urine pregnancy (local) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
Additional pregnancy 
testing may be performed 
if required by local 
regulations 
Follicle-stimulating 
hormone (FSH) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
C-Peptide 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
X 
 
eGFR (CKD-EPI)  
X 
  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
 
  
 
X 
 
UACR 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Pharmacokinetic (PK) 
samples  
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
All randomized 
participants 
Immunogenicity (ADA) 
samples 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
All randomized 
participants 
Stored Samples 
Exploratory biomarker 
samples  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization and Dosing  
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
20 
 
For procedures at the Screening/Lead In Period I (V1-V2) and Treatment Period II (V3-V22) 
For procedures at Visit 23 to Visit 37, ET, UV, 801 and 802 (Study Period III) Safety F/u Period, please see Section 1.3.2 
Study Period I – Screening/Lead-In 
Study Period II - Treatment Period 
Comments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11  
12 
14 
16 
18 
20 
22 
24 
26 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
 
Fasting or Telehealth 
Visit 
 
 
F 
 
 
T 
F 
T 
a 
T 
 
T 
F 
T 
 
T 
 
T 
F 
T = telehealth visit; 
F = fasting visit; asee 
notes below 
Insulin dose 
assessment/adjustment/ 
documentation  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense study 
intervention and related 
supplies 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Site administers study 
intervention and trains 
participant 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observe patient 
administer LY3209590 
study intervention 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose documented in e-
diary immediately 
Assess study intervention 
and storage compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Participant returns 
unused study drug  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
21 
1.3.2. 
SoA for the Treatment Period (V23-V37), ET, UV, and Safety Follow-Up Period (801-802) 
 
For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Concomitant medications 
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 
See Section 10.3 
Physical Evaluation  
Weight 
  
X 
  
X 
 
X 
  
X 
  
X 
 
X 
X 
  
 
X 
See Section 5.3 
Vital signs 
  
X 
  
X 
 
X 
  
X 
  
X 
 
X 
X 
  
 
X 
See Section 
8.2.2 
Physical examination 
  
  
  
  
 
  
  
  
  
  
 
X 
X 
  
 
X 
Additional 
physical 
examinations 
may be 
completed as 
necessary at PI 
discretion 
Hypoglycemia events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG (local) 
  
  
  
  
 
  
  
  
  
  
 
 X 
X  
  
 
  
See Section 
8.2.3 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
22 
 
For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Blinded Continuous Glucose Monitoring  
CGM sensor insertion and 
training 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
Dispense CGM 
supplies as 
needed. 
CGM device return and data 
download 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
Participant Education  
Diabetes counseling, 
SMBG, hypoglycemia 
training/education 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes 
diabetes 
counseling, 
SMBG, 
hypoglycemia 
(see Section 5.4, 
8.3.3 
respectively). 
After V3, 
review as 
needed 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
23 
 
For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Participant Diary (Electronic) and BG Meter  
Dispense ancillary supplies  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
Diary compliance check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review FBG, 
hypoglycemia 
events, insulin 
dose 
Diary return 
  
  
  
  
 
  
  
  
  
  
 
  
X 
  
 
X 
Participants will 
be required to 
return the e-
diary to the 
investigative site 
at the last study 
visit  
Patient-Reported Outcomes (Paper)  
Treatment-Related Impact 
Measure – Diabetes (TRIM-
D) 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
24 
 
For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Patient-Reported Outcomes (Electronic)  
Diabetes Treatment 
Satisfaction Questionnaire - 
Change 
  
  
  
  
 
X 
  
  
  
  
 
X 
 
  
 
  
 
EQ-5D-5L 
  
  
  
  
 
X  
  
  
  
  
 
X 
X 
  
 
  
 
Simplicity Questionnaire – 
Study Drug (SIM-Q) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Administered 
only if ET 
occurs before 
Visit 26 
Basal Insulin Experience: 
Preference  
  
  
  
  
 
  
  
  
  
  
 
X 
X 
  
 
  
 
Basal Insulin Experience: 
Likelihood of Incorporating 
into Routine 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Laboratory Tests and Sample Collections 
Hematology 
  
  
  
  
 
X 
  
  
  
  
 
X 
X 
  
 
X 
 
Hemoglobin A1c (HbA1c) 
  
X 
  
  
 
X 
  
X 
  
  
 
X 
X 
  
 
X 
 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
25 
 
For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Clinical chemistry  
  
  
  
  
 
X 
  
  
  
  
 
X 
X 
  
 
X 
 
Glucose 
  
X 
  
  
 
 
  
X 
  
  
 
 
 
  
 
 
 
Lipid panel 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
Urinalysis  
  
  
  
  
 
  
  
  
  
  
 
X 
X 
  
 
X 
 
Urine pregnancy  
  
  
  
  
 
  
  
  
  
  
 
  
 X 
  
 
X  
Additional 
pregnancy 
testing may be 
performed as 
necessary or if 
required by local 
regulations 
C-Peptide 
  
  
  
  
 
  
  
  
  
  
 
X  
X 
  
 
 
 
eGFR (CKD-EPI)  
  
  
  
  
 
X 
  
  
  
  
 
X 
X 
  
 
X 
 
UACR 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
Pharmacokinetic (PK) 
samples 
  
  
  
  
 
X 
  
  
  
  
 
X 
X 
  
 
X 
All randomized 
participants 
Approved on 13 May 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCU(b) 
 
26 
 
For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Immunogenicity (ADA) 
samples 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
X 
All randomized 
participants. 
Stored Samples 
Exploratory biomarker 
samples  
  
  
  
  
 
  
  
  
  
  
 
X 
X 
  
 
 
 
Randomization and Dosing 
Insulin dose assessment 
/adjustment/documentation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
See Section 6.5. 
Study participant may 
resume nonstudy insulin as 
clinically indicated 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
Nonstudy insulin dose 
assessment/adjustment/ 
Documentation (eCRF) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
See Section 
6.8.5.  
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Dispense study intervention 
and related supplies  
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Dispense ancillary supplies 
to participant 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
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For Treatment Period (V23-V37), ET, UV, and Safety F/u Period (801-802) 
For procedures at Screening Period I (V1-V2) and Treatment Period II (V3-V22), please see Section 1.3.1 
 
 
 
 
Study Period II - Treatment Period 
Study 
Period III 
Safety F/u 
Comments  
Visit Number 
23 
24 
25 
26 
27 
28 
29 
30 
31  
32 
33 
34 
35 
36 
37 
ET 
UV 
801 
802 
 
Weeks from Randomization 
28 
32 
36 
40 
44 
48 
50 
52 
60 
64 
68 
72 
74 
76 
78 
— 
— 
80 
83 
 
Visit Interval Tolerance 
(days) 
±7 
±7 
±7 
±3 
±7 
±3 
±7 
±7 
±7 
±3 
±7 
±3 
— 
— 
+7 
±7 
 
Fasting or Telehealth Visit 
T 
F 
T 
a 
T 
F 
T 
F 
T 
a 
T 
F 
F 
 
T 
F 
T = telehealth 
visit; F = fasting 
visit; asee below 
notes 
Assess study intervention 
compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Participant returns unused 
study drug  
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
Abbreviations: ADA = antidrug antibody; BG = blood glucose; CGM = continuous glucose monitoring; CKD-EPI = Chronic Kidney Disease-Epidemiology 
Collaboration equation; CV = cardiovascular; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; FBG = fasting 
blood glucose; FGM = flash glucose monitoring; F/u = follow-up; IWRS = interactive web-response system; PI = Principal Investigator; SMBG = self-
monitoring of blood glucose; UACR = urinary albumin/creatine ratio; UV = unscheduled visit: V = visit; WOCBP = women of childbearing potential. 
 
Notes: 
 Visit 1 (Week -3) procedures may be conducted over more than 1 day if all activities are completed within 3 days. 
 Visit Interval - The visit intervals including the allowable visit window should be scheduled relative to randomization. 
 Visit 3 (Week 0) should occur 11-17 days after Visit 2. 
 A local urine pregnancy test must be performed at Visit 3 (Week 0) with the result available prior to randomization and first 
injection of study drug(s) for women of childbearing potential only. Additional pregnancy tests (beyond those required per 
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28 
SoA) should be performed at any time during the trial if a menstrual period is missed, there is clinical suspicion of pregnancy, 
or as required by local law or regulation. 
 Visit 3 (Week 0) - ADA sample should be collected pre-dose administration for all randomly assigned participants. 
 Visit 3 (Week 0) (randomization) - LY3209590 or insulin degludec will be administered during the study visit by site 
personnel. 
 Visit 3 (Week 0) – PK sample should be collected at least 15 minutes post-dose. Dose amount and time should be recorded 
immediately after dose administration in the participant’s e-diary. 
 Visit 4 (Week 1) - weekly dose of LY3209590 will be administered by the participant during the study visit under observation 
of site personnel. The insulin dose amount and time is recorded for all doses. 
 PK sampling– after Visit 3 may be collected at any time during the visit 
 
aVisit 9 (Week 6), Visit 28 (Week 48), and Visit 35 (Week 74) are eligible to be conducted remotely (that is, by telehealth visit 
in combination with mobile healthcare), as directed by the sponsor and allowed by local laws and regulations. 
 Fasting “Visits” - participants should not eat or drink anything but water for a minimum of 8 hours before the visit. If a 
participant attends these visits in a non-fasting state, the sample should still be collected as non-fasting. This will not be 
considered a protocol deviation. 
 CGM Visits – CGM collection should allow an interval of approximately14 days during the lead-in period and approximately 
28 days for subsequent sessions post randomization. During the study blinded CGM sessions, only the study CGM device may 
be worn. Participants who routinely use personal CGM/FGM at study entry may not wear a personal CGM/FGM during the 
study required blinded CGM sessions. Refer to Section 8.1.5.2. 
 Telehealth visit – may be telephone or other technology. 
 Unscheduled visits may occur at any time during the study. 
 Grey shaded columns denote Telehealth Visits. 
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2. 
Introduction 
2.1. 
Study Rationale 
LY3209590 is a long-acting insulin receptor agonist in development for the treatment of 
hyperglycemia in patients with T2D and T1D. It has an extended half-life of 17 days, enabling 
once-weekly dosing. 
This Phase 3 study of LY3209590 will evaluate the effects of once-weekly administration of 
LY3209590 on glycemic control compared with daily administration of insulin degludec (U100) 
in adult participants with T2D treated with basal insulin with or without allowed non-insulin 
antihyperglycemic therapies. 
2.2. 
Background 
More than 50% of patients with T2D on basal insulin do not meet the target HbA1c (<7%) and 
clinical inertia, a failure to intensify titration to achieve an optimal basal insulin dose, contributes 
to poor glycemic control (Berard et al. 2018, Mocarski et al. 2018). Clinical inertia may result 
from physician concerns about managing the complex care needs of the patient with T2D or 
limited understanding of treatment algorithms (Berard et al. 2018). Additionally, optimizing 
basal insulin therapy doses may be negatively influenced by provider considerations of patient 
fears of side effects such as hypoglycemia, weight gain, or complex treatment regimens, as well 
as poor adherence by patients (Mocarski et al. 2018). A delay in treatment intensification has 
been shown to significantly increase the risk for cardiovascular events and diabetes-related 
complications, yet studies indicate that treatment intensification in T2D patients with poor 
glycemic control may take several years (Okemah et al. 2018). Therefore, 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. 
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. It was designed as a 
divalent (dimer) insulin receptor agonist consisting of a single-chain insulin analog (comprised 
of an insulin B-chain analog, a short peptide linker, and an insulin A-chain analog) fused to a 
second peptide linker that is fused to an unmodified human IgG2 Fc domain. LY3209590 has a 
mean half-life of approximately 17 days and a peak-to-trough PK profile of 1.14. The low peak-
to-trough ratio and extended half-life of LY3209590 support once-weekly dosing and have the 
potential to decrease patient burden, overcome barriers to initiation of insulin therapy, and may 
improve glycemic control and quality of life for patients with T2D compared to other daily basal 
insulins that require daily administration. 
Phase 1 and Phase 2 studies have been completed to assess the PK/PD, safety, and efficacy of 
LY3209590. The PK of LY3209590 was characterized in Phase 1 with a single-ascending dose 
study that demonstrated clear evidence of glucose-lowering with prolonged time-action profile, 
that supports once-weekly administration. The multiple-ascending study used a single loading 
dose that was 3 times the initial weekly dose and demonstrated comparable exposure in 1 week 
to that observed at Week 6 with once-weekly dosing (1/3 of the loading dose, delivered once 
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weekly). The first Phase 2 Study BDCM has completed and evaluated the efficacy and safety of 
LY3209590 compared with insulin degludec (U100) in participants with T2D previously treated 
with basal insulin with or without other allowed non-insulin-lowering medications. Participants 
were randomly assigned (N = 399) to 1 of 2 dosing algorithms for LY3209590 or to daily 
administration of insulin degludec in a 1:1:1 ratio. 
As Study BDCM was the first Phase 2 study of LY3209590, 2 dosing algorithms for LY3209590 
were evaluated: Algorithm 1, with a titration target of FBG ≤140 mg/dL (7.7 mmol/L) with 
titration every 2 weeks and Algorithm 2 with an FBG target of 120 mg/dL (6.6 mmol/L) and 
titration every 4 weeks. For both dosing algorithms, a one-time loading dose of approximately 
3 times the weekly dose was given, in order to reach steady-state insulin concentrations during 
the first week and avoid breakthrough hyperglycemia during transition from previous daily 
insulin to weekly basal insulin. Titration was based on median FBG values from the previous 
week and any occurrence of hypoglycemic events. Participants assigned to insulin degludec were 
dosed daily per a modified Riddle algorithm (Riddle et al. 2003) with titration target of FBG 
≤100 mg/dL (5.5 mmol/L). 
Results of Study BDCM demonstrated that following 32 weeks of treatment, LY3209590 
effectively and safely improved glycemic control, comparable to insulin degludec. LY3209590 
was non-inferior to insulin degludec with change in HbA1c from baseline to Week 32 for both 
Algorithms 1 and 2 with significant improvement in HbA1c in all treatment groups. The risk of 
all documented and nocturnal hypoglycemia (with blood glucose ≤70 mg/dL [3.9 mmol/L]) was 
statistically significantly lower (20% to 40%) for both LY groups compared to insulin degludec 
consistent with higher fasting glucose values observed with LY3209590. The reported TEAEs 
were balanced across the 3 treatment groups. Other safety measures including cardiovascular 
events, hepatic disorder events, injection-site and hypersensitivity reactions, immunogenicity, 
and treatment-emergent SAEs did not indicate an increased risk of safety with LY3209590 
treatment compared to insulin degludec. Thus, the findings in Study BDCM support continued 
development of LY3209590 as a treatment for diabetes mellitus. 
The objective of this Phase 3 study (BDCU) is to evaluate the efficacy and safety of LY3209590 
as a weekly basal insulin compared to insulin degludec (daily basal insulin) using target FBG 
values of 80–120 mg/dL (4.4–6.6 mmol/L) in participants with T2D currently treated with basal 
insulin. 
2.3. 
Benefit/Risk Assessment 
The potential risks associated with LY3209590 include hypoglycemia, systemic allergic 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 
of LY3209590 would be similar to those of other insulins’ actions. Safety data available to date 
in Study BDCM suggest that there is no increased risk to participants’ safety LY3209590 
treatment compared to insulin degludec. 
Considering the measures taken to minimize risk to participants in this study, the potential risks 
identified in association with LY3209590 are justified by the benefits that may be offered to 
participants with T2D, which includes weekly administration, more consistent glycemic control, 
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31 
and frequent engagement with health care providers during the study which provide 
opportunities for coaching and support. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3209590 may be found in the IB. 
Instructions for the transition from prestudy daily insulin doses and the titration algorithms (see 
Section 6.1) were developed to safely and efficiently initiate and guide LY3209590 and insulin 
degludec dose adjustments to achieve the same glycemic goals (FBG between 80 and 120 mg/dL 
[4.4 and 6.6 mmol/L]) while minimizing hypoglycemia risk. 
2.3.1. 
Protocol Risk Mitigation Factors 
An important feature of the study is the provision of an e-diary to each participant. The study-
provided glucometer will wirelessly transfer participant SMBG to the e-diary. In addition, 
participants will record insulin dosing information and details related to any occurrence of 
hypoglycemia in the e-diary. 
At Visit 2 (Week -2), 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 BG samples collected between study visits. 
A web-interface and reporting system will be available for use by site personnel to view 
participant electronic diary (e-diary), 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 (requiring assistance due 
to neurological impairment) in the e-diary. The dosing algorithm used in the study requires 
consideration and adjustment of insulin dosing by the investigator based on participant FBG and 
hypoglycemia events. As modifications of the basal insulin dose may be influenced by other 
clinical circumstances or safety considerations known to the investigator, the investigator may 
prescribe a dose other than the algorithm recommended dose. If the investigator prescribes a 
dose other than the algorithm recommended dose, the investigator is responsible for 
documenting the clinical rationale for the prescribed dose. 
Investigative site personnel will be thoroughly trained on the protocol design elements, 
inclusion/exclusion criteria, and study conduct. Any alerts received, for patient-reported events 
requiring assistance or treatment/outcomes that may be indicative of severe hypoglycemia will 
be reviewed and reported (Section 8.3.3). 
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3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
 To investigate the hypothesis that 
LY3209590 is noninferior to the 
comparator (insulin degludec) on 
glycemic control in study 
participants with T2D currently on 
basal insulin 
 Change from baseline in HbA1c at Week 26 
Key Secondary (Multiplicity Adjusted) 
 To demonstrate LY3209590 is 
superior to insulin degludec in the 
selected parameters of glycemic 
control 
 Change from baseline in HbA1c at Week 26 
 The event rate of participant-reported clinically significant 
nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) 
during treatment phase up to Week 78 
 Time in glucose range between 70 and 180 mg/dL (3.9 and 
10.0 mmol/L) inclusive measured during the CGM session 
prior to Week 26 
Other Secondary 
 To investigate the efficacy of 
LY3209590 compared with insulin 
degludec in additional parameters of 
glycemic control 
 Change from baseline in HbA1c at Weeks 52 and 78 
 Change from baseline in fasting glucose measured by SMBG 
at Weeks 26, 52, and 78 
 Glucose variability measured during the CGM session prior to 
Weeks 26, 52, and 78 
 Time in glucose range between 70 and 180 mg/dL (3.9 and 
10.0 mmol/L) inclusive measured during the CGM session 
prior to Weeks 52 and 78 
 Insulin dose at Weeks 26, 52, and 78 
 To investigate the safety of 
LY3209590 compared with insulin 
degludec 
 Incidence and rate of composite of Level 2 and 3 
hypoglycemia events during treatment period 
 Body weight change from baseline to Weeks 26, 52, and 78 
 Time in hypoglycemia with glucose <54 mg/dL (3.0 mmol/L) 
measured during the CGM session prior to Weeks 26, 52, and 
78 
 Time in hyperglycemia range defined as glucose >180 mg/dL 
(10.0 mmol/L) measured during the CGM session prior to 
Weeks 26, 52, and 78 
 To evaluate treatment impact 
between LY3209590 and insulin 
degludec based on patient-reported 
outcomes questionnaires 
 Change from baseline in TRIM-D at Weeks 26, 52, and 78 
 DTSQ change from baseline at Weeks 26, 52, and 78 
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33 
Tertiary  
 To investigate the treatment impact 
of LY3209590 compared with 
insulin degludec on other measures 
of efficacy, safety, PK/PD, and 
patient-reported outcomes 
 
Efficacy 
 Percentage of participants achieving HbA1c <7% at Weeks 
26, 52, and 78 
 Percentage of participants achieving HbA1c <7% at Week 26 
without nocturnal hypoglycemia during treatment phase up to 
Week 26 
 Percentage of participants achieving HbA1c ≤6.5% at Weeks 
26, 52, and 78 
 Change from baseline in fasting serum glucose at Weeks 26, 
52, and 78 
Safety 
 Incidence and rate of Level 2 hypoglycemia events during 
treatment period 
 Incidence and rate of Level 3 hypoglycemia events during 
treatment period 
 Incidence of positive treatment-emergent antibody of 
LY3209590 
PK/PD 
 
LY3209590 PK and concentration-response relationships to 
key safety and efficacy measures 
 
Potential intrinsic and extrinsic factors  
Patient-Reported Outcomes 
 Change from baseline in SIM-Q at Week 26 
 Frequency of responses to “Basal Insulin Experience: 
Likelihood of incorporating into routine” at Weeks 26 and 78 
 Frequency of responses to “Basal Insulin Experience: 
Preference” at Weeks 26 and 78 
 Change from baseline in EQ-5D-5L at Weeks 26, 52, and 78 
Abbreviations: DTSQ = Diabetes Treatment Satisfaction Questionnaire – change version; CGM = continuous 
glucose monitoring; HbA1c = Hemoglobin A1c; SMBG = self-monitoring of blood glucose; SIM-Q = Simplicity 
Questionnaire; T2D = type 2 diabetes; TRIM-D = Treatment-Related Impact Measure – Diabetes 
Primary Estimand (for primary objective) 
US registration 
The primary clinical question of interest is: What is the treatment difference between 
LY3209590 and insulin degludec in change from baseline to Week 26 in HbA1c in the study-
eligible participants with T2D currently on basal insulin regardless of treatment discontinuation 
for any reason and regardless of initiation of rescue medication? 
The treatment regimen estimand will be used for the primary objective and is described by the 
following attributes: 
 Treatment condition: randomized treatment regardless of treatment discontinuation and 
use of rescue medications 
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 Population: targeted study population (see Section 9.2 for details) 
 Endpoint: change from baseline to Week 26 in HbA1c 
 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 
 Population-level summary: difference in mean changes between treatment conditions 
 
Rationale for estimand: The treatment regimen estimand estimates how participants with T2D 
are treated in clinical practice and takes into account both efficacy and safety. 
 
Registration for other countries 
The primary clinical question of interest is: What is the treatment difference between 
LY3209590 and insulin degludec in change from baseline to Visit 22 (Week 26) in HbA1c in the 
study-eligible participants with T2D currently on basal insulin and adherent to the randomized 
treatment without intercurrent events during the study treatment period? 
The efficacy estimand will be used for the primary objective and is described by the following 
attributes: 
 Treatment condition: randomized treatment 
 Population: targeted study population (see Section 9.2 for details) 
 Endpoint: change from baseline to Visit 22 (Week 26) in HbA1c 
 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 
 Population-level summary: difference in mean changes between treatment conditions 
 
Rationale for estimand: The treatment 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 22 (Week 26) in HbA1c will also be based 
on the primary estimands described above. 
The time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive measured 
by CGM and collected during the CGM session prior to Visit 22 (Week 26) will also use 
treatment regimen estimated for US registration and efficacy estimand for other countries. 
The participant-reported clinically significant nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] 
or severe) is one of the safety measures for the study. The event rate will be based on all 
available data during the specific analysis period. Relative rate between randomized treatment 
groups will be used for treatment comparison. 
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4. 
Study Design 
4.1. 
Overall Design 
Study BDCU is a Phase 3, multicenter, randomized, open-label, comparator-controlled study to 
evaluate the efficacy and safety of once-weekly basal insulin (LY3209590) compared to insulin 
degludec in participants with T2D treated with basal insulin. 
The study includes a 3-week screening/lead-in period, a 78-week treatment period, and a 5-week 
safety follow-up period. 
Participants will continue prior stable diabetes therapy with 0 to 3 allowed non-insulin 
antihyperglycemic medications during the study. 
Participants will discontinue their previous basal insulin doses at randomization and will be 
assigned to either LY3209590 or insulin degludec U100. The initial dose for the study treatment 
will be determined as described in Section 6.1. 
4.1.1. 
Design Outline 
Study Period I: Screening and Lead-In 
Visit 1 (Week -3): Screening 
Interested participants will sign the appropriate informed consent document(s) prior to initiating 
any procedures. 
The investigator will review symptoms, risk factors, and other non-invasive inclusion and 
exclusion criteria prior to any invasive procedures. If the participant is eligible after this review, 
then the site will perform the invasive procedures to confirm eligibility. 
Visit 2 (Week -2): Lead-In 
Participants will receive their e-diary, BGM, and the Dexcom G6® CGM system. 
Participants will receive training on 
 diabetes self-monitoring and management 
 BGM 
 CGM 
 electronic study diaries, and 
 study requirements. 
Eligibility for the study will be based on participant medical history, physical examination, 
laboratory values, and results of procedures as listed in the SoA. Participant eligibility to 
participate in the study must be confirmed prior to inclusion in the study (see Sections 5.1 and 
5.2). A participant e-diary and BGM will be dispensed at Visit 2 (Week -2), and e-diary 
compliance checks will occur for future visits as specified in the SoA (Section 1.3). Concomitant 
Meds, AEs, including hypoglycemia events, required questionnaires, and other study procedures 
are to be performed and recorded as outlined in the SoA. Participants will continue their current 
insulin therapy until randomization and record the insulin doses in the e-diary. The Dexcom G6 
CGM sensor will be inserted at Visit 2 (Week -2), and participants will be required to wear the 
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sensor and insert a new sensor when indicated and keep the receiver within 20 feet to minimize 
data loss until Visit 3 (Week 0). The CGM will be blinded to both participants and the 
investigator (Section 8.1.5.2). 
Study Period II Treatment Period 
Visit 3 (Week 0): Randomization 
Entry criteria for study enrollment (Sections 5.1 and 5.2) will be confirmed before 
randomization. Participants meeting enrollment criteria will be randomly assigned to one of 
these treatments 
 LY3209590: once-weekly administration, or 
 insulin degludec: once-daily administration. 
All measures except PK, to be performed at Visit 3 (Week 0) (see SoA, Section 1.3) should be 
done prior to injection of the study participant’s assigned IP to ensure that appropriate baseline 
measurements are obtained. PK will be performed postdose. A local urine and serum pregnancy 
test will be done before IP administration. If the local urine pregnancy test is negative, the study 
participant will begin IP. If the result of the local urine pregnancy test is positive, the study 
participant will be considered a screen failure (see SoA Section 1.3). 
Blinded CGM will continue at Visit 3 (Week 0) for an additional four-week period and 
periodically as described in the SoA. Please see Section 8.1.5.2 for specific details on CGM. 
The first dose of both LY3209590 and insulin degludec U100 will be administered by site 
personnel. Participants assigned to insulin degludec will continue daily administration after Visit 
3 (Week 0). Participants will continue to record their insulin doses in the e-diary throughout the 
study. 
Visit 4 (Week 1) 
Participants assigned to LY3209590 will administer their second dose at Visit 4 (Week 1), at the 
site, under observation of site personnel and document the dose administered in the e-diary 
before leaving the site. 
Visit 5 (Week 2) - Visit 37 (Week 78) 
Participants assigned to LY3209590 will administer their weekly doses during the remaining 
treatment period. Non-insulin antihyperglycemic medications will be continued after 
randomization. Study participants must measure their FBG levels each day when possible or at a 
minimum 3 times per week. The participant’s FBG will be used to titrate basal insulin dose 
adjustments throughout the study based on the study titration algorithm (Section 6.1.3). Blinded 
CGM will be worn by participants at designated weeks (SoA Section 1.3, Section 8.1.5.2). 
Concomitant Meds, AEs, including hypoglycemia events, required questionnaires, diary 
compliance, and other study procedures will be recorded and completed as outlined in the SoA. 
The last dose of LY3209590 will be administered in the week prior to Visit 37 (Week 78), and 
the last dose of insulin degludec will be administered a day prior to Visit 37 (Week 78). 
Comprehensive efficacy and safety evaluations will be conducted through the end of the 
treatment period. 
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Randomly assigned participants who are discontinued from IP before the end of the treatment 
period at Visit 37 (Week 78) are encouraged to remain in the study for continued monitoring. 
Both efficacy and safety data will be collected as indicated in the SoA after the early 
discontinuation of IP. 
Study Period III: Safety Follow-up Period 
After the completion of the treatment period, study participants will begin their prestudy basal 
insulin, or a non-study basal insulin as specified by the investigator based on the instructions for 
transitioning to a non-study basal insulin (see Section 6.8.5.1). Current non-insulin 
antihyperglycemic medications will be continued. Investigators will prescribe and document the 
prescribed insulin dose during the safety follow up-period in the eCRF. 
Study participants must measure their FBG levels each day when possible or at a minimum 
3 times per week. Participants will collect blinded CGM for 4-weeks, and the site will download 
the CGM data at Visit 802. 
Study participants will return unused study drug and study devices to the investigative site at the 
final study visit. 
ET Visit 
An ET visit is conducted when the participant discontinues treatment and will not continue the 
remaining visits in the treatment period. Participants should complete an ET visit in a fasting 
state. If a participant is wearing a CGM at the time of ET, the CGM data will be uploaded at the 
ET visit. Following an ET visit, the participant can continue to the safety follow-up period for 
participant safety monitoring. 
4.2. 
Scientific Rationale for Study Design 
This study will evaluate the efficacy and safety of once-weekly basal insulin LY3209590 
compared to once-daily insulin degludec in adult participants with T2D already treated with 
basal insulin. A 2:1 randomization ratio of LY3209590: insulin degludec will allocate more 
participants for safety and exposure information to the LY3209590 treatment group. The 78-
week treatment period provides collection of more efficacy and safety information for the 
experimental treatment. Insulin doses will be titrated to the same FBG targets of 80–120 mg/dL 
(4.4–6.6 mmol/L) for both treatment groups. 
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. 
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. The primary 
endpoint at Visit 22 (Week 26) is based on participants reaching stable insulin dose by 
8 to 12 weeks and achieve glycemic stability in advance of the 26-week primary endpoint. The 
secondary objectives provide complementary information about glycemic control. 
Hypoglycemia, AEs, and immunogenicity will be assessed to characterize safety. 
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38 
Race and Ethnicity 
In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. 
4.3. 
Justification for Dose 
The IP used in this Phase 3 study will be in insulin units delivered via prefilled pens using the 
dosing algorithm provided in Section 6.1. The dosing guidance for starting doses and dose 
titrations of LY3209590 is derived based on findings from Phase 2 studies and model-based 
simulations. These data informed dosing increments designed to balance the goal of achieving a 
balanced FBG target range and minimize occurrence of hypoglycemia. 
Justification for the LY3209590 single loading dose 
Following a once-weekly subcutaneous administration of LY3209590, the time to reach steady-
state PK without a loading dose is estimated to be between 8 and 10 weeks based on the long 
half-life of LY3209590. With a loading dose, the estimated time to reach steady state is within 2-
3-weeks. Participants randomly assigned to LY3209590 with median FBG >120 mg/dL 
(6.6 mmol/L) will receive a single loading dose of LY3209590 that is 3-times the weekly dose 
calculated from their previous daily basal insulin dose multiplied by 7 (see Section 6.1). This 
strategy was designed to minimize loss of glycemic control when transitioning from the shorter 
duration once-daily basal insulins to a weekly insulin. This approach is supported by findings in 
the multiple-ascending dose Study BDCB, the Phase 2 Study BDCM, and model-based 
simulations. 
For participants who are entering the study in good glycemic control 
(FBG ≤120 mg/dL [6.6 mmol/L]), a loading dose is not recommended. In such cases, treatment 
should be started using the weekly dose calculated from their previous daily basal insulin dose 
multiplied by 7 (see Section 6.1). 
Directions for conversion of the prior daily basal insulin dose to the LY3209590 weekly dose are 
described in Section 6.1. The method to calculate the one-time loading dose and the titration 
rules to be used beginning at Visit 5 (Week 2) are also described in Section 6.1. 
Justification for the insulin degludec starting dose 
The starting dose for insulin degludec (U100) is the same as the daily dose of basal insulin the 
participant was taking prior to Visit 3 (Week 0). Insulin degludec will be titrated to achieve FBG 
target of 80-120 mg/dL (4.4-6.6 mmol/L) using an algorithm that is patterned after the well-
established Riddle algorithm and other published algorithms (Meneghini et al. 2007, Kadowaki 
et al. 2017) but modified to balance efficacy and hypoglycemia for the same FBG targets as 
LY3209590 (Section 6.1). 
Safety of study participants will be closely monitored during the early stages of dose titration to 
determine whether adjustments to the dose are needed to safely achieve FBG targets of 80-
120 mg/dL (4.4-6.6 mmol/L) and will continue throughout the study (See Section 6.1). 
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4.4. 
End of Study Definition 
The end of the study is defined as the date of last scheduled procedure shown in the SoA for the 
last participant in the trial. 
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 the following criteria apply: 
Age 
1. 
Are at least 18 years of age at screening (or older per local regulations) 
Type of Participant and Disease Characteristics 
2. 
Have a diagnosis of T2D according to the WHO criteria currently treated with basal 
insulin 
3. 
Are receiving ≥10 units of basal insulin per day and ≤110 units/day at screening 
4. 
Have HbA1c value 6.5%-10% inclusive, as determined by central laboratory at screening 
5. 
Have been treated with a stable regimen in the opinion of the investigator of one of the 
following insulin regimens (includes biosimilars) used according to local product label 
with or without non-insulin diabetes therapy for at least 90 days prior to screening: 
- 
once-daily U100 or U200 insulin degludec 
- 
once-daily U100 or U300 insulin glargine 
- 
once or twice-daily U100 insulin detemir (Levemir [Novo Nordisk A/S., Bagsvaerd, 
Denmark]), or 
- 
once or twice-daily human insulin NPH. 
Acceptable non-insulin diabetes therapies may include 0 to up to 3 of the following: 
- 
dipeptidyl peptidase (DPP-4) IV inhibitors 
- 
SGLT2 inhibitors 
- 
metformin 
- 
alpha-glucosidase inhibitors, or 
- 
GLP-1 receptor agonists. 
Note: All non-insulin diabetes therapies must be used in accordance with the 
corresponding local product label at the time of screening, and participants should be 
willing to continue stable dosing throughout the study according to the protocol. 
Weight 
6. 
Have a body mass index less than or equal to 45 kg/m
2, at screening 
Participant Protocol Compliance 
7. 
Have a usual wake/sleep pattern such that midnight to 0600 hours will reliably reflect a 
usual sleeping period 
8. 
In the investigator’s opinion, are well-motivated, capable, and willing to 
 reliably take study-provided insulin injections as directed and other diabetes 
medications as required for this protocol. 
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o visually impaired persons who are not able to perform the injections must 
have the assistance of a sighted individual trained to inject the IP 
o persons with physical limitations who are not able to perform the injections 
must have the assistance of an individual trained to inject the IP 
 maintain an electronic study diary and use only the glucometer supplied for use in the 
study, including recording information on insulin doses and hypoglycemia events in 
the e-diary as required for this protocol 
 wear the blinded continuous glucose-monitoring device supplied for use in this study 
at the specified times during the study and maintain proximity within 20 feet of the 
CGM receiver as required in the SoA and Section 8.1.5.2. Note: Participants who are 
already using CGM or FGM at study entry will be allowed to continue to use their 
personal CGM/FGM during the study when not wearing the study CGM. Participants 
must use the study-provided glucometer for all FBG values and any other BG values 
reported during the study 
 not wear a personal CGM/FGM during the study blinded CGM assessments 
 not initiate the use of personal CGM/FGM if not already routinely using CGM/FGM 
at study entry. 
Sex and Contraceptive/Barrier Requirements 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
9. 
Male participants: No male contraception required except in compliance with specific 
local government study requirements. See the requirements in Section 10.4, Appendix 4. 
10. 
Female participants: See the requirements in Section 10.4, Appendix 4. 
Informed Consent 
11. 
Capable of giving signed informed consent as described in Section 10.1, Appendix 1, 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria applies: 
Medical Conditions 
12. 
Have had a significant weight gain or loss in the past 3 months in the investigator’s 
opinion (for example, ≥5%) 
13. 
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, drug-
induced or chemical-induced diabetes) 
14. 
Are currently receiving or have received any time in the past 6 months, any of the 
following insulin therapies (outside of pregnancy) prior to screening, except for short-
term treatment of acute conditions, and up to a maximum of 4 continuous weeks: 
- 
prandial insulin 
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- 
insulin mixtures 
- 
inhaled insulin 
- 
U-500 insulin, or 
- 
continuous subcutaneous insulin infusion therapy 
Note: Insulin use of any type or of any duration during a previous pregnancy is not 
considered an exclusion criterion. 
15. 
Have received any of the following nonallowed diabetes medications within 90 days prior 
to screening: glinides, sulfonylureas, pramlintide, or thiazolidinediones 
16. 
Have a history of greater than 1 episode of ketoacidosis or hyperosmolar state/coma 
requiring hospitalization in the 6 months prior to screening 
Prior/Concomitant Therapy 
17. 
Are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding replacement 
therapy for adrenal insufficiency; topical, intraocular, intranasal, or inhaled preparations 
or intra-articular injection) or have received such therapy for >14 days within the month 
preceding screening 
Prior/Concurrent Clinical Study Experience 
18. 
Are currently enrolled in any other clinical study involving an IP or any other type of 
medical research, judged not to be scientifically or medically compatible with this study 
19. 
Have participated, within the last 30 days in a clinical trial involving an IP. If the 
previous IP has a long half-life, 3 months or 5 half-lives (whichever is longer) should 
have passed prior to Visit 1 (Week -3) 
20. 
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 
21. 
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 
22. 
Are Eli Lilly and Company employees or are employees of any third party involved in 
the study who require exclusion of their employees. 
Diagnostic Assessments 
23. 
Cardiovascular: have had New York Heart Association Class IV heart failure or any of 
the following CV conditions in the past 3 months prior to screening: 
 acute myocardial infarction, 
 cerebrovascular accident (stroke), or 
 coronary bypass surgery. 
24. 
Gastrointestinal: have undergone gastric bypass (bariatric) surgery, restrictive bariatric 
surgery (for example, Lap-Band®), or sleeve gastrectomy within 1 year prior to screening 
25. 
Hepatic: have acute or chronic hepatitis, cirrhosis, or obvious clinical signs or symptoms 
of any other liver disease, except NAFLD (that is, study participants with NAFLD are 
eligible for participation), and/or 
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 have elevated liver enzyme measurements, as determined by the central laboratory at 
screening and as indicated below: 
o total bilirubin >2x the ULN (except for participants with Gilbert’s syndrome) 
o ALT/serum glutamic pyruvic transaminase >3x ULN 
o AST/serum glutamic oxaloacetic transaminase >3x ULN, or 
o ALP >2.5x ULN 
26. 
Renal: have a history of renal transplantation, are currently receiving renal dialysis, or 
have an eGFR <20 mL/min/1.73 m
2, calculated by the CKD-EPI equation, as determined 
by the central laboratory at screening 
27. 
Have active or untreated malignancy, have been in remission from clinically significant 
malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years, or 
are at increased risk for developing cancer or a recurrence of cancer in the opinion of the 
investigator 
28. 
Have known hypersensitivity or allergy to any of the study medications or their 
excipients 
29. 
Have any other serious disease or condition (for example, known drug or alcohol abuse 
or psychiatric disorder) that, in the opinion of the investigator, would pose a significant 
risk to the study participant, preclude the study participant from following and 
completing the protocol 
30. 
Have evidence of a current or recent, within 6 months’ time frame, history of any 
substance use disorder(s) of any severity as defined by the Diagnostic and Statistical 
Manual of Mental Disorders-5 (DSM-5) in the opinion of the investigator, except 
disorders of nicotine or caffeine use 
31. 
Hematologic: have had a blood transfusion or severe blood loss within 90 days prior to 
Visit 1 (Week -3) or have known hemoglobinopathy, hemolytic anemia or sickle cell 
anemia, or any other traits of hemoglobin abnormalities known to interfere with the 
measurement of HbA1c in the opinion of the investigator 
32. 
Women of childbearing potential (for example, not surgically sterilized and between 
menarche and 1-year postmenopausal) who 
- 
are pregnant or intend to become pregnant during the study 
- 
are lactating/breastfeeding (including the use of a breast pump) 
- 
are unwilling to remain abstinent or use birth control, and 
- 
test positive for pregnancy at the time of screening (Visit 1 [Week -3] or any time 
before randomization). 
Note: a urine pregnancy test is conducted at Visit 3 (Week 0), and randomization will not 
be allowed with a positive result. 
5.3. 
Lifestyle Considerations 
Per the SoA (Section 1.3), qualified site staff will provide diabetes management counseling, 
which will include instructions on diet and exercise and education about the signs, symptoms, 
and treatment of hypoglycemia, should it occur. Study participants should continue their usual 
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exercise habits and generally follow a healthy meal plan throughout the course of the study. 
Diabetes self-management counseling may be reviewed throughout the study, as needed. 
Study participants should not initiate an intensive diet/exercise program with the intent of 
reducing body weight at any time during the study, other than the lifestyle and dietary measures 
for diabetes treatment. 
Study participants should be instructed not to donate blood or blood products during the study or 
for 4 weeks following the study. 
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 for 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/used by a study participant 
according to the study protocol. 
Investigators and other study team members 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/national standards of care for diabetes, the investigators 
should follow current published standards of care from the American Diabetes Association 
(ADA 2021). 
Site Responsibilities Related to Study Drugs 
The investigator or their designee is responsible for the following: 
 explaining the correct use and storage of the study drug to the participant and 
verifying those instructions are followed properly 
 using the dosing algorithm to assess and titrate the doses weekly for the first 
12 weeks and at least monthly throughout the remainder of the study 
 maintaining accurate records of IP dispensing, and 
 collecting of all unused study medication at the end of the study, returning it to 
Lilly, or designee, unless the sponsor and sites have agreed all unused medication 
is to be destroyed by the site, as allowed by local law. 
6.1. 
Study Intervention(s) Administered 
This table lists the interventions used in this clinical study. 
Intervention Name 
LY3209590 
Insulin Degludec 
Type 
Drug 
Drug 
Dosage Formulation 
Solution 
Solution 
Unit Dose Strength(s) 
500 units/mL 
100 units/mL 
Dosage Levels 
Individualized dosing 
Individualized dosing 
Frequency of Administration 
Once weekly 
Once daily 
Routes of Administration 
Subcutaneous 
Subcutaneous 
Use 
Experimental 
Active comparator 
IMP  
IMP 
IMP 
Sourcing  
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Abbreviation: IMP = Investigational Medicinal Product. 
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. 
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6.1.1. 
Medical Devices 
1. Provided for use in this study are the prefilled pen injectors, for the delivery and 
administration of either LY3209590 or insulin degludec. 
2. Instructions for device use and storage requirements are provided in the “Instructions for 
Use.” 
3. All Product Complaints, including malfunction, use error, and inadequate labeling, shall 
be documented and reported by the investigator throughout the study (see Section 8.3) 
and appropriately managed by the sponsor. 
6.1.2. 
LY3209590 and Insulin Degludec Dosing 
Frequency of Dosing with LY3209590 and Insulin Degludec 
LY3209590 will be administered once weekly at approximately the same time and day each 
week using an insulin-prefilled pen (with 5-unit increments). 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 an interval of less than 3 days remains before the next scheduled dose, the missed dose 
should be skipped and the next dose should be administered 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, as long as the last dose has been 
administered at least 3 days earlier. 
Insulin degludec (U100) will be administered daily at approximately the same time each day 
using commercially available insulin-prefilled pens (with 1-unit increments). 
Maximum Units of Dosing with LY3209590 and Insulin Degludec 
For LY3209590, the maximum number of units per injection in the LY3209590-prefilled pen is 
400 units. Doses greater than 400-units a week (approximately 57-units per day of basal insulin 
[57 × 7 days = 399]) will require more than 1 injection. The maximum one-time loading dose for 
this study is 1600-units, and the maximum weekly dose is 1400-units. The maximum doses are 
supported by the current product safety assessment. 
For insulin degludec, the maximum number of units per injection of insulin degludec (U100) is 
80 units. For participants who require >80-units per day, more than 1 injection will be required to 
administer the full daily dose of insulin degludec. 
Anatomical Location of Injections 
For both treatments, participants will be instructed to 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. 
6.1.3. 
General Insulin Dose Considerations for Both Treatment Groups 
Transition to Study Insulins 
The participants’ initial and weekly dose of LY3209590 or daily dose of insulin degludec will be 
determined based on the participant’s usual daily basal insulin dose prior to randomization. The 
starting doses take into consideration the prestudy basal insulin’s label with regards to the ability 
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to do unit-to-unit conversions across insulin types/regimens. For participants whose prestudy 
basal insulin regimens are typically adjusted to the more conventional once-daily (U-100) basal 
insulin regimens (for example, twice-daily NPH or once-daily U-300 glargine), the total daily 
dose is reduced by 20% before multiplying by 7 to obtain the weekly dose equivalent. 
The dosing and titration algorithms to be used will be based on the participant’s treatment 
assignment to either LY3209590 or insulin degludec as described in Sections 6.1.4 and 6.1.5 
respectively. Participants will be instructed to not take their prestudy basal insulin on the day of 
randomization since they will be dosed at the site with the allocated study insulin. 
Insulin Dose Titration and Dose Maintenance 
In this treat-to-target study, both treatment groups will undergo titration to achieve and maintain 
an FBG target within the range of 80-120 mg/dL (4.4-6.6 mmol/L). Active titration will occur in 
both treatment groups between Visits 3 to 15 (Weeks 0 to 12) which will be designated as the 
Titration Period with the goal to achieve insulin dose stabilization by Visit 15 (Week 12) with a 
minimum of monthly adjustments as necessary during the Maintenance Period from Visit 15 to 
37 (Weeks 12 to 78). 
Using the e-diary-linked study-provided glucometer, participants in both treatment groups will 
perform daily self-monitored FBGs. A minimum of 3 FBG readings on separate days each week 
must be obtained so that investigators can review the data to make dose adjustments using the 
titration algorithms for once-weekly or once-daily insulins (Sections 6.1.4 and 6.1.5). The 
median FBG to use in determining the dose adjustments starting at Visit 5 (Week 2) is obtained 
from the 3 most recent FBGs in the previous week. The median is the middle value when the 3 
values are placed in ascending or descending order. For example, if a participant’s FBGs for the 
past 3 consecutive measurements were 180, 202, and 190, the median is 190. 
Note: If the participant has only 2 FBG readings for the week, then the lesser of the 
readings should be used to determine the dose adjustments. If only 1 FBG measurement 
is available, determination if dose is changed using only a single FBG value is at the 
discretion of the investigator. 
When considering any dose adjustments (in either treatment group), the investigator will review 
whether the participant experienced any documented episodes of hypoglycemia. If the participant 
experienced any documented BG ≤70 mg/dL (≤3.9 mmol/L) in the previous week, the dose 
should not be increased. If criteria for hypoglycemia dose reduction are met, the prior week’s 
basal dose is decreased according to the treatment as indicated in the Hypoglycemia Dose 
Reduction Criteria for LY3209590 or the Hypoglycemia Dose Reduction Criteria for Insulin 
Degludec tables below. Investigators are expected to follow the dosing algorithms for the 
protocol; however, modifications of the basal insulin dose may be influenced by other clinical 
circumstances or safety considerations known to the investigator. If the investigator prescribes a 
dose other than the algorithm recommended dose, the investigator is responsible for 
documenting the clinical rationale for the prescribed dose in the Study Works web portal. 
6.1.4. 
LY3209590 Dose Initiation and Modification 
In this section, dosing instructions for LY3209590 are provided for 
 dose initiation at Visit 3 (Week 0) 
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 administration of the weekly dose at Visit 4 (Week 1), and 
 dose titration beginning at Visit 5 (Week 2) and continuing throughout the 
treatment period. 
Note: The first dose is administered by site personnel; subsequent doses are self-
administered. 
Visit 3 – (Week 0): Randomization Visit 
Determine the median FBG from the week prior to randomization (Visit 3 [Week 0]) 
Follow instructions in the LY3209590 Loading Dose Calculation table below for participants 
with FBG >120 mg/dL (6.6 mmol/L) 
Follow instructions in the LY3209590 Starting Weekly Dose Calculation table below for 
participants with FBG ≤120 mg/dL (6.6 mmol/L) 
Note: If a participant is on NPH twice-daily or U300 glargine, the prestudy basal insulin 
dose should be reduced by 20% when determining Usual Daily Dose of the prestudy 
basal insulin before calculating the Starting Weekly Dose. 
LY3209590 Loading Dose Calculation –Participants with FBG >120 mg/dL (6.6 mmol/L) 
Step 
Action 
Example Participant A 
(FBG >120 mg/dL 
[6.6 mmol/L]) 
1.  
Determine usual prior daily basal dose from lead-in period 
30 units/day  
2.  
Calculate Starting Weekly Dose (Usual Daily Dose multiplied by 7 and 
round to nearest 10) 
210 units/Week 
3.  
Multiply Starting Weekly Dose by 3 to determine the Loading Dosea 
630 units Loading Dose 
a The Loading Dose should not exceed a dose of 1600 units. 
If the calculated Loading Dose is >1600 units, the maximum loading dose of 1600 units is given 
as the one-time dose at Visit 3 (Week 0). 
LY3209590 Starting Weekly Dose Calculation – Participants with FBG ≤120 mg/dL 
(6.6 mmol/L) 
Step 
Action 
Example Participant B 
(FBG ≤120 mg/dL 
[6.6 mmol/L]) 
1.  
Review usual prior daily basal dose from lead-in period 
30 units/day 
2.  
Calculate Starting Weekly Dose 
➢ (Usual Daily Dose multiplied by 7 and round to nearest 10) 
210 units/Week 
The maximum weekly dose should not exceed 1400 units. If the calculated weekly dose is 
greater than 1400 units, prescribe only 1400 units. 
Visit 4 (Week 1): Starting Weekly Dose 
If the participant experienced hypoglycemia in the previous week and met any of the criteria for 
a dose reduction listed in the Hypoglycemia Dose Reduction for LY3209590 table below, 
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subtract 40 units from the Starting Weekly Dose to obtain the dose for administration at Visit 4 
(Week 1). 
If the Hypoglycemia Dose Reduction criteria are not met, administer the Starting Weekly Dose. 
CAUTION: DO NOT REPEAT ADMINISTRATION OF THE LOADING DOSE 
Hypoglycemia Dose Reduction for LY3209590 
Hypoglycemia Dose Reduction Criteria 
Based on BG Values  
Unit Dose Decrease  
≥3 episodes ≤70 mg/dL (3.9 mmol/L) 
40 units  
≥1 nocturnal episode ≤70 mg/dL (3.9 mmol/L) 
≥1 episode <54 mg/dL (3.0 mmol/L) 
Any confirmed severe hypoglycemia 
The following steps illustrate an example calculation for Visit 4 (Week 1) of Starting Weekly 
Dose. 
Step 
Action 
Example Participant B 
1. 
Review Starting Weekly Dose from Visit 3 
(Week 0) calculations 
210 units/day 
2. 
Determine if any of Hypoglycemia Dose 
Reduction criteria are met in prior week: 
If yes, subtract 40 units from Starting Weekly 
Dose 
If not, administer Starting Weekly Dose 
a. If a Hypoglycemia Dose Reduction criterion is 
met, 
➢ Week 1 Dose = 210 - 40 = 170 units/week 
b. If no Hypoglycemia Dose Reduction criterion 
was met, the Week 1 Dose=210 units/week 
Visit 5 (Week 2): Titration to Week 77 
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 participant experienced hypoglycemia in the previous week and met criterion for a dose 
reduction as described in the Hypoglycemia Dose Reduction for LY3209590 table above, 
subtract 40 units from the previous weekly dose. 
If no BG ≤70 mg/dL (3.9 mmol/L) was reported, use the median FBG from the previous week to 
obtain the dose adjustment from the titration algorithm in the LY3209590 Dose Adjustment 
Based on Median FBG table below. If participant’s median FBG from the week prior to 
randomization is ≤120 mg/dL (6.6 mmol/L) or prestudy basal insulin dose <20 units/day as 
described below, use dose adjustments that correspond to that column. If the median FBG is 
within the target range from 80 to 120 mg/dL (4.4 to 6.6 mmol/L) inclusive, no change would be 
made to the dose from the previous week. 
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LY3209590 Dose Adjustment Based on Median FBG 
Median FBG  
LY3209590 Dose Adjustment 
Units (U) 
mg/dL 
mmol/L 
When Median FBG ≤120 mg/dL 
(6.6 mmol/L) 
or 
Prestudy Basal Insulin Dose <20 U 
When Median FBG >120 mg/dL (6.6 
mmol/L) Units 
<80 
<4.4 
(–) 20 U  
(–) 20 U  
80–120 
4.4–6.6 
No change to dose 
No change to dose 
121–140 
6.7–7.7 
(+) 10 U  
(+) 20 U  
>140 
>7.7 
(+) 20 U  
(+) 40 U  
(–) = decrease dose; (+) = increase dose 
6.1.5. 
Insulin degludec Dose Initiation and Modification 
In this section, dosing instructions for insulin degludec are provided for 
 dose initiation at Visit 3 (Week 0), and 
 administration of the daily dose at Visit 4 (Week 1) and subsequent dosing/dose 
adjustments throughout the treatment period. 
Note: The first dose is administered by site personnel; subsequent doses are self-administered. 
Visit 3 – (Week 0): Randomization Visit Insulin Degludec Dose Determination from 
Equivalent of Prestudy Insulin Dose 
Follow instructions in the Equivalent Dose of Insulin Degludec table below, to calculate the 
equivalent dose of insulin degludec to be administered by the participant once daily. 
Note: If a participant is on NPH twice-daily or U300 glargine, the prestudy basal insulin dose 
should be reduced by 20% when determining the once-daily dose of insulin degludec to initiate 
in the study. 
Equivalent Dose of Insulin Degludec 
Step 
Action 
Example Participant C 
Prestudy insulin: glargine, 
U100 20 units once-daily 
Example Participant D 
Prestudy insulin: NPH, 10 units twice-
daily 
1. 
Determine usual prior 
daily basal dose from 
lead-in period 
20 units/day 
10 units × 2 = 20 units/day 
2. 
Determine daily dose of 
insulin degludec 
20 units/day 
20 units – [20 × 0.2] units = 20 units – 4 
units = 16 units/day 
Visit 4 (Week 1) to Visit 37 (Week 78) 
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 participant experienced hypoglycemia in the previous week that met dose reduction 
criterion, decrease the daily dose as described in the Hypoglycemia Dose Reduction Criteria for 
Insulin Degludec table below. 
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Hypoglycemia Dose Reduction Criteria for Insulin Degludec 
Hypoglycemia Dose Reduction Criteria 
Based on BG Values 
Unit Dose Decrease 
≥3 episodes of ≤70 mg/dL (≤3.9 mmol/L) 
2–6 units a 
≥1 nocturnal episode ≤70 mg/dL (3.9 mmol/L) 
≥1 episode <54 mg/dL (3.0 mmol/L) 
Any confirmed severe hypoglycemia 
a Dose reductions of 2 or 4 units may occur every 3 days to achieve a gradual weekly reduction of 6 units as 
clinically indicated. 
If hypoglycemia dose reduction criteria are not met, use the median FBG from the previous week 
to obtain the dose adjustment from the titration algorithm in the Insulin Degludec Dose 
Adjustment table below. If the median FBG is within the target range from 80 to 120 mg/dL (4.4 
to 6.6 mmol/L), no change would be made to the dose from the previous week. 
Insulin Degludec Dose Adjustment 
Median FBG 
Insulin Degludec Dose Adjustment  
mg/dL 
mmol/L 
units 
<80 
<4.4 
(-) 3 units (decrease) 
80-120 
4.4-6.6 
No change 
121-140 
6.7-7.7 
(+) 3 units (increase) 
>140  
>7.7 
(+) 6 units (increase) 
6.1.6. 
Management of Hypoglycemia 
At Visit 2 (Week -2), participants who have not screen failed will be trained by authorized site 
personnel about signs and symptoms of hypoglycemia and how to treat hypoglycemia and how 
to document episodes in the e-diary. 
This section provides guidance on management of episodes of hypoglycemic events. For 
effective implementation of measures described here, it is important that participants, and their 
caregivers, if applicable, be well-educated about the signs and symptoms of hypoglycemia (for 
example, intense hunger, sweating, tremor, restlessness, irritability, depression, headaches, 
disturbed sleep, or transient neurological disorders) and its treatment. Participants should be 
instructed how to treat all levels of hypoglycemia and that if they experience an event of severe 
hypoglycemia, they should notify the site as soon as possible after the event has been 
successfully treated (see Section 8.3.3). 
The allowable non-insulin antihyperglycemic medications are not insulin secretagogues; 
therefore, clinically relevant increases in the risk of hypoglycemia due to these medications are 
not expected. To date, effects of LY3209590 on hypoglycemia are not different as compared to 
other basal insulins, so the management of hypoglycemia is similar for the study participants in 
both treatment groups. 
Study participants will be instructed to use standard precautions prior to and during exercise. 
Study participants will be instructed to check their BG, when they experience signs and 
symptoms suggestive of hypoglycemia, and to administer appropriate treatment for when BG 
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≤70 mg/dL (3.9 mmol/L). They will be instructed to recheck BG levels 15 minutes following 
treatment of hypoglycemia and repeat treatment and BG recheck after another 15 minutes until 
the BG level has returned to the target range of 80-120 mg/dL (4.4-6.6 mmol/L) (CDC 2021). 
Instructions will be provided for clinical management of participants who experience frequent or 
repeated hypoglycemia. As necessary, additional instruction/education may be provided to 
participants by investigative staff, including increased BG monitoring, treatment adjustments, or 
other approaches (for example, behavioral interventions and lifestyle modification) to mitigate 
hypoglycemia frequency or severity. 
Investigators should prescribe glucagon to participants, and family members, housemates, or 
support care providers should be educated about glucagon administration. 
In cases where a participant experiences hypoglycemia as described above, to confirm the 
increased risk, the study sites must ensure that the participant has been fully compliant with the 
assigned therapeutic regimen and ensure that there is no evidence of other possible causes of 
hypoglycemia, for example, omission of meal, inadequate meal, and unexpected increase in 
exercise. 
Participants experiencing severe hypoglycemia at any time should be evaluated by the 
investigator to determine if criteria are met for adjustment of the basal insulin based on the 
dosing algorithm (Section 6.1) first and then if needed, consider adjusting current concomitant 
antihyperglycemic medications. If discontinuation of IP is required for hypoglycemia that is 
refractory to decreasing the dose of non-insulin anti-hyperglycemic medications or other 
interventions or there are other safety concerns, the investigator should notify the sponsor and 
complete an AE form, indicating discontinuation of IP related to hypoglycemia. The investigator 
and the Lilly research scientist or physician will determine alternative treatment (if applicable) 
and whether continued participation in study and safety follow-up while not on IP is appropriate. 
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. 
In-use storage conditions must 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 
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intervention. Study participants will be provided with cartons containing the required number of 
pens at clinic visits as shown in the SoA (Section 1.3). 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Investigators and participants will be unblinded to the assigned 
treatment groups. Assignment to treatment groups will be determined by an IWRS. Participants 
will be randomly assigned to 1 of the 2 treatment groups in 2:1 ratio (LY3209590:insulin 
degludec) at Visit 3 (Week 0). Stratification will be by country, HbA1c stratum at Visit 1 (Week 
-3) (<8.0%, ≥8.0%), and the type of basal insulin regimen at randomization (a. typical once-daily 
basal insulin; b. U-300 or NPH BID regimens which need reduction in total daily dose 
(TDD)/conversion to equivalent dose for typical once-daily U-100 basal insulin regimen). 
All study IP will be assigned by IWRS. Site personnel will confirm that they have located and 
are dispensing the correct IP by entering a confirmation number found on the IP label into the 
IWRS. 
The Lilly study team members who are closely involved in data interpretation and analysis 
planning will remain blinded throughout the course of the trial; 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. 
Interim analyses will be conducted under the auspices of an external DMC. Only the external 
statisticians from the SAC will have access to the unblinded data that are presented to the DMC. 
The SAC and members of the DMC will abide by the principles and responsibilities described in 
the DMC charter, which include all unblinded information confidential until the planned 
unblinding of the trial. 
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 
The investigator or trained designee will assess the treatment (LY3209590 or insulin degludec) 
compliance at each contact (visit or phone contact) based on review of the participant glycemic 
control, e-diary completion, and adherence to prescribed dose and study procedures. 
Study participants considered to be poorly compliant with their medications and/or study 
procedures (for example, missed visits or specific diagnostic tests) will be retrained as needed by 
designated site personnel. 
6.5. 
Dose Modification 
Dosing will be individualized based on FBG and the sponsor provided algorithm for both study 
drugs (LY3209590 or insulin degludec) as mentioned in Sections 6.1.4 and 6.1.5. In particular, 
the dose will be reduced as specified if hypoglycemia criteria are met (See Section 6.1). 
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6.6. 
Continued Access to Study Intervention after the End of the Study 
The sponsor will not provide participants with ongoing supplies of study medication after they 
have completed the study treatment period or permanently discontinued the study IP. 
6.7. 
Treatment of Overdose 
Study intervention overdose (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/treating physician should 
● contact the Lilly-designated medical monitor (for example, CRP/CRS) 
immediately. 
● evaluate the participant to determine, in consultation with the Lilly-designated 
medical monitor, whether study intervention should be interrupted or whether the 
dose should be reduced 
● closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention no longer has a clinical effect, and 
● if the participant is assigned to LY3209590, a plasma sample for PK analysis may 
be obtained. 
6.8. 
Concomitant Therapy 
Study participants will be permitted to use concomitant medications that they require during the 
study, except excluded medications described in Section 5.2 (Exclusion Criteria) and the table 
below. 
Investigative site staff will inform study participants that they must consult with the investigator 
or a designated site staff member when prescribed any new medications that may substantially 
affect glycemic values during the study, except when initiated for treatment of medical 
emergencies. Any additional medication initiated during the study (including OTC drugs, such as 
aspirin) must be documented in the CRF with the name of the drug and date(s) of administration. 
In addition, for permitted concomitant non-insulin antihyperglycemic medications, the dosage 
will also be documented and collected. 
Non-study medications taken by study participants who are screened but not randomly assigned 
will not be reported to Lilly unless an SAE or AE occurs that the investigator believes may have 
been caused by a study procedure. 
This table provides a summary of criteria for use of concomitant medications during the study. 
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Criteria for Use of Concomitant Medications 
Drug Class 
Use 
during 
Screening/ 
Lead-In 
Conditions for Use after Randomization 
 
 
During 
Treatment 
Period 
Acute Therapy 
Rescue Therapy  
During 
Safety 
Follow-
Up 
Period 
Drugs with 
approved weight 
loss indicationa 
Y 
Y 
N  
N/A 
N 
Systemic 
glucocorticoid 
therapy
b 
N 
N 
Yc 
N/A 
N 
Antihyperglycemia Medications 
GLP-1 RAs 
Yd 
Yd 
N/A 
Y 
Y 
DPP-4 inhibitors 
Yd 
Yd 
N/A 
Y 
Y 
SGLT2 inhibitors 
Yd 
Yd 
N/A 
Y 
Y 
Non-study basal 
insulins  
Yd 
(allowed 
only if study 
basal insulin 
is 
discontinued) 
(allowed only if 
study basal insulin is 
temporarily 
discontinued) 
 
See note  
Y 
Insulin mixtures 
N 
N 
(allowed only if 
study basal insulin is 
discontinued) 
See note 
Y 
Prandial insulin 
N 
N 
Y 
Y 
Y 
Meglitinides 
N 
N 
N 
N 
Y 
Alpha-glucosidase 
inhibitors 
Yd 
Yd 
N/A 
Y 
Y 
Sulfonylureas 
N 
N 
N/A 
N 
Y 
Thiazolidinediones 
N 
N 
N/A 
N 
Y 
Metformin
e 
Yd 
Yd 
N/A 
Y
f 
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 Participants should not initiate, or change the dose of, any weight loss medication for any reason after screening. 
Continued use is allowed during study lead-in and treatment period if on stable therapy 90 days prior to 
screening. These include, but not limited to, liraglutide 3.0 mg, orlistat, sibutramine, mazindol, phentermine, 
lorcaserin, phentermine/topiramate combination, naltrexone/bupropion, semaglutide injection 2.4 mg, or similar 
other body weight loss medications, including OTC medications, for example, orlistat 60 mg capsules. 
b Does not apply to topical, intraocular, intranasal, intra-articular, or inhaled preparations. 
c Acute therapy = treatment for up to 14 days. 
d Continued use is allowed during study lead-in and treatment period if on stable therapy 90 days prior to 
screening. 
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e Switching metformin manufacturers 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. 
f For rescue therapy, concomitant antihyperglycemic medication doses may be increased if the dose is below 
maximum approved dose per country-specific label. 
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. 
6.8.1. 
Rescue Therapy for Management of Participants with Severe / Persistent 
Hyperglycemia during the Treatment Period 
Participants in this clinical trial will be treated with basal insulin (LY3209590 or insulin 
degludec) that will be titrated to achieve FBG levels at 80-120 mg/dL (4.4- 6.6 mmol/L). They 
will also be instructed to regularly perform SMBG (predominantly FBG but investigator may 
instruct the participant to check BG at other timepoints to better inform dose adjustments and 
manage other aspects of clinical care). An additional antihyperglycemic medication should be 
considered if a participant develops severe, persistent hyperglycemia after randomization, based 
on meeting one of the following criteria and in the absence of intercurrent cause of the 
hyperglycemia (investigators should first confirm that the participant is fully compliant with the 
assigned therapeutic regimen and that they do not have an acute condition causing severe 
hyperglycemia): 
 average of FBG over 2-week period >270 mg/dL (15 mmol/L) from Visit 11 (Week 8) to 
Visit 15 (Week 12) 
 average of FBG over 2-week period >240 mg/dL (13 mmol/L) from Visit 15 (Week 12) 
to Visit 22 (Week 26), and 
 average of FBG over 2-week period >200 mg/dL (11 mmol/L) from Visit 22 (Week 26) 
to Visit 37 (Week 78). 
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. 
Rescue therapy for consideration will commence with dose optimization of the participant’s 
concomitant antihyperglycemic medications and/or addition of allowed concomitant 
antihyperglycemic medications if applicable so the participant is on up to 3 antihyperglycemic 
medications at effective doses before considering insulin rescue therapy. If severe, persistent 
hyperglycemia is not improving and there is participant compliance with the assigned therapeutic 
regimen and optimization of other/concomitant glucose-lowering agents, the addition of prandial 
insulin may be considered. 
At Visit 22 (Week 26) or after, addition of prandial insulin may also be considered for rescue 
therapy without changing the participant’s concomitant glucose-lowering medications if it is 
apparent that overbasalization is a problem. Situations that may suggest potential 
overbasalization include persistent elevated FBG due to elevated post-dinner BG, or elevated 
BGs at other times of the day (for example, following or in-between meals) while FBG is 
relatively well controlled or accompanied by hypoglycemia that is unexplained by activity, diet, 
or other factors. 
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Participants who receive rescue therapy for hyperglycemia management should also continue 
administering IP for the remaining period in the trial. 
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. 
6.8.2. 
Concomitant Antihyperglycemia Medication 
Where appropriate, allowable non-insulin antihyperglycemic medication therapy may be 
obtained locally by the Lilly affiliate in the participating country from local commercial supplies 
and distributed to sites. It is acceptable for study participants to continue obtaining their non-
insulin antihyperglycemic medications by the previous prescribing process. In the United States 
and Puerto Rico, a prescription card will be available for study participants to obtain their non-
insulin antihyperglycemic medications with a prescription. 
Dose adjustments of allowable non-insulin antihyperglycemic medications are permitted after 
randomization (during the treatment period) under the following circumstances and should be 
documented: 
 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 eGFR 
 in the case of increased hypoglycemia risk during the treatment period (as described in 
Section 8.3.3) 
 a dose increases as part of rescue therapy, and 
 for safety reasons at the discretion of the investigator. 
6.8.3. 
Medications that Promote Weight Loss 
Prescription or OTC medications that promote weight loss cannot be initiated after screening. If 
started after screening, these medications should be stopped immediately. 
6.8.4. 
Systemic Glucocorticoids 
Chronic systemic glucocorticoid therapy is allowed for no more than 14 consecutive days during 
the first 26 weeks, and during the periods from 26 to 52- weeks and 52 to 78- weeks. 
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. 
6.8.5. 
Treatment after the End of the Study 
6.8.5.1. 
Treatment after Study Completion 
Study interventions will not be made available to study participants after Visit 37 (Week 78) or 
after the participant’s early discontinuation from study treatment. 
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At the last treatment visit (Visit 37 [Week 78] or ET visit), the investigator will 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: Study participants will receive the last injection 
of LY3209590 at Week 77 of the study and can begin the transition to the non-study insulin after 
Visit 37 (Week 78). At Visit 37 (Week 78), 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 during the safety follow-up period based on FBG and 
according to the modified Riddle algorithm or investigator judgement in accordance with any 
country-specific label. 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. 
Study Participants treated with insulin degludec: Study participants assigned to the insulin 
degludec treatment arm will transition to a non-study basal insulin after Visit 37 (Week 78). The 
investigator will prescribe the non-study insulin and titrate the dose based on their 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. 
6.8.5.2. 
Emergency Situations and Special Circumstances 
In emergency situations or special circumstances (for example, elective surgery, acute illness, 
and interrupted access to medicines), it may be necessary for study participants to change their 
dose of non-insulin antihyperglycemic medications and/or be treated with a non-study insulin. 
This will be allowed for up to 3 consecutive weeks for degludec or 3 consecutive doses for 
LY3209590 prior to Visit 22 (Week 26). After Week 26, dose changes to non-insulin 
antihyperglycemic medications or temporary treatment with a non-study insulin is allowed but 
must be documented by the investigator. 
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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 Section 10.1, 
Appendix 1. 
7.1. 
Discontinuation of Study Intervention 
Permanent Discontinuation of Study Intervention 
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant may remain in the study and follow procedures for remaining study visits, as 
shown in the SoA. 
A participant will be permanently discontinued from study intervention in the following 
situations: 
 if the participant decides to stop study intervention 
 if the participant becomes pregnant 
 if participant has any significant study intervention-related hypersensitivity reaction 
 if a participant is diagnosed with an active or untreated malignancy (except for 
successfully treated basal or squamous cell skin carcinoma) 
 if the participant has not taken insulin degludec for more than 21 consecutive days or has 
missed more than 3 consecutive doses of LY3209590 during the period from 
randomization to Visit 22 (Week 26) unless the investigator has instructed the participant 
to temporarily stop treatment 
o 
if the investigator determines that the participant is persistently noncompliant 
after the 26-week treatment period 
 if the investigator or sponsor decides that the study participant should be withdrawn from 
IP. If the decision is made because of a severe AE, an SAE, or a clinically significant 
laboratory value, the appropriate measures are to be collected and Lilly or its designee 
should be alerted 
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 Lilly-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 
Lilly-designated medical monitor. 
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7.1.1. 
Liver Chemistry Stopping Criteria 
The study drug should be interrupted or discontinued if one or more of these conditions occur: 
Elevation from baseline 
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 drug interruption/ 
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 drug interruption/ 
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%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009, 
and other consensus guidelines, with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT= alanine aminotransaminase; AST = aspartate aminotransferase; 
FDA = Food and Drug Administration; INR = International normalized ratio; TBL = Total bilirubin level; ULN = 
Upper Limit of Normal 
Resumption of the study drug 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-drug 
etiology is identified. 
7.1.2. 
Temporary Interruption of Study Treatment 
The investigator may interrupt study treatment, due to an AE, clinically significant laboratory 
value, hospital visits, travel, or shortage of study treatment supply. Refer to Section 6.8.5.2 for 
allowable intervals for temporary study treatment interruptions. 
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. 
Participant should resume the dose prescribed before the temporary dosing interruption at the 
discretion of the investigator. Participant noncompliance should not be recorded as interruption 
of study intervention on the eCRF. 
The dates of study intervention interruption and restart must be documented in source documents 
and entered on the eCRF. 
Participants who have a temporary interruption of the study intervention will continue 
participating in the trial and continue study visits through the safety follow-up according to the 
protocol. 
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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 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 
 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, and 
 if a study participant is diagnosed with any type of diabetes mellitus other than 
T2D. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and post-treatment follow-up, if applicable, 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. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel 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. 
 
Section 10.2, Appendix 2 lists the laboratory tests that will be performed for this study. 
 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 
8.1.1. 
Primary Efficacy Measure 
The primary efficacy measure is HbA1c change from baseline to Visit 22 (Week 26). 
8.1.2. 
Key Secondary Efficacy Measures 
The following Secondary efficacy measures will be collected as shown in the SoA (Section 1.3): 
 HbA1c 
 Number of nocturnal hypoglycemia episodes 
 Time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive 
measured by CGM 
8.1.3. 
Other Secondary Measures 
 Fasting glucose measured by SMBG 
 CGM measurements: 
o Time in glucose range 
o Glucose variability 
o Time in hyperglycemia or hypoglycemia. 
 Number of level 2 and 3 hypoglycemia episodes 
 Body weight 
 Insulin dose 
 TRIM-D 
 DTSQ 
8.1.4. 
Other Efficacy Measures 
The following efficacy measures will be collected as shown in the SoA (Section 1.3): 
 Fasting serum glucose by central lab 
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 Number of level 2 or level 3 hypoglycemia episodes 
 Antibody against LY3209590 
 SIM-Q 
 Responses to “Basal Insulin Experience: Likelihood of incorporating into routine” 
 Responses to “Basal Insulin Experience: Preference” 
8.1.5. 
Additional Information on Efficacy and Health Outcomes Measures 
8.1.5.1. 
Self-Monitoring of Blood Glucose 
Self-Monitoring of Blood Glucose (SMBG) 
At Visit 2, participants who are enrolled in the study will receive a glucometer and related testing 
supplies for use during the study. Site personnel will train the participant on correct use of the 
glucometer for self-monitoring blood glucose and reporting of hypoglycemia data. Participants 
must use only the study-provided glucometer until the participant completes the 5-week safety 
follow-up period. 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. (Section 8.3.3). 
Fasting Blood Glucose (FBG) Measurement 
Study participants will be instructed 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. 
SMBG for Hypoglycemia or Hyperglycemia 
Participants should perform SMBG with the study-provided BG meter whenever hypoglycemia 
is experienced or suspected (with or without symptoms), when there is perceived, increased risk 
related to changes in dietary intake, physical activity, or inadvertent or atypical insulin dosing. 
The participant’s FBG and events of hypoglycemia will be used to determine the insulin dose 
and titration based on the dosing and titration algorithm (Section 6.1). 
Participants may perform SMBG more frequently to check for instances of hyperglycemia, or as 
directed by the investigator. Investigators may also instruct participants to collect SMBG, at time 
points other than at fasting, to evaluate glycemic control. 
8.1.5.2. 
CGM Monitoring 
The Dexcom G6 Continuous Glucose Monitoring System 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. 
Training and Initiation 
Site personnel will dispense CGM supplies and initiate blinded CGM sessions at the times 
specified in 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. A CGM 
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Participant User Guide that provides an overview of device components and study specific 
instructions is available for at-home use. 
Participants are not allowed to connect the transmitter of the Dexcom G6 system to a personal 
smartphone, smartphone application, or other system and to use a personal CGM or FGM during 
the sessions when they are wearing the study-provided blinded CGM. 
CGM Data Compliance 
At the end of each CGM session, participants will return the CGM system 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 a 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 
when sessions do not meet the compliance threshold. CGM compliance reports will also be 
provided to the Sponsor and site monitors for review and to determine if further mitigation is 
necessary. 
8.1.5.3. 
e-diary – Study Procedures 
At Visit 2 (Week -2), participants who are enrolled in the study will receive an e-diary and be 
trained on use of the e-diary for documenting data related to study intervention dose 
administration, and events of hypoglycemia including related signs and symptoms. Data from the 
participant’s study-provided glucometer will wirelessly transmit all blood glucose measurements 
to the e-diary. Participants should complete e-diary entries each week. If a participant is not 
compliant with diary completion, site personnel will re-educate the participant on study 
requirements for continued study participation. 
8.1.5.4. 
Insulin Dose Entry 
Participants will be instructed to enter the date of their daily or weekly insulin dose and dose 
amount in the dosing record. The participant will return the e-diary to the site at Visit 802 or at 
the ET visit if the participant will not complete the safety follow-up period. 
8.1.5.5. 
Investigator Portal 
Participant e-diary information including insulin dosing data, SMBG values, and events of 
hypoglycemia will be available for review through a web-based portal that can be accessed by 
designated investigative site personnel at any time. The site personnel can remotely view the 
completed e-diary data at any time during the study including between visits and print reports of 
diary data. 
8.1.5.6. 
Patient-Reported Outcomes Assessments 
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 (Section 1.3) At these visits, the 
questionnaires should be completed before the participant has discussed their medical condition 
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or progress in the study with the investigator and/or site staff, if the participant is not adversely 
affected by their fasting condition. 
Preferred administration order of these questionnaires throughout the trial are 
1. TRIM-D 
2. DTSQ (status) (baseline only) 
3. DTSQ (change) (after randomization) 
4. EQ-5D-5L 
5. SIM-Q 
6. Basal Insulin Experience: Preference, and 
7. Basal Insulin Experience: Likelihood of incorporating into routine. 
8.1.5.6.1. Treatment-Related Impact Measure – Diabetes (TRIM-D) 
The TRIM-D is a self-administered instrument, which assesses the impact of diabetes treatment 
on participants’ functioning and well-being across available diabetes treatments (Brod et al. 
2009). The TRIM-D consists of 28 items each assessed on a 5-point scale, where higher scores 
indicate a better health state, with a recall period of “over the past 2 weeks.” In addition to an 
overall score, the TRIM-D items assess 5 domains of impact: 
 Treatment Burden (6 items) 
 Daily Life (5 items) 
 Diabetes Management (5 items) 
 Compliance (4 items), and 
 Psychological Health (8 items). 
8.1.5.6.2. Diabetes Treatment Satisfaction Questionnaire – Status (DTSQs) 
The Diabetes Treatment Satisfaction Questionnaire-Status Version (DTSQs) (Bradley and Lewis 
1990; Bradley 1994) is a diabetes-specific patient-reported outcome instrument that assesses the 
overall treatment satisfaction and perceived frequency of hyperglycemia and hypoglycemia. It is 
appropriate for use in both T1D and T2D. 
The DTSQs consists of 8 items that assess treatment satisfaction as well as concerns about 
hyperglycemia and hypoglycemia over the past few weeks, prior to the visit. Each item is rated 
on a 7-point Likert scale. Items 1 and 4-8 are rated from 0 (very dissatisfied) to 6 (very satisfied) 
and can be summed up to produce a treatment satisfaction score. Items 2 and 3 evaluate the 
perceived frequency of hyperglycemia and hypoglycemia and are rated from 0 (none of the 
time) to 6 (most of the time). 
8.1.5.6.3. Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
The Diabetes Treatment Satisfaction Questionnaire-Change Version (DTSQc) (Bradley 
1999) was designed to overcome potential ceiling effects in the status version. The DTSQc has 
the same 8 items as the status version but is reworded slightly to measure the change 
in treatment satisfaction rather than absolute treatment satisfaction. 
Each item is scored on a scale of -3 to +3. For all items except item 2 (perceived frequency of 
hyperglycemia) and item 3 (perceived frequency of hypoglycemia): 
 the higher the score, the greater the improvement in treatment satisfaction 
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 the lower the score, the greater the deterioration in treatment satisfaction, and 
 a score of 0 represents no change. 
For Items 2 and 3: the lower the score, the better the perception. 
8.1.5.6.4. 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 
profile and a single index value for health status 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 
 selfcare 
 usual activities 
 pain/discomfort, and 
 anxiety/depression. 
The 5L version, scores each dimension at 5 levels: 
 no problems 
 slight problems 
 moderate problems 
 severe problems, and 
 unable to perform/extreme problems. 
 
In addition to the health profile, a 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 (where 0 is a health state equivalent to death; negative values are valued as 
worse than dead) to 1 (perfect health). The second part of the questionnaire consists of EQ 
Visual Analog Scale which records the respondent’s self-rated health status. The participant rates 
his/her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable 
health). In conjunction with the health state data, it provides a composite picture of the 
respondent’s health status. 
8.1.5.6.5. Simplicity Questionnaire (SIM-Q) Single Medication status version 
The Simplicity of Diabetes Treatment Questionnaire (SIM-Q) single medication status version is 
a brief 10-item measure developed to assess the simplicity and complexity of treatment for T2D. 
This measure asks participants to think about a specific medication (prior basal insulin or current 
study medication) when completing each item on a 5-point scale ranging from ‘Very complex’ to 
‘Very simple’. In Study BDCU, 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?” 
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8.1.5.6.6. Basal Insulin Experience: Likelihood of incorporating into routine 
This is a Lilly-developed, participant-completed question to understand the participant’s 
likelihood of incorporating their study insulin into their diabetes management routine. The 
question is rated on a 5-point scale with responses ranging from “very unlikely” to “very likely.” 
8.1.5.6.7. Basal Insulin Experience: Preference 
This is a Lilly-developed, participant-completed question to understand the participant’s 
preference for their pre-study or current study treatment. The question is rated on a 5-point scale 
with responses ranging from “strongly prefer the study insulin” to “strongly prefer my previous 
insulin.” The question also includes a “not applicable” option for participants that stayed on the 
same insulin in the treatment phase. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
 A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 
 Investigators should pay special attention to clinical signs and symptoms related 
to T2D as well as related illnesses. 
 Additionally, investigators should inspect injection sites during the physical examination. 
8.2.2. 
Vital Signs 
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3). 
 Sitting BP and pulse rate will be measured. 
 Vital sign measurements should be taken before obtaining an ECG tracing and 
before collection of blood samples for laboratory testing, at visits where required 
(see SoA, Section 1.3). 
 The participant should be required to sit quietly for 5 minutes before vital sign 
measurements are taken. An appropriately sized cuff (cuff bladder encircling at 
least 80% of the arm) should be used to ensure the accuracy of BP measurements. 
The arm used for the BP measurement should be supported at heart level. BP 
should be measured consistently using the same arm throughout the study. 
 For each parameter (pulse rate, systolic BP, and diastolic BP), 3 measurements 
will be taken using the same arm; the recordings should be taken at least 1 minute 
apart, and each measurement of sitting pulse rate and BP will be recorded in the 
eCRF. 
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8.2.3. 
Electrocardiograms 
 Local 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3). 
 Study participants must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection. ECGs will be 
performed prior to collection of any blood samples. 
 ECGs will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon as possible after the time of ECG collection, and 
ideally while the study participant is still present, to determine whether the study 
participant meets entry criteria at the relevant visit(s) and for immediate study 
participant management should any clinically relevant findings be identified. 
 ECGs may be performed at additional visits based on investigator’s discretion for safety 
assessment. 
 If there is a clinically significant finding identified by the investigator, the investigator or 
qualified designee will determine if the participant should remain in study and if any 
changes should be made to participant care. The review of the electrocardiogram (ECG) 
printed at the time of collection must be documented. Any new clinically relevant finding 
should be reported as an AE. 
8.2.4. 
Clinical Safety Laboratory Tests 
 See Section 10.2, Appendix 2 for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for the timing and frequency. 
 The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study, or within 5 weeks after the last dose of study intervention, 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or Lilly- designated medical monitor 
(CRP/CRS). 
o If such values do not return to normal/baseline within a time judged reasonable by 
the investigator, the etiology should be identified, and the sponsor notified. 
o All protocol-required laboratory assessments, as defined in Section 10.2, 
Appendix 2, must be conducted in accordance with the SoA, standard collection 
requirements, and the laboratory manual. 
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● 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 Safety Monitoring 
Please see Section 10.5, Appendix 5 for details on Hepatic Safety Monitoring. 
8.2.6. 
Pregnancy Monitoring 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 5-weeks (~35 days) 
days after the last dose. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Section 10.3, 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). 
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 the 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/contacts. All SAEs and AESI as defined in 8.3, respectively, will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up (as defined in Section 7.3). For PCs, the investigator is responsible for ensuring that follow-up 
includes any supplemental investigations as indicated to elucidate the nature and/or causality. 
Further information on follow-up procedures is provided in Section 10.3, Appendix 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 ICF 
The last 
safety follow-
up visit  
As soon as 
possible upon 
site awareness 
AE eCRF 
N/A 
Serious Adverse Event (SAE) 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
with study 
procedures 
Signing of the ICF 
 
 
Start of 
intervention 
Within 24 
hours of 
awareness 
SAE eCRF  
SAE paper form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
The last 
safety follow-
up visit OR 
participation 
in study has 
ended 
Within 24 
hours of 
awareness 
SAE eCRF  
SAE paper form 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After participant’s 
study participation 
has ended 
N/A 
Promptly 
SAE paper 
form 
N/A 
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Event 
Collection Start 
Collection 
Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-up Method 
of Reporting 
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 of 
learning of the 
pregnancy (see 
Section 8.3.2) 
Pregnancy 
form  
Pregnancy paper 
form 
Product Complaints (PCs) 
PC associated 
with an SAE or 
might have led to 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 
hours of 
awareness 
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 (after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware) 
Participation in 
study has ended 
N/A 
Promptly 
Product 
Complaint 
form 
 
Abbreviations: AE = adverse event; eCRF= electronic case report form; ICF = informed consent form; N/A = not 
applicable; PC = product complaint; SAE = serious adverse event. 
a Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
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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 study intervention. 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of gestational 
age, fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
 The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy. 
 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 stillbirth 
(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, he or she may learn of an SAE through 
spontaneous reporting. 
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 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. 
Hypoglycemia 
The following classifications of hypoglycemia are used to characterize hypoglycemic events: 
Level 1 hypoglycemia: 
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 hypoglycemia: 
Glucose <54 mg/dL (3.0 mmol/L): Level 2 hypoglycemia is also referred to as documented or 
blood glucose confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose 
threshold is clinically relevant regardless of the presence or absence of symptoms of 
hypoglycemia. 
Level 3 hypoglycemia: 
Severe hypoglycemia: A severe event characterized by altered mental and/or physical status 
requiring assistance for treatment of hypoglycemia. For example, a participant with altered 
mental status, and could not assist in their own care, or was semiconscious or unconscious, or 
experienced coma with or without seizures, and the assistance of another person was needed to 
actively administer carbohydrate, glucagon, or other resuscitative actions. 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. 
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, 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. 
If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator must 
record the event as serious on the AE CRF and report it to Lilly as an SAE. In addition, the 
investigator will be asked to determine whether the episode was preceded by repeated or 
prolonged episodes of hypoglycemia. 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that occurs at 
night and presumably during sleep (between midnight and 6 AM). 
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8.3.4. 
Systemic Hypersensitivity Reactions 
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Section 10.2, Appendix 2, “Laboratory Assessments for 
Hypersensitivity Events”. Laboratory results are provided to the sponsor via the central 
laboratory. 
8.3.5. 
Injection site reactions 
Symptoms and signs of a local injection/infusion site reaction may include erythema, induration, 
pain, pruritus, and edema. 
If an ISR (Injection-Site Reaction) is reported by a participant or site staff, the ISR CRF will be 
used to capture additional information about this reaction (for example, injection-site pain, 
degree and area of erythema, induration, pruritis and edema). If an injection-site event is 
reported, the AE will be recorded, and additional data will be provided to the sponsor in the 
eCRF. 
8.3.6. 
Adjudicated events: Cerebrocardiovascular Events 
Potential cerebrocardiovascular events will be identified by the investigative site or by a medical 
review conducted by the sponsor or designee. 
A blinded external Clinical Event Committee will adjudicate the events in a consistent and 
unbiased manner. Events include 
 death 
 myocardial infarction 
 stroke or Transient Ischemic Attack (TIA) 
 hospitalization for unstable angina 
 hospitalization for heart failure, and 
 coronary revascularization procedure. 
8.4. 
Pharmacokinetics 
At the visits and times specified in the SoA (Section 1.3), 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. 
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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. 
8.5. 
Pharmacodynamics 
Pharmacodynamic parameters will be evaluated as described in Sections 3 and 9.3.6.1. 
8.6. 
Genetics 
Genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of study participant response (including 
safety), and clinical outcome. Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, and other cellular elements. 
Serum and plasma samples for non-pharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 1.3) where local regulations allow. 
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 and/or 
research methods, or in validating diagnostic tools or assay(s) related to T2D. 
8.8. 
Immunogenicity Assessments 
At the visits and times specified in the SoA (Section 1.3), venous blood samples from all study 
participants will be collected for analysis 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 predose; however, the PK sample for 
LY3209590 will be taken postdose. 
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 or medical resource utilization and 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 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 noninferior to 
insulin degludec on glycemic control as measured by change from baseline to Week 26 (Visit 
22) in HbA1c in participants with T2D currently on basal insulin. The null hypothesis (H0) to be 
tested is the difference in the change from baseline to Week 26 (Visit 22) in HbA1c (LY3209590 
– insulin degludec) is greater than the noninferiority margin (NIM). The NIMs of 0.4% and 0.3% 
will both be tested to meet different regulatory requirements. The 2-side 95% confidence interval 
(CI) will be used for testing the noninferiority. 
Secondary Hypotheses 
The key secondary (multiplicity adjusted) objectives are to test the hypotheses that LY3209590 
is superior to insulin degludec with respect to 
 change from baseline in HbA1c at Week 26 (Visit 22) 
H0: the difference (LY3209590 – insulin degludec) ≥0.0 
 the event rate of nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during 
treatment period up to Week 78 (Visit 37) 
H0: the relative event rate (LY3209590 vs. insulin degludec) ≥1 
 time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive 
measured by CGM collected during the CGM session prior to Week 26 (Visit 22) 
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 9.1.1.1). 
9.1.1.1. 
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 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. 
 
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9.2. 
Analyses Sets 
The following populations are defined for purpose of analysis: 
Analysis Populations/Data 
Sets 
Description 
Entered Population 
All participants who sign the informed consent form. 
Randomized Population 
All randomized participants. Participants will be analyzed according to the 
treatment they were assigned. 
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. 
EAS1 
The data will include 
 
mITT population excluding participants discontinuing the study 
treatment due to inadvertent enrollment, and 
 
all measurements regardless of the use of study treatment or the 
initiation of rescue medication. 
EAS2 
The data will include 
 
mITT population excluding participants discontinuing the study 
treatment due to inadvertent enrollment, and 
 
measurements up to the discontinuation of study treatment or the 
initiation of rescue medication. 
SS 
The data will include 
 
mITT population, and 
 
all measurements regardless of the use of study treatment or the 
initiation of rescue medication. 
Abbreviations: EAS = efficacy analysis set; mITT = modified intent-to-treat; SS = safety analysis set. 
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 (for treatment 
regimen estimand) or EAS2 (for efficacy estimand) and the safety analyses will be conducted on 
SS. All tests of treatment effects using statistical models will be conducted at a 2-sided alpha 
level of 0.05 and 2-sided 95% CI will be provided. Unless otherwise specified, other secondary 
and tertiary efficacy measures will be analyzed using EAS2 with the data up to the 
discontinuation of study treatment (defined by the date of last study dose + 10 days) or the 
initiation of rescue medication whichever is earlier. 
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9.3.2. 
Primary Endpoint/Estimand Analysis 
The primary objective is to compare the HbA1c change from baseline to Week 26 between 
LY3209590 and insulin degludec and will be based on either of the 2 estimands: treatment 
regimen estimand for the US FDA submission and efficacy estimand for registrations in other 
countries. 
The treatment regimen estimand will be estimated using the HbA1c data at baseline and Week 
26 (Visit 22) for the EAS1, regardless of the use of study treatment or rescue medications. The 
missing measures at the primary endpoint will be imputed using multiple imputation by the 
retrieve dropout approach. The retrieved dropout participants are those who discontinue IP prior 
to Week 26 (Visit 22) but have non-missing measures at Week 26 (Visit 22). 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 26 (Visit 22) will be imputed by return-to-
baseline multiple imputations. After the imputation, the observed and imputed data will be 
analyzed by the analysis of covariance (ANCOVA). The model will include treatment, strata 
(country, and the type of basal insulin at randomization), and baseline value of the dependent 
variable. The statistical inference will be based on the multiple imputation framework by Rubin 
(1987). 
The efficacy estimand is the treatment differences in the change in HbA1c from baseline to 
Week 26 (Visit 22) if all participants would adhere to the treatment without intercurrent events. 
The EAS2 with data up to the discontinuation of study treatment or the initiation of rescue 
medication, whichever is earlier, and the HbA1c collected at all planned postbaseline visits will 
be used in the analysis. There may be missing values due to the early discontinuation of study 
treatment or use of rescue medication. The mixed-model repeated measures (MMRM) model 
will be used, and the missing values will be handled in the MMRM analysis under the 
assumption of missing at random. The MMRM model will include treatment, strata (country, and 
the type of basal insulin 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. 
 
The 2-sided 95% CI of the least-squares (LS) mean for individual treatment groups, treatment LS 
mean difference (LY3209590 – insulin degludec) in the HbA1c change from baseline to Week 
26 (Visit 22) will be estimated. For both estimands, LY3209590 will be declared noninferior to 
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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). 
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 the superiority of LY3209590 compared with insulin degludec for 
1) change from baseline in HbA1c at Week 26 (Visit 22) 
2) the event rate of nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during 
treatment period up to Week 78 (Visit 37), and 
3) 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 (Visit 22). 
The superiority test in change from baseline to Week 26 (Visit 22) in HbA1c will be based on the 
same primary endpoint analysis described above. 
The rate of nocturnal hypoglycemia will be analyzed by a negative binomial regression with 
treatment, baseline HbA1c, baseline incidence of nocturnal hypoglycemia as independent 
variables, and log (exposure in year) as the offset. 
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%], and the type of basal insulin at randomization), and 
baseline of the dependent variable will be used. The MMRM model will include treatment, strata 
(country, baseline HbA1c stratum [<8.0%, ≥8.0%], and the type of basal insulin 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. 
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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 IP or reported to worsen in severity from 
baseline will be considered TEAEs. The Medical Dictionary for Regulatory Activities 
(MedDRA) lowest level term (LLT) will be used in the treatment-emergent assessment. The 
maximum severity for each LLT during the baseline period will be used as baseline severity. 
TEAEs will be summarized in tables using the Medical MedDRA preferred term (PT), sorted by 
decreasing frequency within the LY3209590 treatment group for all TEAEs, TEAEs by 
maximum severity and common TEAEs (defined as ≥1% before rounding for LY3209590-
treated participants). TEAEs will also be summarized by PT sorted by decreasing frequency 
within System Organ Class (SOC). For events that are specific to one sex, the denominator and 
computation of the percentage will include only participants from the given sex. 
The number and percentage of participants who reported a serious AE (SAE) will be summarized 
by treatment group using MedDRA PT. A listing of all SAEs will also be provided. 
The AEs leading to study treatment discontinuation will be summarized by treatment group 
using MedDRA PT. A listing of AEs leading to study treatment discontinuation will also be 
provided. 
The participant-reported hypoglycemia: Level 1 (defined by glucose value ≥54 to <70 mg/dL 
[≥3.0 to <3.9 mmol/L]), Level 2 (defined by glucose <54 mg/dL [3.0 mmol/L]), Level 3 (severe 
hypoglycemia) and the composite of Level 2 and Level 3, will be analyzed using data from e-
diary. The analysis periods of 0-6, 0-12, 0-26, 0-52, 0-78, 12-26, 26-52, 26-78 weeks of 
treatment will be considered. Episodes for the 24-hour period, the non-nocturnal period (defined 
by 6 AM to midnight), and nocturnal period (defined by midnight to 6 AM) will be used to 
define all documented hypoglycemia, non-nocturnal hypoglycemia, and nocturnal hypoglycemia 
respectively. 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, 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 Analyses 
9.3.6.1. 
Pharmacokinetic and Pharmacodynamic Analyses 
LY3209590 concentration data will be analyzed using a population PK approach via nonlinear 
mixed-effects modeling with the NONMEM software. The relationships between LY3209590 
dose 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, gender, and renal function on PK and/or PD 
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parameters, may be examined. Should antidrug antibody be detected from immunogenicity 
testing, its impact on LY3209590 PK or any relevant PD parameters will also be examined. 
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 treatment-emergent ADA (TEADA) 
defined as participants with non-missing baseline and at least one non-missing postbaseline 
measurement. 
The number and percentage of participants who are treatment-emergent ADA positive 
(TEADA+) will be summarized by treatment group. A participant who is evaluable for TEADA 
is TEADA+ if either of the following holds: 
 treatment induced ADA: the participant has 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: the participant has 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. That is, the participant has baseline 
status of ADA Present, with titer 1:B, and at least 1 postbaseline status of 
ADA Present, with titer 1:P and P/B≥4. 
The frequency of cross-reactive binding to endogenous insulins may also be summarized for the 
participants with TE ADA+. 
The relationship between the presence of TEADA and the safety and efficacy measures may be 
assessed. 
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. 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 939 participants will be randomly assigned to LY3209590 and insulin degludec 
in a 2:1 ratio. With the assumption of 15% dropout at Week 26, approximately 532 and 266 
participants will complete 26 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 Week 26 
(Visit 22) in HbA1c in participants with T2D currently on basal insulin. 
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Assuming a noninferiority margin (NIM) of 0.4%, no true difference between treatment groups, 
and a SD of 1.1%, 798 completers (532 on LY3209590 and 266 on insulin degludec) will 
provide greater than 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). 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 26. 
The 798 completers will provide 95% statistical power to demonstrate the superiority 
(LY3209590 vs. insulin degludec) of change in HbA1c from baseline to 26 weeks (assuming a 
SD of 1.1% and true mean difference is -0.3%) using the alpha of 0.05. 
The 798 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 26 between LY3209590 and insulin degludec (assuming 
a SD of 18% and true mean difference is 5%) at alpha = 0.05. 
The 798 participants will provide at least 80% statistical power to show the superiority of the 
event rate of clinically significant nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) 
during treatment phase up to Week 78 (assuming event rate of 0.67 [SD = 2.6] and 1.1 
[SD = 2.6] events per participant per year for LY3209590 and insulin degludec, respectively) 
using a negative binomial distribution at alpha = 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: 
 consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and CIOMS International Ethical 
Guidelines 
 applicable ICH GCP Guidelines, and 
 applicable laws and regulations. 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
o 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 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, and 
o 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. 
● Investigator sites are compensated for participation in the study as detailed in the 
CTA. 
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 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
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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 or the participant’s 
legally authorized representative and answer all questions regarding the study. 
● Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 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 or the participant’s 
legally authorized representative 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. 
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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. 
10.1.5.2. Clinical Event Committee for Adjudication of Cerebrocardiovascular Events 
A blinded Clinical Event Committee, external to Lilly, will adjudicate cerebrocardiovascular 
events. 
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. 
An early PK/PD unblinded transfer may also be conducted. Only a small group of personnel may be 
unblinded to the data for the potential PK/PD analysis and must keep information confidential until 
the planned unblinding of the trial. 
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. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK. 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, blank or annotated case 
report forms, will be provided in a secure data sharing environment for up to 2 years per 
proposal. 
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For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance 
● 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. 
● Quality tolerance limits (QTLs) will be predefined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study and important 
excursions from the QTLs 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 
entered 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 and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the period outlined in the 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. 
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● 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. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture (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, electronic Clinical Outcome Assessment (eCOA) data (participant-focused 
outcome instrument) will be directly recorded by the participant or investigator site personnel, 
into an instrument (for example, handheld smart phone, tablet, or web portal). 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 collected via the sponsor-provided data capture system(s) will be stored at a third-party. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s). Prior to decommissioning, the investigator will 
receive or access an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global PC 
management system. 
10.1.8. 
Source Documents 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on or entered in the eCRF and that 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 Section 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: 
For study termination: 
 discontinuation of further study intervention development. 
For site termination: 
● 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 
● inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, and 
● 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. 
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 for the studied indication. 
 
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Sample Type 
Custodian 
Retention Period After Last Participant Visita 
Biomarkers 
Sponsor or designee 
15 years 
Pharmacokinetics Sponsor or designee 
1 year  
Immunogenicity 
Sponsor or designee 
15 years 
a Retention periods may differ locally. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
● The tests detailed in the table below will be performed by local or Lilly-
designated laboratory. 
● Local laboratory results are only required in the event that the Lilly-designated 
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. 
● In circumstances where the sponsor approves local laboratory testing in lieu of 
Lilly-designated 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. 
 
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 
  
  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) 
  
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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) 
  
  
  
Urinalysis 
Assayed by Lilly-designated laboratory. 
Specific gravity 
  
pH 
  
Protein 
  
Glucose 
  
Ketones 
  
Bilirubin 
  
Urobilinogen 
  
Blood 
  
Nitrite 
  
Urine leukocyte esterase 
  
Microscopic examination of sediment 
  
Albumin 
 
Creatinine 
 
  
  
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. 
  
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI)  
  
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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. Fasting per SoA 
HbA1c 
  
C-Peptide  
 
Glucose 
 
 
 
Exploratory Biomarker 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. 
Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology Collaboration; EDTA = 
ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c. 
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 tests 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. 
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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 only if not already collected 
on the same day as the event. 
● 
Note: If collecting, collect up 
to 12 hr after the start of the 
event. 
Serum 
LY3209590 ADAs 
Serum/plasma 
LY3209590 concentration 
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. 
Abbreviations: ADA = anti-drug antibody; IL = interleukin. 
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 (ISO) 14155. 
 Both the investigator and the sponsor will comply with all local medical device 
reporting requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. 
10.3.1. 
Definition of AE 
AE Definition 
 Drug 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. 
 Device definition: 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 medication errors under Section 10.8. 
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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/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy and appendectomy): the 
condition that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
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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. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
10.3.3. 
Definition of Product Complaints 
Product Complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, 
the following are also PCs: 
o deficiencies in labeling information, and 
o use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected to ensure the 
safety of participants, monitor quality, and to facilitate process and product 
improvements. 
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 Investigators will instruct participants to contact the site as soon as possible if 
he or she has a PC or problem with the study intervention so that the situation 
can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, 
it should be reported as both a PC and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and PC 
information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
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 AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
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assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
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. 
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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 Lilly-designated medical monitor/SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in site training materials.  
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the Lilly-designated medical monitor or the SAE coordinator. 
 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 materials. 
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 related 
BDCU study documents 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 
Woman of Childbearing Potential (WOCBP) 
Females are considered a WOCBP if they have had at least 1 cycle of menses. Any amount of 
spotting should be considered menarche. 
Women in the following categories are not considered WOCBP 
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, or tubal 
ligation. 
 
Postmenopausal State 
The postmenopausal state should be defined as: 
1. A woman at any age at least 6 weeks postsurgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note; or 
2. A woman at least 40 years of age and up to 55 years old with an intact uterus, not on 
hormone therapya, who has had cessation of menses for at least 12 consecutive months 
without an alternative medical cause, AND with an FSH >40 mIU/mL; or 
3. A woman 55 or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or 
4. A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone replacement therapy. 
a Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
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10.4.2. 
Females 
 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same 
sex relationship, as part of their preferred and usual lifestyle 
Must… 
Must Not… 
agree to either remain abstinent, or 
stay in a same sex relationship without sexual 
relationships with males 
 use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation 
 declare abstinence just for the duration of 
a trial, or 
 use the withdrawal method. 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a 
same sex relationship, as part of their preferred and usual lifestyle 
Topic 
Condition 
Pregnancy testing 
Negative serum result at screening followed 
by a negative serum result at randomization. 
Contraception 
Agree to use 1 highly effective method (less 
than 1% failure rate) of contraception, or a 
combination of 2 effective methods of 
contraception. 
These forms of contraception must be used 
for the duration of the study. 
 
Examples of different forms of contraception: 
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 
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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, 
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 
 lactational amenorrhea 
Please also refer to Sections 5.1 and 5.2. 
10.4.3. 
Males 
No male contraception required except in compliance with specific local government study 
requirements. See Section 5.1. 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments 
 
Close hepatic monitoring 
Laboratory tests (Section 10.2, Appendix 2), including alanine aminotransaminase, aspartate 
aminotransferase, alkaline phosphatase, total bilirubin level, direct bilirubin, gamma-glutamyl 
transferase, 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 one or more of these conditions 
occur: 
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) 
Abbreviations: ALP = alkaline phosphatase; ALT= alanine aminotransaminase; AST = aspartate aminotransferase; 
TBL = Total bilirubin level; ULN = Upper Limit of Normal 
If the abnormality 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 (CRP/CRS). 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, history of 
alcohol drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and TBL 
should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions 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/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/symptomsa, or 
ALT or AST ≥3x baseline 
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ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT= alanine aminotransaminase; AST = aspartate aminotransferase; 
TBL = Total bilirubin level; ULN = Upper Limit of Normal 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal 
pain, fever, rash, and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study: 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN). 
 In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline on 2 
or more consecutive tests. 
2. Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome). 
 In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline. 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN). 
 In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline on 2 
or more consecutive blood tests. 
4. Hepatic event considered to be an SAE. 
5. Discontinuation of study intervention due to a hepatic event. 
 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
Hepatic Evaluation Testing 
See above for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
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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) 
  Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
  HBV DNA b 
Anti-actin antibody c 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
  HCV antibody 
  EBV antibody 
  HCV RNA b 
  EBV DNA b 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
  HDV antibody 
  CMV antibody 
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Hepatitis E virus (HEV) testing: 
  CMV DNA b 
  HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
  HEV IgM antibody 
  HSV (Type 1 and 2) antibody  
  HEV RNA b 
  HSV (Type 1 and 2) DNA b 
Microbiology d 
Liver kidney microsomal type 1 (LKM-1) 
antibody 
Culture: 
  Blood 
  Urine 
 
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio. 
a Not required if anti-actin antibody is tested. 
b Reflex/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 Section 10.3, Appendix 3 for definitions and procedures for recording, evaluating, 
follow-up, and reporting of all events. 
 
 
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10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, 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. 
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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. 
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, if written approval is provided by the sponsor. Assessments will 
be completed according to the SoA. 
Mobile healthcare: 
Healthcare visits may be performed by a mobile healthcare provider at locations other 
than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor. 
Other alternative locations: 
Laboratory draws may be done at an alternate location in exceptional circumstances if 
written approval is provided by the sponsor. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
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Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
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, as per the SoA. 
 All labs will be reviewed by the investigators. Lilly Medical should be informed of 
any labs that meet criteria for temporary or permanent study intervention 
discontinuation. 
 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. 
 Safety labs should be obtained as specified in the SoA. 
 The local laboratory must be qualified in accordance with applicable local regulations. 
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, 
 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. 
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Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening/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 screening/lead-in visits to randomization 
visit: the participant will proceed to the next study visit per the usual SoA, provided that 
randomization visit must be conducted within 30 days from first screening/lead-in visit. 
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 screening/lead-in visits to 
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 screening visit to 
ensure participant eligibility by 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. 
Primary endpoint visit (Visit 22; Week 26) should be completed as 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 (that is, ±7 days), additional study drug 
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, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
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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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10.8. 
Appendix 8: Abbreviations and Definitions 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
Blinding/masking 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment, but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment, but the investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
BG 
blood glucose 
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 to 10 mmol/L) and 70 to 140 mg/dL 
(3.9 to 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. 
CIOMS 
Council for International Organizations of Medical Sciences 
BGM 
blood glucose meter 
Companion diagnostic  An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product 
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. 
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Compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration equation 
CRF 
case report forms 
CRP 
clinical research physician/clinical research scientist: Individual responsible for the 
medical conduct of the study. Responsibilities of the CRP may be performed by a 
physician, clinical research scientist, global safety physician or other medical officer. 
CTA 
Clinical Trial Agreement 
CT  
Computed tomography 
CV 
cardiovascular 
DMC 
Data monitoring committee. A data monitoring committee, or data monitoring board 
(DMB) 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. 
Device deficiencies 
equivalent to product complaint 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
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. 
FBG 
fasting blood glucose 
FGM 
flash glucose monitoring 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GLP-1 
glucagon-like peptide-1 
HbA1c 
hemoglobin A1c 
IB 
investigator’s brochure 
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ICF 
informed consent form 
ICH 
International Council for Harmonization 
IFU 
instructions for use 
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 his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form. 
Interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
IP 
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/IEC 
Institutional Review Boards/Independent Ethics Committees 
ITT 
Intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
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 involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five 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, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
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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 
NAFLD 
nonalcoholic fatty liver disease 
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. 
 
NPH 
Neutral Protamine Hagedorn 
OTC 
over the counter  
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 
PPS 
per-protocol set: The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model. 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
QTc 
corrected QT interval 
SAC 
statistical analysis center 
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 
SMBG 
self-monitoring of blood glucose 
SS 
safety analysis set 
T1D 
type 1 diabetes mellitus 
T2D 
type 2 diabetes mellitus 
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TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
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10.9. 
Appendix 9: 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]: (28-JAN-2022) 
Overall Rationale for the Amendment 
The overall rationale for the changes implemented in the protocol amendment is to update the 
titration algorithm for insulin degludec so that it will more closely match the total weekly dose 
adjustments used in the LY3209590 titration algorithm and to include requirement that 
medication errors will be reported as adverse events. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Deleted descriptive acronym text  
For consistency 
Table of Contents 
List of tables removed and table numbers 
were removed throughout the protocol 
For consistency 
with protocol 
template 
Section 1.1. Synopsis 
Key secondary objective modified deleting 
“by CGM collected” 
For clarity and 
consistency 
Section 1.2. Schema 
Moved one telephone visit from treatment 
period to the Safety Follow-Up period 
For consistency 
with SoA 
Edited visit numbers (renumbered) and 
added additional visit in the Safety Follow-
Up period 
Section 1.3. Schedule of 
Activities 
 
Text added directing participants to Section 
10.7 for exceptional circumstances 
For clarity 
Added “Lead/In” to Section 1.3.1 header and 
updated subheading to include Visit numbers 
38, 801 and 802 
For consistency 
Deletion of “history of CV disease” 
For consistency 
Added “X” at 16 weeks for weight 
This procedure 
was previously 
inadvertently 
omitted 
Added “X” at 8 and 16 weeks for vital signs 
These 
procedures were 
previously 
inadvertently 
omitted 
Added additional telehealth visit to the 
Safety Follow-Up period at Week 80; this 
Telehealth visit 
to allow 
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Section # and Name 
Description of Change 
Brief Rationale 
visit is numbered 801 and the Week 83 visit 
is now numbered 802. Updated the visit 
numbers throughout the protocol. Updated 
header rows for both of the SoA tables. A 
“T” and “F” were added to indicate 
telehealth and fasting visits. 
continued 
titration of non-
study insulin as 
participants 
transition off 
study drug 
Added interval tolerance for Weeks 50 and 
76 (Visits 29 and 36, respectively) 
For consistency 
and clarity 
Deleted “Fasting” from “Fasting Glucose” 
For consistency 
Added text “participant” to “Site administers 
study intervention and trains participant” 
For clarity 
Added text “and storage” to “Assess study 
and compliance” 
For clarity 
Deleted patient and added “participant” to 
“Patient returns unused study drug” 
Correction 
Addition of “X” for “Concomitant 
medications” “Adverse events (AEs)” 
“Hypoglycemia events” “Diary compliance 
check” “IWRS” 
To add activities 
that should 
occur in the 801 
visit 
Added Activity for Diary Compliance Check 
at Visit 801 
For consistency 
Diary Return comment was revised. “added 
the last study visit” 
For clarity 
Added “X” at 52 weeks for EQ-5D-5L 
To indicate that 
EQ-5D-5L 
should be 
administered at 
52 weeks 
Added note to SIM-Q stating “Administered 
only if ET occurs before Visit 26” 
For clarity 
Urine pregnancy collection added for ET and 
802 visits. Comment was updated 
To verify 
WOCBP 
participants 
pregnancy status 
at study 
discontinuation 
or completion 
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Section # and Name 
Description of Change 
Brief Rationale 
Deletion of “X” from “Insulin dose 
assessment /adjustment/documentation” 
The activity is 
not necessary at 
the 801 visit 
Moved activity “Study participant may 
resume nonstudy insulin as clinically 
indicated” up within the table  
To align with 
other similar 
activities 
Added an activity “Nonstudy insulin dose 
assessment/adjustment/documentation” with 
“X” at Visits 37, ET, 801 and 802 
For clarity 
Removed the 801 visit for insulin dose 
assessment/adjustment/documentation 
Not necessary 
Note bullet point 6: text revised 
For clarity 
Note bullet point 8: text revised regarding 
PK sampling  
Section 2.3.1. Protocol Risk 
Mitigation Factors 
Text added 
To allow 
investigator to 
use clinical 
judgement to 
adjust the dose 
and not use the 
algorithm if 
clinically 
indicated 
Section 3. Objectives, 
Endpoints, and Estimands 
Key secondary modified adding “during the” 
and deleting “by …collected” 
For consistency 
and clarity 
 
Other secondary modified adding text 
“measured”  
 
 
PK/PD objective added to Tertiary 
Objectives the endpoints added are as 
follows: 
 LY3209590 PK and concentration-
response relationships to key safety 
and efficacy measures 
  Potential intrinsic and extrinsic factors 
To specify 
PK/PD 
objectives 
 
Tertiary patient-reported outcomes modified 
to add text to include ED-5D-5L scale 
To indicate 
tertiary 
objective for 
EQ-5D-5L 
outcome 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1.1. Design 
Outline 
Visit 2: text added “and record the insulin 
doses in the e-diary.” 
To clarify that 
participants will 
record their 
insulin doses in 
the e-diary 
throughout the 
study 
Visit 3: text added “Participants will 
continue to record their insulin doses in the 
e-diary throughout the study.” 
Visit 4: text added “and document the dose 
administered in the e-diary before leaving 
the site.” 
For clarity that 
participants will 
record their 
insulin doses in 
the e-diary 
throughout the 
study 
 
Visit 5 (Week 2) - Visit 37 (Week 78): Visit 
38 was changed to Visit 37 
To accurately 
reflect the visit 
numbers in the 
SoA 
 
Study Period III: Safety Follow-up Period: 
text added “Non-insulin antihyperglycemic 
medications will be continued. Investigators 
will prescribe and document the prescribed 
insulin dose during the safety follow-up 
period.” 
For clarity 
regarding Visit 
801 
 
Text added “Study participants must 
measure their FBG levels each day when 
possible or at a minimum 3 times per week.” 
For clarity 
regarding Visit 
802 
Section 4.2. Scientific 
Rationale for Study Design 
Text edited regarding stable insulin dose 
Added “ and other published algorithms” 
and the associated references 
For clarity 
Section 4.3. Justification for 
Dose 
Justification for the LY3209590 single 
loading dose: text revised to state 
“Following a once-weekly subcutaneous 
administration of LY3209590, the time to 
reach steady-state PK without a loading dose 
is estimated to be between 8 and 10 weeks 
based on the long half-life of LY3209590. 
To clarify 
difference in 
time to steady 
state with and 
without a 
loading dose 
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Section # and Name 
Description of Change 
Brief Rationale 
With a loading dose, the estimated time to 
reach steady state is within 2-3 weeks.” 
Section 4.4. End of Study 
Definition 
Text revised 
For consistency  
Section 5.1. Inclusion 
Criteria 
Inclusion criteria modified to add “insulin 
regimens (includes biosimilars)” 
For clarity 
Section 6.1. Study 
Intervention(s) 
Administered 
Added text “This table lists the interventions 
used in this clinical study.” 
For clarity 
 
In table: edited Use text to indicate 
“Experimental” and “ Active comparator” 
 
 
Packaging and Labeling text moved from 
Section 6.7 and revised 
For consistency 
Section 6.1.1. Medical 
Devices 
Medical devices text moved to Section 6.1.1 
For consistency 
with clinical 
protocol 
template 
Section 6.1.2 LY3209590 
and Insulin Degludec 
Dosing 
Added Section titled “LY3209590 and 
Insulin Degludec Dosing” 
For clarity 
 
Text added to indicate the anatomical 
locations 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 protocol 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1.3. General 
Insulin Dose Considerations 
for Both Treatment Groups 
Deleted last sentence 
Duplicate 
Text added regarding hypoglycemia dose 
reduction criteria 
For clarity 
Section 6.1.3 General 
Insulin Dose 
Insulin Dose Titration and 
Dose Maintenance 
Minor text revisions 
For clarity 
Text added “Investigators are expected to 
follow the dosing algorithms for the 
protocol; however, modifications of the 
basal insulin dose may be influenced by 
other clinical circumstances or safety 
considerations know to the investigator. If 
the investigator prescribes a dose other than 
the algorithm recommended dose, the 
investigator is responsible for documenting 
the clinical rationale for the prescribed dose 
in the Study Works web portal.” 
 
For clarity 
Section 6.1.4. LY3209590 
Dose Initiation and 
Modification 
Text and two tables (Tables 7 and 8) were 
deleted and a single table was created 
combining the dose adjustment information 
For clarity 
Section 6.1.5. Insulin 
Degludec Dose Initiation 
and Modification 
Hypoglycemia dose reduction criteria for 
insulin degludec unit dose decrease revised 
to 2-6 units. Footnote a was also added. 
To align with 
FDA 
recommendation 
for insulin 
degludec dose 
reduction 
criteria to match 
the LY3209590 
weekly unit 
dose reduction 
more closely 
Units of insulin degludec in the Insulin 
degludec Dose Adjustment table were 
revised.  
To align with 
FDA 
recommendation 
for cumulative 
daily insulin 
units for week 
used in degludec 
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Section # and Name 
Description of Change 
Brief Rationale 
titration 
algorithm to 
more closely 
match the 
LY3209590 
weekly unit 
titration 
algorithm  
Section 6.1.6. Management 
of Hypoglycemia 
Revised text regarding prescription of 
glucagon to participants 
For clarity 
Section 6.2 Preparation, 
Handling, Storage, and 
Accountability 
Text was updated information from 
“instructions for use” to “pharmacy manual” 
Also removed statement around insulated 
bags 
 
Corrected text  
Section 6.7 Treatment of 
Overdose 
Added medical monitor to include “lilly designated” 
For clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.8. Concomitant 
Therapy 
Deleted text “In addition, certain permitted 
medications (for example, treatments for 
blood pressure or dyslipidemia) may be 
continued.” 
For clarity 
Added text “that may substantially affect 
glycemic values” 
For clarification 
that participants 
do not have to 
consult with the 
investigator 
before any new 
medication is 
prescribed 
Added the word “non-insulin” to the last 
sentence 
For clarity 
Added “This table” to This table provides a 
summary of criteria for use of concomitant 
medications during the study. 
 
Inadvertently 
deleted 
Criteria for Use of Concomitant Medications 
table revised: the rescue therapy column not 
applicable for non-study basal insulins and 
insulin mixtures 
For consistency 
Section 6.8.5.1. Treatment 
after Study Completion 
Added text “and continue to monitor their 
FBG and complete the e-diary.” to the 
sentence Participants will continue their 
concomitant non-insulin antihyperglycemic 
medications at the discretion of the 
investigator 
To add 
monitoring 
information  
 
Study Participants treated with LY3209590: 
revised text  
For clarity 
Study Participants treated with insulin 
degludec: revised text 
Deleted: If their pre-study basal insulin was 
insulin degludec, they can continue with the 
same dose used of the study. If they 
transition to another basal insulin (for 
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CONFIDENTIAL 
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126 
Section # and Name 
Description of Change 
Brief Rationale 
example, insulin glargine), study participants 
should inject a daily dose and titrate 
Added text 
The investigator will prescribe the non-study 
insulin and titrate the dose based on their 
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. 
 
Section 6.8.5.2. Emergency 
Situations and Special 
Circumstances 
Text added “consecutive” was also added in 
front of “weeks”; “glucose-lowering” was 
changed to “antihyperglycemic” “After 
Week 26, dose changes to non-insulin 
antihyperglycemic medications or temporary 
treatment with a non-study insulin is allowed 
but must be documented by the 
investigator.” 
For clarity 
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127 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1. 
Discontinuation of Study 
Intervention 
Permanent Discontinuation of Study 
Intervention: edited text—deleted 
“In rare instances, it may be necessary for a 
participant to permanently discontinue study 
intervention. If study intervention is 
permanently discontinued, the participant 
may receive another glucose-lowering 
intervention and will continue participation 
in the study for continued monitoring. Both 
efficacy (including HbA1c) and safety data 
will continue to be collected per the SoA.” 
Updated to template text 
To align with 
template 
required text 
and for 
consistency 
Sub-bullet added “if the investigator 
determines that the participant is persistently 
noncompliant after the 26-week treatment 
period” 
For clarity 
Bullet deleted: “if a study participant is 
inadvertently enrolled and it is determined 
that continued treatment with IP would not 
be medically appropriate” 
For consistency 
Sub-bullets deleted 
 Discontinuation due to a hepatic 
event or liver test abnormality 
 Participants who are discontinued 
from IP due to a hepatic event or 
liver test abnormality should have 
additional hepatic safety data 
collected via eCRF.  
Information is 
duplicate of 
Section 7.1.1 
Added Hypersensitivity reactions 
standardized text 
To align with 
protocol 
template 
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128 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.1 Liver 
Chemistry Stopping Criteria 
Section title was added along with the 
following text “The study drug should be 
interrupted or discontinued if one or more of 
these conditions occur:” “Resumption of the 
study drug 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-drug etiology is identified.” 
To align with 
protocol 
template 
Section 7.1.2. QTc 
Stopping Criteria 
Deleted the section 
There is no 
specific QTc 
stopping criteria 
due to no known 
or suspected 
safety-related 
risk with 
insulins or 
LY3209590 
Section 7.2. Participant 
Discontinuation/Withdrawal 
from the Study 
Edited discontinuation and withdrawal text 
 
To align with 
template 
required text 
Section 7.3. Lost to Follow-
Up 
Deleted text regarding collection of vital 
status information 
To align with 
template 
required text 
Section 8.2.3. 
Electrocardiograms 
Text added “If there is a clinically significant 
finding identified by the investigator, the 
investigator or qualified designee will 
determine if the participant should remain in 
study and if any changes should be made to 
participant care. The review of the 
electrocardiogram (ECG) printed at the time 
of collection must be documented. Any new 
clinically relevant finding should be reported 
as an AE.” 
Responsibility 
of investigator 
to determine 
participation in 
study if 
clinically 
significant 
findings on 
ECG 
Section 8.3.1 Timing and 
Mechanism for Colleting 
Events 
Throughout the table added the word “last” 
to safety follow-up visit 
For clarity 
Section 8.3.2 Pregnancy 
Text added “This applies only to male 
participants who receive study intervention.” 
To align with 
protocol 
template 
required text 
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129 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.3. Adverse 
Events of Special Interest 
Deleted the section  
Section is not 
applicable 
Section 8.3.4 Systemic 
Hypersensitivity Reactions 
Updated first paragraph language to 
standardized template text  
For consistency 
Section 8.3.5 Injection Site 
Reactions 
Added Section header  
For consistency 
and clarity 
Section 8.4. 
Pharmacokinetics 
Text revised regarding sample collection 
For consistency 
Section 8.8. 
Immunogenicity 
Assessments 
Section edited to describe instructions for 
handling blood samples 
For clarity and 
consistency 
Section 9.1. Statistical 
Hypotheses 
Section edited 
For clarity and 
consistency 
Section 9.3.2. Primary 
Endpoint/Estimand 
Analysis 
Deleted the text for superiority of HbA1c 
The superiority 
of HbA1c 
belongs to key 
secondary 
objectives and 
similar text is in 
Section 9.3.3 
Secondary 
Endpoints 
Analysis 
Section 9.3.3. Secondary 
Endpoints Analysis 
Section edited 
To clarify the 
treatment 
regimen 
estimand on the 
time in glucose 
range measured 
by CGM to 
address FDA 
feedback 
Section 9.3.3.1 Multiplicity 
Adjustment Endpoints 
Updated text deleting Visit 1[Week 3] and 
adding “randomization” 
Correction 
Section 9.3.6.1. 
Pharmacokinetic and 
pharmacodynamic analyses 
Section added 
To characterize 
the PK/PD 
analyses 
Section 10.1.5. Committees 
Structure 
Section added 
Section was 
inadvertently 
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CONFIDENTIAL 
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130 
Section # and Name 
Description of Change 
Brief Rationale 
deleted in 
previous version 
Section 10.1.7 Data Quality 
Assurance 
 Deleted text “that is laboratory tests’ 
Under Data Capture System added “or web 
portal;” 
For clarity 
Section 10.1.12 Sample 
Retention 
The following note was deleted 
“Note: The sponsor has a right to retain a 
portion of submitted biopsy tissue. Archival 
blocks will be returned to the study site. 
Slides and tissue samples collected on study 
will not be returned.” 
The note was 
not applicable 
since biopsy 
tissues are not 
collected in this 
study. 
Section 10.2 Clinical 
Laboratory tests 
Added comment to glucose under the 
Urinalysis section “Fasting or random (Refer 
to SoA) 
For clarity 
Added comment to Additional Testing 
“Fasting per SoA” 
For clarity 
Section 10.2.1. Laboratory 
Samples to be Obtained at 
the Time of A Systemic 
Hypersensitivity Event 
Updated section heading, text, and table 
To align with 
updated 
standardized 
protocol text 
Section 10.3.1. Appendix 3: 
Adverse Events and Serious 
Adverse Events: Definitions 
and Procedures for 
Recording, Evaluating, 
Follow-Up, and Reporting 
Events Meeting the AE Definition: edited 
text regarding medication error 
Footnotes were updated to refer to the 
correct ones in the table 
To align with 
template 
required text 
Section 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 
Added Section and Section numbers were 
updated 
Section was 
inadvertently 
deleted in 
previous 
protocol version 
Section 10.7 Provisions for 
Changes in Study Conduct 
During Exceptional 
Circumstances 
Screening period guidance updated to 24 
days instead of 14 days 
For consistency 
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131 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial and document formatting 
revisions 
Minor, 
therefore, have 
not been 
summarized 
 
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132 
11.
References
[ADA] American Diabetes Association. Standards of medical care in diabetes—2021. Diabetes 
Care. 2021. 
Berard L, Bonnemaire M, Mical M, Edelman S. Insights into optimal basal insulin titration in 
type 2 diabetes: Results of a quantitative survey. Diabetes Obes Metab. 2018;20(2):301-308. doi: 
10.1111/dom.13064. Epub 2017 Sep 12. PMID: 28719066; PMCID: PMC5811840. 
https://doi.org/10.1111/dom.13064 
Bradley C, Lewis KS. Measures of psychological well-being and treatment satisfaction 
developed from the responses of people with tablet-treated diabetes. Diabet Med. 1990;7(5):445-
451. DOI: 10.1111/j.1464-5491.1990.tb01421.x
Bradley C. (Ed). Handbook of psychology and diabetes: a guide to psychological measurement 
in diabetes research and practice; Harwood Academic Publishers, 1994. 
https://doi.org/10.1186/1477-7525-5-57 
Bradley C. Diabetes Treatment Satisfaction Questionnaire: Change version for use alongside 
status version provides appropriate solution where ceiling effects occur. Diabetes Care. 
1999;22(3):530-532. https://pubmed.ncbi.nlm.nih.gov/10097946 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Statist Med. 2009;28:586-604 
https://pubmed.ncbi.nlm.nih.gov/19051220 
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 
Brod M, Hammer M, Christensen T, et al. Understanding and assessing the impact of treatment 
in diabetes: the Treatment-Related Impact Measures for Diabetes and Devices (TRIM-Diabetes 
and TRIM-Diabetes Device). Health Qual Life Outcomes. 2009;7(83). 
https://doi.org/10.1186/1477-7525-7-83 
CDC 2021. How to treat low blood sugar (hypoglycemia). 
https://www.cdc.gov/diabetes/basics/low-blood-sugar-treatment.html 
EuroQol Research Foundation. EQ-5D-5L user guide, version 3.0. Updated September 2019. 
https://euroqol.org/publications/user-guides. 
Kadowaki T, Jinnouchi H, Kaku K, et al. Insulin degludec in a simple or stepwise titration 
algorithm in a Japanese population of patients with type 2 diabetes: a randomized, 26-week, 
treat-to-target trial. Diabetol Int (2017) 8:87-94. 
Meneghini L., Koenen C., Weng W. et al. The usage fo a simplified self-titration dosing 
guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes-results of the 
randomized, controlled PREDICTIVEtm 303 study. Diabet. Obesity Metab.2007;9(6):902-913. 
https://doi.org/10.1111/j.1463-1326.2007.00804.x 
Mocarski M, Yeaw J, Divino V, et al. Slow titration and delayed intensification of basal insulin 
among patients with type 2 diabetes. J Manag Care Spec Pharm. 2018;24(4):390-400. 
https://www.jmcp.org/doi/10.18553/jmcp.2017.17218 
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Okemah J, Peng J, Quiñones M. Addressing clinical inertia in type 2 diabetes mellitus: a review. 
Adv Ther. 2018;35(11):1735-1745. https://pubmed.ncbi.nlm.nih.gov/30374807 
Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The treat-to-
target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 
diabetic patients. Diabetes Care. 2003;26:3080-3086. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley; 1987. 
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