A Phase 3, Parallel-Design, Open-Label, Randomized Controlled Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Glargine in Adults With Type 2 Diabetes on Multiple Daily Injections
Phase: PHASE3
Conditions: Type 2 Diabetes, Type 2 Diabetes Treated With Insulin
Sponsor: Eli Lilly and Company

Protocol I8H-MC-BDCV (b)
A Phase 3, Parallel-Design, Open-Label, Randomized Controlled Study to Evaluate the Efficacy
and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Glargine in Adults With
Type 2 Diabetes on Multiple Daily Injections
NCT05462756
Approval Date: 17-OCT-2022

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I8H-MC-BDCV(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 Basal Insulin Fc (LY3209590), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: 
A Phase 3, Parallel-Design, Open-Label, Randomized Controlled Study to Evaluate the Efficacy 
and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Glargine in Adults 
with Type 2 Diabetes on Multiple Daily Injections 
Protocol Number: I8H-MC-BDCV 
Amendment Number: b 
Compound: LY3209590 
Brief Title:  
Efficacy and Safety of LY3209590 Compared with Daily Insulin Glargine in Adults with Type 
2 Diabetes on Multiple Daily Injections 
Study Phase: 3   
Acronym: QWINT-4  
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
IND: 129390 
EudraCT: 2021-005878-25 
Document ID: VV-CLIN-074596 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
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I8H-MC-BDCV(b) 
 
2 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment a 
10-May-2022
Original Protocol 
05-Apr-2022
Amendment [b] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The overall rationale for the current amendment is to add the Diabetes Injection Device 
Experience Questionnaire (DID-EQ) scale. Additional minor clarifying changes and corrections 
have also been made. Individual changes are described in this table. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Added DID EQ to Other Secondary 
objectives. 
To meet regulatory 
requirement 
1.3. Schedule of 
Activities (SoA) 
Added bullet above the SoA to describe 
Visit Interval.  
For clarity 
1.3. Schedule of 
Activities (SoA) 
Patient-Reported Outcomes line item: 
Removed “(Electronic)” from line title 
and added “Collected using electronic 
device (eCOA)” in comment column for 
the existing sub rows under Patient-
Reported Outcomes. 
For clarity 
1.3. Schedule of 
Activities (SoA) 
Added entry for DID-EQ. 
To meet regulatory 
requirement 
1.3. Schedule of 
Activities (SoA) 
The comment column of the 
Pharmacokinetic (PK) samples line item 
was edited to add “For participants 
randomly assigned to glargine who are 
not dosed onsite during Visit 3, the 
sample may be collected anytime during 
Visit 3.” 
For clarity 
3. Objectives, Endpoints,
and Estimands
Added DID EQ to Other Secondary 
objectives. 
To meet regulatory 
requirement 
3. Objectives, Endpoints,
and Estimands
Secondary estimands (for multiplicity-
adjusted objectives) sub section: 
Analysis details removed from protocol 
and described in the SAP. 
To address regulatory 
feedback 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
Edited inclusion criterion 7, changing 
the final part of the 2nd sentence, 
replacing “prior to” with “at”; it now 
reads “at the evening meal.” 
For clarity 
6.5.2.2. Insulin Glargine 
Dose Adjustment 
In the first sentence, “Visit 5” was 
changed to “Visit 4”. 
Error correction 
8.1. Efficacy 
Assessments 
Added the DID-EQ in the list of 
questionnaires and reordered the list. 
To meet regulatory 
requirement 
8.1.2. Patient-reported 
Outcomes 
Added the DID-EQ in the list of 
questionnaires. 
To meet regulatory 
requirement 
8.1.2.2. Diabetes 
Injection Device 
Experience 
Questionnaire 
Added DID-EQ description. 
To meet regulatory 
requirement 
9.1 Statistical 
Hypotheses 
Added “Each NIM will have its own 
familywise error rate” for NIM 0.4% 
and 0.3%. 
For clarity  
9.3.3.2. Other Secondary 
Endpoints 
Added “patient-reported outcome 
measures” and “and patient-reported 
outcome" in first and second sentences, 
respectively. 
To meet regulatory 
requirement 
10.2.1. Laboratory 
Samples to be Obtained 
at the Time of a Systemic 
Hypersensitivity Event 
In row 1 of table, added “Plasma” in the 
sub row associated with laboratory tests 
for complements C3, C3a, and C5a. 
Error correction 
10.7.1.2. Changes 
Related to “Legally 
Authorized 
Representative,” “Legal 
Guardian,” “Parents” 
Deleted “10.1.3 Informed Consent 
Process” from table. 
Error correction 
10.10. Appendix 10: 
Protocol Amendment 
History 
In 2nd entry for Section 5.1 Inclusion 
Criteria, inserted “added”; now it reads 
“In inclusion criterion 7, removed 
“stable regimen” and added “any”. 
Error correction 
11. References 
Added reference for Matza et al. 2018 
to support addition of the DID-EQ. 
To meet regulatory 
requirement 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................13 
2. 
Introduction ...................................................................................................................23 
2.1. 
Study Rationale ...............................................................................................................23 
2.2. 
Background .....................................................................................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................24 
2.3.1. 
Risk Assessment .............................................................................................................24 
2.3.2. 
Benefit Assessment .........................................................................................................25 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................25 
3. 
Objectives, Endpoints, and Estimands .......................................................................26 
4. 
Study Design ..................................................................................................................30 
4.1. 
Overall Design ................................................................................................................30 
4.2. 
Scientific Rationale for Study Design ............................................................................32 
4.3. 
Justification for Dose ......................................................................................................33 
4.4. 
End of Study Definition ..................................................................................................34 
5. 
Study Population ...........................................................................................................35 
5.1. 
Inclusion Criteria ............................................................................................................35 
5.2. 
Exclusion Criteria ...........................................................................................................37 
5.3. 
Lifestyle Considerations .................................................................................................39 
5.4. 
Screen Failures ................................................................................................................40 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................40 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................41 
6.1. 
Study Intervention(s) Administered................................................................................41 
6.1.1. 
Medical Devices..............................................................................................................42 
6.1.2. 
Background Therapy .......................................................................................................42 
6.1.3. 
Rescue Therapy for Management of Participants with Severe, 
Persistent Hyperglycemia during the Treatment Period .................................................42 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................44 
6.4. 
Study Intervention Compliance ......................................................................................44 
6.5. 
Dose Modification ..........................................................................................................45 
6.5.1. 
LY3209590 Dose Initiation and Adjustment ..................................................................46 
6.5.2. 
Insulin Glargine Dose Initiation and Adjustment ...........................................................49 
6.5.3. 
Prandial Insulin Lispro Dose Initiation and Adjustment ................................................50 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................52 
6.6.1. 
Transitioning off of Study Basal Insulin .........................................................................52 
6.7. 
Treatment of Overdose ...................................................................................................53 
6.8. 
Concomitant Therapy .....................................................................................................54 
6.8.1. 
Medications with Approved Weight Loss Indication .....................................................54 
6.8.2. 
Chronic Systemic Glucocorticoid Medication ................................................................55 
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6.8.3. 
Antihyperglycemic Medications .....................................................................................55 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................57 
7.1. 
Discontinuation of Study Intervention ............................................................................57 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................57 
7.1.2. 
Hypersensitivity Reactions .............................................................................................58 
7.1.3. 
Temporary Discontinuation ............................................................................................58 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................59 
7.3. 
Lost to Follow up ............................................................................................................59 
8. 
Study Assessments and Procedures.............................................................................60 
8.1. 
Efficacy Assessments .....................................................................................................60 
8.1.1. 
Glucose Monitoring ........................................................................................................60 
8.1.2. 
Patient-reported Outcomes ..............................................................................................62 
8.2. 
Safety Assessments .........................................................................................................64 
8.2.1. 
Physical Examinations ....................................................................................................64 
8.2.2. 
Vital Signs .......................................................................................................................64 
8.2.3. 
Electrocardiograms .........................................................................................................64 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................64 
8.2.5. 
Hepatic Monitoring .........................................................................................................65 
8.2.6. 
Pregnancy Testing ...........................................................................................................68 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................68 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................69 
8.3.2. 
Pregnancy ........................................................................................................................71 
8.3.3. 
Adjudicated Events: Cerebrocardiovascular Events .......................................................72 
8.3.4. 
Systemic Hypersensitivity Reactions ..............................................................................72 
8.3.5. 
Injection-Site Reactions ..................................................................................................72 
8.3.6. 
Hypoglycemia .................................................................................................................72 
8.4. 
Pharmacokinetics ............................................................................................................73 
8.5. 
Pharmacodynamics .........................................................................................................74 
8.6. 
Genetics ..........................................................................................................................74 
8.7. 
Biomarkers ......................................................................................................................74 
8.8. 
Immunogenicity Assessments.........................................................................................74 
8.9. 
Health Economics ...........................................................................................................75 
9. 
Statistical Considerations .............................................................................................76 
9.1. 
Statistical Hypotheses .....................................................................................................76 
9.1.1. 
Multiplicity Adjustment ..................................................................................................76 
9.2. 
Analyses Sets ..................................................................................................................77 
9.3. 
Statistical Analyses .........................................................................................................77 
9.3.1. 
General Considerations ...................................................................................................77 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................78 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................79 
9.3.4. 
Tertiary Endpoint(s) Analysis .........................................................................................80 
9.3.5. 
Safety Analyses ...............................................................................................................80 
9.3.6. 
Other Analyses ................................................................................................................81 
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9.4. 
Interim Analysis ..............................................................................................................82 
9.5. 
Sample Size Determination ............................................................................................82 
10. 
Supporting Documentation and Operational Considerations ..................................84 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................84 
10.1.1. Regulatory and Ethical Considerations ...........................................................................84 
10.1.2. Financial Disclosure........................................................................................................85 
10.1.3. Informed Consent Process ..............................................................................................85 
10.1.4. Data Protection................................................................................................................85 
10.1.5. Committees Structure......................................................................................................85 
10.1.6. Dissemination of Clinical Study Data.............................................................................86 
10.1.7. Data Quality Assurance ..................................................................................................87 
10.1.8. Source Documents ..........................................................................................................88 
10.1.9. Study and Site Start and Closure ....................................................................................89 
10.1.10. Publication Policy ...........................................................................................................89 
10.1.11. Investigator Information .................................................................................................89 
10.1.12. Sample Retention ............................................................................................................90 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................91 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................94 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................95 
10.3.1. Definition of AE .............................................................................................................95 
10.3.2. Definition of SAE ...........................................................................................................96 
10.3.3. Definition of Product Complaints ...................................................................................97 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................98 
10.3.5. Reporting of SAEs ........................................................................................................100 
10.3.6. Regulatory Reporting Requirements .............................................................................100 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ........................................................102 
10.4.1. Definitions.....................................................................................................................102 
10.4.2. Contraception Guidance................................................................................................103 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ..................................................................................................................105 
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: Country-specific Requirements ...............................................................108 
10.7.1. Germany ........................................................................................................................108 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................110 
10.9. 
Appendix 9: Abbreviations and Definitions .................................................................114 
10.10. 
Appendix 10: Protocol Amendment History ................................................................119 
11. 
References ....................................................................................................................121 
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1.
Protocol Summary
1.1. 
Synopsis 
Protocol Title: 
A Phase 3, Parallel-Design, Open-Label, Randomized Controlled Study to Evaluate the Efficacy 
and Safety of LY3209590 as a Weekly Basal Insulin Compared to Insulin Glargine in Adults 
with Type 2 Diabetes on Multiple Daily Injections 
Brief Title: 
Efficacy and Safety of LY3209590 Compared with Daily Insulin Glargine in Adults with Type 
2 Diabetes on Multiple Daily Injections 
Regulatory Agency Identifier Numbers: 
IND: 129390 
EudraCT: 2021-005878-25 
Rationale: 
This Phase 3 study will evaluate the efficacy and safety of once-weekly administration of 
LY3209590 compared to daily administration of insulin glargine in participants with type-2 
diabetes (T2D) who are on once- or twice-daily basal insulin and at least 2 injections per day of 
prandial insulin prior to entering the study. Participants will continue prior stable therapy with 0 
to 3 allowed noninsulin diabetes medications during the study. 
This study will inform the clinical development of LY3209590. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
Demonstrate noninferiority of 
LY3209590 compared to insulin 
glargine on glycemic control. 
Change in HbA1c from baseline at Week 26 
Key Secondary (Multiplicity 
Adjusted) 
Demonstrate LY3209590 is superior 
to insulin glargine in the selected 
parameters of glycemic control. 
Change in HbA1c from baseline at Week 26
The percentage of participants achieving HbA1c <7%
at Week 26 without nocturnal hypoglycemia (<54
mg/dL [3.0 mmol/L] or severe) during treatment
phase up to Week 26
The event rate of participant-reported clinically
significant nocturnal hypoglycemia (<54 mg/dL [3.0
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mmol/L] or severe) during treatment phase up to 
Week 26 
Other Secondary 
 
To investigate the effect of 
LY3209590 compared with insulin 
glargine in additional parameters of 
diabetes management. 
 Change in fasting glucose measured by SMBG from 
baseline to Week 26 
 Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), inclusive measured during the 
CGM session that occurs between Week 22 and Week 
26  
 Time in hypoglycemia range with glucose <54 mg/dL 
(3.0 mmol/L), measured by CGM that occurs between 
Week 22 and Week 26  
 Time in hyperglycemia range with glucose >180 
mg/dL (10.0 mmol/L), measured by CGM that occurs 
between Week 22 and Week 26  
 Glucose variability measured during the CGM session 
that occurs between Week 22 and Week 26 
 Insulin dose at Week 26 
o basal 
o bolus 
o total, and 
o basal/total insulin dose ratio. 
To investigate the safety of 
LY3209590 compared with insulin 
glargine. 
 Incidence and rate of composite of Level 2 and 3 
hypoglycemia events during treatment period 
 Body weight change from baseline to Week 26  
To investigate the treatment impact 
of LY3209590 compared with 
insulin glargine on patient-reported 
outcome measures. 
 Treatment experience at Week 26 for DID-EQ 
Abbreviations: CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; SMBG = self-monitoring of 
blood glucose. 
Overall Design: 
Study I8H-MC-BDCV is a Phase 3, parallel-design, open-label, randomized control trial that will 
evaluate the efficacy and safety of LY3209590 compared to insulin glargine in participants with 
T2D who are on once- or twice-daily basal insulin and at least 2 injections per day of prandial 
insulin prior to entering the study. Participants will continue prior stable therapy with 0 to 3 
allowed noninsulin diabetes medications during the study. 
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Brief Summary: 
The study consists of a 1-week screening period, a 2-week lead-in period, a 26-week treatment 
period, and a 5-week safety follow-up period.  
All participants will use a study-provided, blinded continuous-glucose monitoring (CGM) 
system, glucometer, and e-diary to facilitate diabetes and hypoglycemia management and for 
data collection throughout the study. 
The primary outcome is the change in hemoglobin A1c (HbA1c) from baseline at Week 26. 
Study Population: 
In general, participants may take part in the study if they 
 are at least 18 years of age or older 
 have a diagnosis of T2D currently treated with basal insulin and at least 2 injections of 
prandial insulin per day  
 are receiving at least 10 units of total basal insulin per day 
 are receiving less than or equal to 2 units/kg/day of total daily insulin at screening, and   
 have an HbA1c value of 7.0% to 10%, inclusive, at screening.  
In general, participants may not take part in the study if they 
 have a diagnosis of type 1 diabetes mellitus or latent autoimmune diabetes, or specific 
type of diabetes other than T2D 
 are persons of childbearing potential who are pregnant, lactating, or breastfeeding 
 have a history of renal transplantation, are currently receiving renal dialysis, or have an 
estimated glomerular filtration rate <30 mL/min/1.73 m2, or 
 have any other serious disease or condition that, in the opinion of the investigator, would 
pose a significant risk to the study participant, or preclude the study participant from 
following and completing the protocol. 
Number of Participants: 
Approximately 670 participants will be randomly assigned to LY3209590 and insulin glargine in 
a 1:1 ratio. With the assumption of 15% dropout at Week 26, approximately 284 participants on 
LY3209590 and 284 participants on insulin glargine will complete 26 weeks of treatment. 
Intervention Groups and Duration: 
Participants who meet entry criteria will be randomly assigned in a 1:1 ratio to LY3209590 or 
insulin glargine basal insulin treatment. LY3209590 will be administered once weekly, and 
insulin glargine will be administered once daily. 
Participants will also be treated with insulin lispro as prandial insulin.   
The study treatment period duration is 26 weeks. 
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Ethical Considerations of Benefit/Risk: 
Considering the clinical data to date and measures taken to minimize risk for the participants in 
this study, the potential risks identified in association with LY3209590 are justified by the 
anticipated benefits that may be afforded to persons with T2D.  
Data Monitoring Committee: Yes 
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1.2. 
Schema 
 
Abbreviation: CGM = continuous glucose monitoring.
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1.3. 
Schedule of Activities (SoA) 
Screening 
Screening procedures may be conducted over 1 to 3 days. 
Telehealth visits 
Telehealth visits may be by telephone or other technology. Gray shaded columns in the SoA represent telehealth visits. 
Unscheduled visits 
Unscheduled visits (UV) may occur as needed. The SoA reflects some of the procedures that may occur during these visits. Perform 
additional procedures per investigator discretion.  
Fasting visits 
Participants should not eat or drink anything but water for a minimum of 8 hours before a fasting visit.   
If a participant attends these visits in a non-fasting state, the sample should be collected as non-fasting, and this will not be considered 
a protocol deviation. 
Visit interval 
The visit intervals, including the allowable visit window, should be scheduled relative to randomization Visit 3 (Week 0). Visit 3 
(Week 0) should occur 11 to 17 days after Visit 2. 
 
 
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Screen-
ing and 
Lead-In 
Treatment 
 
Safety 
Follow-
up 
 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization  
-3 
-2 
0 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
 
29 
31 
 
Visit Interval 
Tolerance (days) 
 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
 
+7 
±7 
 
Visit Detail 
 
 
F 
 
 
T F T 
 
T 
 
T T T F T 
 
T T 
 
T T F 
F 
 
T 
F 
T = telehealth visit; F = fasting visit 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The ICF must be signed before any 
protocol-specific tests/procedures are 
performed. See Section 10.1.3 for 
additional details. 
Inclusion and 
exclusion criteria, 
review and confirm 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm inclusion and exclusion criteria 
prior to randomization and 
administration of first dose of study 
intervention. 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes ethnicity (where permissible), 
year of birth, sex, and race. 
Preexisting conditions 
and medical history, 
including relevant 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect all ongoing conditions and 
relevant past surgical and medical 
history. 
Prespecified medical 
history (indication and 
history of interest)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior treatments for 
indication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screen-
ing and 
Lead-In 
Treatment 
 
Safety 
Follow-
up 
 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization  
-3 
-2 
0 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
 
29 
31 
 
Visit Interval 
Tolerance (days) 
 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
 
+7 
±7 
 
Visit Detail 
 
 
F 
 
 
T F T 
 
T 
 
T T T F T 
 
T T 
 
T T F 
F 
 
T 
F 
T = telehealth visit; F = fasting visit 
Substance use (alcohol, 
caffeine, recreational 
drugs, and tobacco use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
 
Adverse events (AEs) 
X 
X 
X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
AEs are any events that occur after 
signing the informed consent.  
Hypoglycemia events 
X 
X 
X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
Clinical assessment based on participant 
history and e-diary entries. 
Physical Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant should remove shoes. 
Weight  
X 
X 
X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X X 
 
 
X 
 
Vital signs 
X 
X 
X X X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X X 
 
 
X 
Includes blood pressure and pulse rate. 
Measure 3 times, using the same arm, 
after participant has been sitting at least 
5 minutes and before ECG tracing and 
collection of blood samples for 
laboratory testing. Additional vital signs 
may be measured as necessary at 
investigator discretion. 
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Screen-
ing and 
Lead-In 
Treatment 
 
Safety 
Follow-
up 
 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization  
-3 
-2 
0 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
 
29 
31 
 
Visit Interval 
Tolerance (days) 
 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
 
+7 
±7 
 
Visit Detail 
 
 
F 
 
 
T F T 
 
T 
 
T T T F T 
 
T T 
 
T T F 
F 
 
T 
F 
T = telehealth visit; F = fasting visit 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X X 
 
 
X 
Additional physical examinations may 
be completed as necessary at 
investigator discretion. 
12-lead ECG (local) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X X 
 
 
 
Collect prior to collection of blood 
samples for laboratory testing. 
Participants should be supine for 
approximately 5 to 10 minutes before 
ECG collections and remain supine but 
awake during the ECG collection.   
ECGs may be repeated at the 
investigator’s discretion at any visit. 
Blinded Continuous Glucose Monitoring 
Dispense CGM system  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Dispense supplies as needed. 
CGM sensor insertion   
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
At Visits 3 and 23, sites may continue 
with the current sensor rather than 
removing and inserting a new sensor 
before the end of the 10-day wear 
period. 
CGM system return  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
ED Visit: if the ED visit occurs during a 
CGM session, the device must be 
returned.   
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I8H-MC-BDCV(b) 
 
17 
                                       
Screen-
ing and 
Lead-In 
Treatment 
 
Safety 
Follow-
up 
 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization  
-3 
-2 
0 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
 
29 
31 
 
Visit Interval 
Tolerance (days) 
 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
 
+7 
±7 
 
Visit Detail 
 
 
F 
 
 
T F T 
 
T 
 
T T T F T 
 
T T 
 
T T F 
F 
 
T 
F 
T = telehealth visit; F = fasting visit 
CGM data download 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X X 
 
 
X 
ED Visit: if the ED visit occurs during a 
CGM session, the data must be 
downloaded.   
Participant Education  
Diabetes counseling, 
training and education 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes glucose monitoring and 
hypoglycemia (see Sections 5.3, 8.1.1, 
and 8.3.6).  
After Visit 3, conduct as needed. 
e-diary, glucometer, 
CGM training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, conduct as needed. 
Participant Diary (Electronic) and Glucometer and Related Supplies 
Dispense e-diary and 
glucometer 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense supplies as needed. 
e-diary compliance 
check 
 
 
X X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
Review entries of BG, hypoglycemia 
events, and insulin dose. If participant is 
not compliant, study personnel will re-
educate the participant on study 
requirements for continued study 
participation. 
e-diary return 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
The e-diary must be returned on the last 
participant visit.  
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I8H-MC-BDCV(b) 
18 
Screen-
ing and 
Lead-In 
Treatment 
Safety 
Follow-
up 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization 
-3
-2 
0
1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
29 
31 
Visit Interval 
Tolerance (days) 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
+7
±7 
Visit Detail 
F 
T F T 
T 
T T T F T 
T T 
T T F 
F 
T 
F 
T = telehealth visit; F = fasting visit 
Patient-Reported Outcomes 
EQ-5D-5L 
X 
X X 
Collected using electronic device 
(eCOA). 
Basal Insulin 
Experience: Preference 
X X 
Collected using electronic device 
(eCOA). 
Basal Insulin 
Experience: Likelihood 
of Incorporating into 
Routine 
X X 
Collected using electronic device 
(eCOA). 
Diabetes Injection 
Device Experience 
Questionnaire (DID-
EQ) 
X X 
Collected on paper form. 
Laboratory Tests and Sample Collections 
Hematology 
X 
X 
X 
X X 
X 
Hemoglobin A1c 
(HbA1c) 
X 
X 
X 
X 
X 
X 
X X 
X 
Clinical chemistry 
X 
X 
X 
X X 
X 
Glucose 
X 
Lipid panel 
X 
X X 
X 
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I8H-MC-BDCV(b) 
19 
Screen-
ing and 
Lead-In 
Treatment 
Safety 
Follow-
up 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization 
-3
-2 
0
1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
29 
31 
Visit Interval 
Tolerance (days) 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
+7
±7 
Visit Detail 
F 
T F T 
T 
T T T F T 
T T 
T T F 
F 
T 
F 
T = telehealth visit; F = fasting visit 
Urinalysis 
X 
X X 
X 
Serum pregnancy 
X 
X 
Collect for WOCBP only. 
Urine pregnancy 
(local) 
X 
X 
X 
The result must be available prior to first 
dose of intervention.  
Perform additional pregnancy tests if a 
menstrual period is missed, if there is 
clinical suspicion of pregnancy, or as 
required by local law or regulation. 
Follicle-stimulating 
hormone (FSH) 
X 
Perform as needed to confirm 
postmenopausal status. Definition in 
Section 10.4. 
C-peptide
X 
X X 
eGFR (CKD-EPI) 
X 
X 
X 
X X 
X 
Urinary 
albumin/creatinine 
ratio (UACR) 
X 
X 
X 
X X 
X 
Pharmacokinetic (PK) 
samples 
X 
X 
X 
X 
X X 
X 
Visit 3: collect sample at least 15 
minutes after dosing. For participants 
randomly assigned to glargine who are 
not dosed onsite during Visit 3, the 
sample may be collected anytime during 
Visit 3. 
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I8H-MC-BDCV(b) 
 
20 
                                       
Screen-
ing and 
Lead-In 
Treatment 
 
Safety 
Follow-
up 
 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization  
-3 
-2 
0 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
 
29 
31 
 
Visit Interval 
Tolerance (days) 
 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
 
+7 
±7 
 
Visit Detail 
 
 
F 
 
 
T F T 
 
T 
 
T T T F T 
 
T T 
 
T T F 
F 
 
T 
F 
T = telehealth visit; F = fasting visit 
For all other visits, collect at any time 
during the visit. 
Immunogenicity 
(ADA) samples 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X X 
 
 
X 
Visit 3: Collect sample before dosing. 
If an immediate or nonimmediate 
systemic drug hypersensitivity reaction 
occurs, collect additional unscheduled 
samples as detailed in Section 10.2.1.  
Stored Samples 
Exploratory biomarker 
samples  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X X 
 
 
 
Visit 3: Collect before dosing. 
Randomization and Dosing 
Process visit using 
IWRS 
X 
X 
X X X X X X X X X X X X X X X X X X X X X X 
 
X 
X 
ED: Register the participant’s 
discontinuation at next numbered visit. 
Randomization using 
IWRS 
 
 
X 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
Insulin dose 
assessment/adjustment/
documentation 
 
 
X X X X X X X X X X X X X X X X X X X X 
 
 
 
 
 
See Section 6.5. 
Visits 3-15, 17, 19, and 21 are routine 
basal insulin titration visits but doses 
should be assessed and titrated at any 
time, if clinically indicated. 
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I8H-MC-BDCV(b) 
 
21 
                                       
Screen-
ing and 
Lead-In 
Treatment 
 
Safety 
Follow-
up 
 
Visit Number 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 ED UV V801 V802 
V1 = Screening 
V2 = Lead-In 
ED: Early Discontinuation 
UV: Unscheduled Visit 
V801, V802: Safety Follow-up 
Weeks from 
Randomization  
-3 
-2 
0 1 2 3 4 5 6 7 8 9 10 11 12 14 16 18 20 22 24 25 26 — 
 
29 
31 
 
Visit Interval 
Tolerance (days) 
 
±3 — ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 — 
 
+7 
±7 
 
Visit Detail 
 
 
F 
 
 
T F T 
 
T 
 
T T T F T 
 
T T 
 
T T F 
F 
 
T 
F 
T = telehealth visit; F = fasting visit 
Dispense LY3209590 
or insulin glargine  
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Provide prandial 
insulin 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Dispense ancillary 
supplies 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Dispense ancillary supplies at other 
visits as needed.  
Administer study 
intervention at study 
site 
 
 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Visits 3 and 4: (Weeks 0 and 1) - 
LY3209590 will be administered 
during the study visit. 
 Visit 3: Insulin glargine may be 
administered by participants during 
study visit if usual basal dosing time 
overlaps with visit. 
Study intervention 
training  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, review as needed. 
Assess study 
intervention 
compliance 
 
 
 
X X X X X X X X X X X X X X X X X X X X X 
 
 
 
 
Participant returns 
unused study 
intervention 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X X 
 
 
 
 
Assess post-study basal 
and bolus insulin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X X 
 
X 
X 
 
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22 
Abbreviations: ADA = anti-drug antibody BG = blood glucose; CGM = continuous-glucose monitoring; CKD-EPI = Chronic Kidney Disease Epidemiology 
Collaboration; ED = early discontinuation; eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; EQ-5D-5L = EuroQol 5 Dimensions 5 
Levels; ICF = informed consent form; IWRS = interactive web-response system; SMBG = self-monitoring of blood glucose; WOCBP = women of 
childbearing potential.  
 
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I8H-MC-BDCV(b) 
 
23 
2. 
Introduction 
LY3209590 is a long-acting insulin receptor agonist in development for the once-weekly 
treatment of hyperglycemia in patients with T2D and T1D.   
2.1. 
Study Rationale 
This Phase 3 study will evaluate the efficacy and safety of once-weekly administration of 
LY3209590 compared to daily administration of insulin glargine in participants with T2D who 
are on once- or twice-daily basal insulin and at least 2 injections per day of prandial insulin prior 
to entering the study. Participants will continue prior stable therapy with 0 to 3 allowed 
noninsulin diabetes medications during the study. 
This study will inform the clinical development of LY3209590. 
2.2. 
Background 
Current state of diabetes care  
Most people with diabetes are not achieving glycemic targets. Treatment complexity, fear of 
hypoglycemia, delays in insulin initiation and intensification, and suboptimal dosing may pose 
challenges to diabetes care. There is a need for a basal insulin experience that incorporates 
simple dosing algorithms, rapid achievement of glycemic targets, and a predictable PK/PD 
profile with low likelihood of contributing to hypoglycemia. 
Potential for improved treatment regimens and compliance 
For people already using basal insulin to manage diabetes, availability of basal insulin 
administered weekly may improve treatment compliance and lead to better real-world patient 
outcomes. A weekly insulin with a lower peak-to-trough profile across a week and a nearly flat 
within-day insulin profile could also reduce within-day glucose variability and result in more 
consistent and predictable glycemic control.  
LY3209590  
LY3209590 is a novel insulin receptor agonist that is in development as a once-weekly basal 
insulin for the treatment of hyperglycemia in patients with T2D and T1D. LY3209590 has the 
potential to decrease patient burden, overcome barriers to initiation of insulin therapy, and may 
improve glycemic control and quality of life for these patients. 
A detailed description of the chemistry, pharmacology, non-clinical and clinical efficacy, and 
safety of LY3209590 is provided in the IB. 
Summary of clinical results  
Phase 1 and Phase 2 studies, including healthy participants and participants with T1D or T2D, 
have been completed to assess the PK/PD, safety, and efficacy of LY3209590. The results thus 
far support continued development of LY3209590 as a treatment for diabetes mellitus.  
 
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I8H-MC-BDCV(b) 
 
24 
Phase 1 results  
LY3209590 pharmacokinetics show a low peak-to-trough ratio and extended half-life that 
supports once-weekly dosing.  
Single-ascending doses of LY3209590 lowered fasting glucose in a dose- and concentration-
dependent manner, with a prolonged time-action profile.   
Overall, LY3209590 was well tolerated in healthy participants and participants with T2D. 
Phase 2 Study BDCM results  
Phase 2 Study BDCM evaluated the effects of LY3209590 on glycemic control using 2 different 
dosing algorithms compared with insulin degludec in study participants with T2D previously 
treated with basal insulin. The two LY3209590 dosing algorithms and the degludec dosing 
algorithm each had a different FBG target. 
Safety data indicate that there was no increased risk with LY3209590 treatment compared to 
insulin degludec. 
LY3209590, when administered according to either dosing algorithm, was noninferior to insulin 
degludec for glycemic control as measured by change in HbA1c after 32 weeks of treatment. 
Treatment differences in FBG were consistent with the preset FBG targets of the dosing 
algorithms used. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3209590 may be found in the IB. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of insulin glargine may be found in the local product package insert. 
2.3.1. 
Risk Assessment 
Potential risks for this study 
The potential risks associated with LY3209590 include  
 hypoglycemia  
 hyperglycemia 
 hypersensitivity reaction  
 injection-site reactions, for example, injection-site rash, erythema, pruritus, or 
lipohypertrophy  
 immunogenicity, and  
 cardiovascular risks.  
It is expected that the known risks would be similar to other insulins.  
Safety data available to date suggests that there is no increased risk to participants’ safety with 
LY3209590 treatment compared to degludec, a best-in-class basal insulin. 
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I8H-MC-BDCV(b) 
 
25 
Management of risks 
Sections 5.1, 5.2, 6.8.1, 7, and 8.3 address known potential risks associated with LY3209590. 
Protocol risk management measures 
Participant education for hypoglycemia 
After signing informed consent, all participants will be educated about signs and symptoms of 
hypoglycemia, how to treat hypoglycemia, and how to collect appropriate information for each 
episode of hypoglycemia. Hypoglycemia may be identified by spontaneous reporting of 
symptoms from participants, whether confirmed or unconfirmed by simultaneous glucose values, 
or by blood glucose samples collected between study visits. 
Monitoring of participant blood glucose levels 
Each participant will have a study-provided glucometer that will wirelessly transfer participant 
SMBG to their study-provided e-diary. Participants should use the glucometer to check glucose 
values whenever hypoglycemia is experienced or suspected. 
A web-interface and reporting system will be available for use by study personnel to view 
participant e-diary entries, including SMBG, insulin doses, and hypoglycemia information 
throughout the study. Automated alerts will be transmitted to the investigator any time the 
participant reports a potential severe episode of hypoglycemia, defined as requiring assistance due 
to neurological impairment, in the e-diary.  
Dose modification 
The visit schedule allows for close clinical oversight and dose modification. 
The dosing algorithm used in the study requires consideration and adjustment of insulin dosing 
by the investigator based on participant FBG and hypoglycemia events (see Section 6.5). 
All participants will be treated with basal-bolus MDI therapy, which will be titrated to glycemic 
targets and as clinically indicated for hyperglycemia. 
2.3.2. Benefit Assessment 
Participants may benefit by receiving personal health information, routine safety assessments, 
and frequent engagement with health care providers during the study which provide 
opportunities for coaching and support.  
The weekly administration of LY3209590 along with prandial insulin has the potential to offer 
more consistent glycemic control. 
2.3.3. Overall Benefit Risk Conclusion 
Considering the clinical data to date and measures taken to minimize risk for the participants in 
this study, the potential risks identified in association with LY3209590 are justified by the 
anticipated benefits that may be afforded to participants with T2D.  
 
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26 
3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
 
Demonstrate noninferiority of 
LY3209590 compared to insulin 
glargine on glycemic control. 
Change in HbA1c from baseline at Week 26 
Key Secondary (Multiplicity 
Adjusted) 
 
Demonstrate LY3209590 is superior 
to insulin glargine in the selected 
parameters of glycemic control. 
 Change in HbA1c from baseline at Week 26 
 The percentage of participants achieving HbA1c <7% 
at Week 26 without nocturnal hypoglycemia (<54 
mg/dL [3.0 mmol/L] or severe) during treatment 
phase up to 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 26 
Other Secondary 
 
To investigate the effect of 
LY3209590 compared with insulin 
glargine in additional parameters of 
diabetes management. 
 Change in fasting glucose measured by SMBG from 
baseline to Week 26 
 Time in glucose range between 70 and 180 mg/dL 
(3.9 and 10.0 mmol/L), inclusive measured during the 
CGM session that occurs between Week 22 and Week 
26  
 Time in hypoglycemia range with glucose <54 mg/dL 
(3.0 mmol/L), measured by CGM that occurs between 
Week 22 and Week 26  
 Time in hyperglycemia range with glucose >180 
mg/dL (10.0 mmol/L), measured by CGM that occurs 
between Week 22 and Week 26  
 Glucose variability measured during the CGM session 
that occurs between Week 22 and Week 26 
 Insulin dose at Week 26 
o basal 
o bolus 
o total, and 
o basal/total insulin dose ratio. 
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27 
To investigate the safety of 
LY3209590 compared with insulin 
glargine. 
 Incidence and rate of composite of Level 2 and 3 
hypoglycemia events during treatment period 
 Body weight change from baseline to Week 26  
To investigate the treatment impact 
of LY3209590 compared with 
insulin glargine on patient-reported 
outcome measures. 
 Treatment experience at Week 26 for DID-EQ 
Tertiary 
 
 Investigate the treatment impact of 
LY3209590 compared with insulin 
glargine on other measures of 
efficacy, safety, and patient-
reported outcomes. 
Efficacy 
 Percentage of participants achieving HbA1c <7% 
at Week 26 
 Percentage of participants achieving HbA1c 
≤6.5% at Week 26 
 Change from baseline to Week 26 in fasting 
serum glucose as measured by central laboratory 
Safety 
 Rate and incidence of Level 2 hypoglycemia 
events during treatment period 
 Rate and incidence of Level 3 hypoglycemia 
events during treatment period 
 Incidence of positive treatment-emergent antibody 
of LY3209590 
Patient-reported outcomes 
 Frequency of responses to “Basal Insulin 
Experience: Likelihood of incorporating into 
routine” at Week 26 
 Frequency of responses to “Basal Insulin 
Experience: Preference” at Week 26 
 Change in EQ-5D-5L from baseline at Week 26 
 To characterize the PK/PD of 
LY3209590. 
 LY3209590 PK and concentration response 
relationships to key safety and efficacy measures. 
Abbreviations: CGM = continuous glucose monitoring; DID-EQ = Diabetes Injection Device Experience 
Questionnaire; EQ-5D-5L = EuroQol 5 dimensions 5 levels; HbA1c = hemoglobin A1c; SMBG = self-
monitoring of blood glucose. 
 
Primary estimand (for primary objective) 
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I8H-MC-BDCV(b) 
 
28 
United States registration 
The primary clinical question of interest is:  
What is the treatment difference between LY3209590 and insulin glargine in change 
from baseline at Week 26 in HbA1c in study eligible participants regardless of treatment 
discontinuation for any reason or initiation of rescue therapy?  
The treatment regimen estimand will be used for the primary objective and is described by the 
attributes in this table. 
Treatment Regimen Estimand Attribute 
Description 
Treatment condition 
randomized treatment regardless of treatment 
discontinuation or initiation of rescue therapy.  
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 therapy, are addressed by the 
treatment condition of interest attribute. 
Population-level summary 
difference in mean changes between treatment 
conditions. 
 
Rationale for treatment regimen 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 countries outside the United States 
The primary clinical question of interest is:  
What is the treatment difference between LY3209590 and insulin glargine in change 
from baseline at Week 26 in HbA1c in study eligible participants who adhere to the 
randomized treatment without an intercurrent event during the study treatment period?  
The efficacy estimand will be used for the primary objective and is described by the attributes in 
this table. 
Efficacy Regimen Estimand Attribute 
Description 
Treatment condition 
randomized treatment 
Population 
targeted study population. See Section 9.2 for 
details. 
Endpoint  
change from baseline to Week 26 in HbA1c. 
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29 
Remaining intercurrent events 
none. The 2 intercurrent events, treatment 
discontinuation for any reason and initiation 
of rescue therapy, are 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 efficacy estimand: The treatment efficacy estimand supports the interpretation of 
the treatment effect as participants adhere to study treatment. 
 
Secondary estimands (for multiplicity-adjusted objectives) 
The superiority test in change from baseline to Week 26 in HbA1c will also be based on the 
primary estimands described above.  
The percentage of participants achieving HbA1c <7% at Week 26 without nocturnal 
hypoglycemia (<54 mg/dL [3.0 mmol/L], or severe) during treatment phase up to Week 26 will 
be based on a composite estimand. The details will be described in the SAP. 
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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30 
4. 
Study Design 
4.1. 
Overall Design 
This is a Phase 3, parallel-design, open-label, randomized controlled trial that will evaluate the 
efficacy and safety of LY3209590 compared to insulin glargine in participants with T2D who are 
on once- or twice-daily basal insulin and at least 2 injections per day of prandial insulin prior to 
entering the study. Participants will continue prior stable therapy with 0 to 3 allowed noninsulin 
diabetes medications during the study. 
The study consists of a 1-week screening period, a 2-week lead-in period, a 26-week treatment 
period, and a 5-week safety follow-up period.  
Screening and Lead-In 
Visit 1: Screening 
Interested participants will sign the appropriate informed consent document(s) prior to initiating 
any procedures. 
The investigator will review medical history, symptoms, risk factors, and other inclusion and 
exclusion criteria prior to any diagnostic procedures. If the participant is eligible after this 
review, then the site will perform the diagnostic procedures to confirm eligibility. 
Visit 2: Lead-In 
Participants will receive their e-diary, glucometer, and the CGM system. 
Participants will receive training on 
 diabetes self-monitoring and management 
 study glucometer 
 CGM 
 electronic study diaries, and 
 study requirements.  
The CGM sensor will be inserted at Visit 2, and participants will be required to wear the sensor 
when indicated per the SoA.  
Starting with Visit 2, participants must measure their FBG levels each day when possible or at a 
minimum 3 times per week. Starting with Visit 2, participants are strongly encouraged to 
measure 4-point SMBG profiles at least 3 times per week. Participants will use the study 
supplied glucometer and e-diary for data collection throughout the study. 
Participants will continue their current insulin therapy until randomization. On the day of Visit 3, 
participants who typically take a morning dose of basal insulin should omit their morning dose of 
basal insulin as they will receive basal insulin at Visit 3. 
Treatment period 
Visit 3 (Week 0): Randomization 
This is the general flow for Visit 3: 
 Study personnel confirm enrollment criteria 
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31 
 Participants are randomly assigned to an intervention group 
 Study personnel complete baseline procedures and sample collection 
 Study personnel will provide dosing training  
 Study personnel or the participant will administer the first study dose of LY3209590. 
Insulin glargine can be taken at the site or after the visit depending upon whether the 
study visit timing coincides with the participant’s usual time to administer basal insulin. 
Administered insulin doses will be entered into the e-diary 
 Study personnel train participants on administering insulin lispro at mealtimes  
 Study personnel will download the CGM 
 Participant will continue CGM wear per the SoA, and  
 Study personnel complete all visit procedures.  
All participants will be treated with insulin lispro as prandial insulin throughout the treatment 
period as described in Section 6.5.3. Participants assigned to insulin glargine will administer 
glargine daily after Visit 3. 
Visit 4 (Week 1) 
Study personnel and participants complete all visit procedures described in the SoA. 
Study personnel will provide dosing training and observe participants administering their second 
dose of LY3209590. Participants assigned to insulin glargine can continue routine daily 
administration. 
Visit 5 through Visit 23 (Week 2 through Week 26) 
Study personnel and participants complete all visit procedures described in the SoA. 
The participant’s median FBG from the 3 most recent FBGs in the prior week will be used to 
titrate basal insulin dose adjustments throughout the study based on the study titration algorithm 
described in Section 6.5.1. Prandial insulin doses should be adjusted as needed. 
Participants will collect blinded CGM for 
 4 weeks prior to Visit 7, and the site will download the CGM data at Visit 7 
 4 weeks prior to Visit 15, and the site will download the CGM data at Visit 15, and  
 4 weeks prior to Visit 23, and the site will download the CGM data at Visit 23. 
The investigator or study staff will review participant e-diary compliance for  
 SMBGs 
 hypoglycemia events including related signs and symptoms, and 
 dosing information, including date and time of doses.  
Last study treatment visit: either Visit 23 (Week 26) or ED visit 
Participants should complete all visit procedures in a fasting state. 
Participants will return unused study intervention to the investigative site. 
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Assessments for the transition to non-study diabetic treatment after the participant’s last dose. 
 The investigator will determine a participant’s transition from study basal insulin to 
another basal insulin. Investigators will also start the participant on a non-study prandial 
insulin (see Section 6.6.1).  
 Participants will continue their concomitant antihyperglycemic medications at the 
discretion of the investigator. 
Safety follow-up visits 801 and 802 
Study personnel and participants complete all visit procedures described in the SoA. 
Participants will collect blinded CGM for 4 weeks following Visit 23, and the site will download 
the CGM data at Visit 802. 
The investigator will follow-up on the participant’s transition from study treatment to another 
non-study diabetic treatment.  
Participants will return study devices at the final study visit. 
4.2. 
Scientific Rationale for Study Design 
Primary endpoint 
The primary efficacy measurement is HbA1c, a widely used measure of glycemic control that 
reflects a cumulative history of glucose levels in the preceding 2 to 3 months. 
Overall design 
Blinding 
This is an open-label study. Investigators, participants, and study-site personnel will be 
unblinded to the assigned treatment. To eliminate potential biases, designated members of the 
Lilly study team will remain blinded throughout the study (see Section 6.3). Only a minimum 
number of Lilly personnel will see the randomization table and treatment assignments before the 
study is complete. 
Study duration 
The treatment duration is a reasonable timeframe to observe the effects of LY3209590 compared 
to insulin glargine. The primary endpoint at Visit 23 (Week 26) is based on participants reaching 
a stable insulin dose in order to achieve glycemic stability approximately 12 weeks in advance of 
the 26-week primary endpoint. HbA1c is the primary endpoint and reflects glycemic control 
from the prior 8 to 12 weeks. 
The follow-up visits after the last dose are designed to capture any additional safety signals and 
to monitor the transition from study basal insulin to non-study basal insulin. 
Comparator 
Insulin glargine was chosen as the comparator because it is a widely used basal insulin. 
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Collection of race and ethnicity data 
In this study, collection of demographic information includes ethnicity (where permissible) and 
race. The scientific rationale is based on the need to assess variable response in safety or efficacy 
based on race or ethnicity. This question can be answered only if all the relevant data are 
collected.  
4.3. 
Justification for Dose 
The dosing guidance for starting doses and dose titrations of LY3209590 and insulin glargine are 
derived based on findings from Phase 2 studies and model-based simulations. These data 
informed the development of a titration algorithm to safely and efficiently initiate and guide 
LY3209590 and insulin glargine dose adjustments to achieve the same glycemic goals of FBG 
between 80 and 120 mg/dL (4.4 and 6.6 mmol/L) while minimizing hypoglycemia risk. 
See Section 6.5 for dose modification and titration details.   
LY3209590  
Initial loading dose  
The initial loading dose aims to optimize and accelerate glycemic control by allowing 
participants to reach a steady-state concentration faster. The use of a single one-time-only 
loading dose enables participants to achieve concentrations close to steady state within a few 
days rather than a period of weeks. This approach minimizes the risk for hyperglycemia during 
transition to LY3209590 while reaching steady state. In all cases, starting doses will be based 
upon existing total daily basal insulin doses.  
This approach is supported by the Phase 2 Study BDCM and PK model-based simulations.  
Details on deriving the loading dose are described in Section 6.5.    
Starting weekly dose 
The second dose is the starting weekly dose which is equal to the pre-study total daily basal 
insulin dose multiplied by 7. The dose will be equivalent to pre-study basal insulin doses, with 
further adjustment for participants who used insulin glargine U-300 or NPH as their pre-study 
basal insulin. Details on deriving the starting weekly dose are described in Section 6.5.  
Dose adjustments 
Dosing will be individualized based on FBG and hypoglycemia events in the prior week, and 
adjustments may occur weekly from Visit 5 to 15 (Week 2 to 12) and then every 4 weeks 
thereafter, or more often as clinically indicated. 
Insulin glargine 
Insulin glargine will be titrated to achieve the FBG target using an algorithm that is patterned 
after the well-established Riddle algorithm (Riddle et al. 2003) but modified to balance efficacy 
and hypoglycemia risk for the same FBG targets as LY3209590. 
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Starting dose 
The starting dose of insulin glargine is designed to be equivalent to the pre-study basal insulin 
dose, with further adjustment for participants who used insulin glargine U-300 or NPH as their 
pre-study basal insulin. Details on deriving the starting weekly dose are described in Section 6.5. 
Dose adjustments 
Dosing will be individualized based on FBG and hypoglycemia events in the prior week and 
adjustments may occur weekly from Visit 4 to 15 (Week 1 to 12) and then every 4 weeks 
thereafter, or more often as clinically indicated.  
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last scheduled procedure shown in the SoA. 
 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Are 18 years of age or older, at screening (Visit 1), 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 and at least 2 injections of prandial insulin per day.  
3. Are receiving ≥10 units of total basal insulin per day at screening (Visit 1).  
4. Are receiving ≤2 units/kg/day of total daily insulin at screening (Visit 1).  
5. Have an HbA1c value of 7.0% to 10%, inclusive, as determined by the central laboratory 
at screening (Visit 1).  
6. Have been treated with a stable regimen of one of the following basal insulins used 
according to local product label with or without noninsulin diabetes therapy for at least 
90 days prior to screening (Visit 1).  
 
once daily U-100 or U-200 insulin degludec  
 
once daily U-100 or U-300 insulin glargine   
 
once or twice daily U-100 insulin detemir (Levemir® [Novo Nordisk A/S., 
Bagsvaerd, Denmark]), or  
 
once or twice daily human insulin Neutral Protamine Hagedorn.   
7. Have been treated with at least twice daily dosing of any of the following insulins used 
according to local product label for at least 90 days prior to screening (Visit 1). One dose 
of prandial insulin must occur at the evening meal.  
 
Insulin lispro (U-100 and U-200)  
 
Insulin lispro-aabc (Lyumjev™ [Eli Lilly and Co., Indianapolis, IN], U-100 or U-
200)  
 
Insulin aspart (U-100; including Fiasp® and NovoLog® [Novo Nordisk A/S., 
Bagsvaerd, Denmark])  
 
Insulin glulisine (U-100), or  
 
Regular insulin (U-100).  
8. Acceptable noninsulin diabetes therapies may include 0 to up to 3 of the following with a 
stable dose for at least 90 days prior to screening (Visit 1).  
 
dipeptidyl peptidase IV inhibitors  
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 
sodium-glucose co-transporter-2 inhibitors  
 
biguanides (for example, metformin), or  
 
glucagon-like peptide-1 receptor agonists.  
Note: All noninsulin diabetes therapies must be used in accordance with the 
corresponding local product label at the time of screening (Visit 1), and participants 
should be willing to continue stable dosing throughout the study according to the 
protocol.   
Weight 
9. Have a body mass index ≤45 kg/m
2. 
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. 
10. Male study participants: No male contraception required except in compliance with 
specific local government study requirements. 
Female study participants: For the contraception requirements of this protocol, see 
Section 10.4. 
Study procedures 
11. In the investigator’s opinion, are well-motivated, capable, and willing to 
 
self-inject treatment, as required for this protocol; visually impaired persons who 
are not able to perform the injections must have the assistance of a sighted 
individual trained to inject the IP; persons with physical limitations who are not 
able to perform the injections must have the assistance of an individual trained to 
inject the IP  
 
adhere to the study basal-bolus insulin MDI regimen and use of study insulins 
according to injection instructions and protocol 
 
use LY3209590 or insulin glargine, and insulin lispro 
 
use the glucometer supplied for this study for glucose monitoring, diabetes 
management, and data collection per protocol 
 
wear blinded CGM during specified periods 
 
maintain an electronic study diary as required for the protocol, and  
 
must have a normal wake/sleep pattern, such that midnight to 0600 hours will 
reliably reflect a usual sleeping period. 
Informed consent 
12. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
Diabetes related 
13. Have a diagnosis of type 1 diabetes mellitus or 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 any of the following insulin therapies anytime in the past 90 days: 
 
insulin mixtures 
 
Afrezza® (insulin human) inhalation powder (MannKind Corporation, Danbury, 
CT), or 
 
continuous subcutaneous insulin infusion therapy 
 
regular insulin U-500 
15. Have a history of greater than 1 episode of ketoacidosis or hyperosmolar state/coma 
requiring hospitalization in the 6 months prior to screening (Visit 1). 
16. Have had any episodes of severe hypoglycemia, defined as requiring assistance due to 
neurologically disabling hypoglycemia, within the 6 months prior to screening (Visit 1).  
17. Have hypoglycemia unawareness in the opinion of the investigator. 
18. Anticipate making changes in personal CGM or FGM use (for example, initiation, 
stopping, or changing device) during the study. 
Cardiovascular  
19. Have had New York Heart Association Class IV heart failure or any of the following 
cardiovascular conditions in the past 3 months prior to screening (Visit 1): acute 
myocardial infarction, cerebrovascular accident (stroke), or coronary bypass surgery. 
Gastrointestinal  
20. Have undergone gastric bypass (bariatric) surgery, restrictive bariatric surgery, for 
example Lap-Band, or sleeve gastrectomy within 1 year prior to screening (Visit 1). 
21. Have presence of clinically significant gastroparesis in the opinion of the investigator. 
Hepatic  
22. Have acute or chronic hepatitis, cirrhosis, or obvious clinical signs or symptoms of any 
other liver disease, except NAFLD (that is, persons with NAFLD are eligible for 
participation), or have elevated liver enzyme measurements, as determined by the central 
laboratory at screening (Visit 1): 
 
Total bilirubin >2x ULN, with the exception of previously diagnosed Gilbert’s 
syndrome 
 
ALT or serum glutamic pyruvic transaminase (SGPT) >3x ULN, or  
 
AST or serum glutamic oxaloacetic transaminase (SGOT) >3x ULN, or 
 
ALP >2.5x ULN. 
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Renal 
23. Have a history of renal transplantation, are currently receiving renal dialysis, or have an 
estimated glomerular filtration rate <30 mL/min/1.73 m2, calculated by the Chronic 
Kidney Disease-Epidemiology equation, as determined by the central laboratory at 
screening (Visit 1). 
Hematologic 
24. Have had a blood transfusion or severe blood loss within 90 days prior to screening 
(Visit 1). 
25. 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. 
Malignancy 
26. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy within 5 years prior to screening (Visit 1). 
Exceptions: 
 
Basal cell or squamous cell skin cancer. 
27. Are at increased risk for developing cancer or a recurrence of cancer.  
General 
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, or preclude the study participant from following and 
completing the protocol. 
30. Have evidence of current or recent, within 6 months timeframe, history of any substance 
use disorder(s) of any severity as defined by the DSM-5 in the opinion of the investigator, 
excepting disorders of nicotine or caffeine use. 
31. Have had a significant weight gain or loss in the past 3 months in the investigator’s 
opinion (for example, ≥5%). 
32. Persons of childbearing potential who 
 
are pregnant or intend to become pregnant 
 
are lactating/breastfeeding (including the use of a breast pump) 
 
are unwilling to remain abstinent or use birth control, or 
 
test positive for pregnancy at the time of screening. 
 
Prior or concomitant therapy 
33. Have received any of the following nonallowed diabetes medication within prior 90 days 
including 
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 
meglitinides (glinides) 
 
sulfonylureas 
 
pramlintide 
 
alpha-glucosidase inhibitors, or  
 
thiazolidinediones. 
34. Are receiving chronic or received systemic glucocorticoid therapy for >14 days within 
the 30 days before screening (Visit 1). 
Exceptions: 
 
replacement therapy for adrenal insufficiency 
 
topical, intraocular, intranasal, or inhaled preparations, or 
 
intra-articular injection. 
Prior or concurrent clinical study experience 
35. 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. 
36. 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. 
37. Have previously completed or withdrawn from this study after having signed the 
informed consent form (ICF) or any other study investigating LY3209590 after receiving 
at least 1 dose of the study basal insulin. 
38. 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. 
39. Are Eli Lilly and Company employees or are employees of any third party involved in 
the study who require exclusion of their employees.  
5.3. 
Lifestyle Considerations 
Diabetes management counseling 
Qualified study personnel will provide diabetes management counseling, which will include 
instructions on diet and exercise and education about the signs, symptoms, and treatment of 
hypoglycemia, should it occur. Diabetes self-management counseling should be reviewed 
throughout the study, as needed. 
Dietary and exercise considerations 
Study participants should generally follow a healthy meal plan and continue their usual exercise 
habits throughout the course of the study.  
Dietary and exercise restrictions 
Study participants should not initiate an intensive diet/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.  
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Blood donation 
Study participants should not donate blood or blood products during the study or for 4 weeks 
following their last study visit. 
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 LY3209590 or insulin glargine. 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 personnel are expected to treat participants according to the 
nationally established standards of care for diabetes management in respective participating 
countries, except when 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 2022). 
6.1. 
Study Intervention(s) Administered 
This table lists the interventions used in this clinical study. 
Intervention 
Name 
LY3209590 
Insulin glargine 
Insulin lispro 
Dose 
Formulation 
Solution 
Solution 
Solution 
Unit Dose 
Strength(s) 
500 units/mL 
100 units/mL 
100 units/mL 
Dosage Level(s) 
Individualized dosing 
(see Section 6.5.1) 
Individualized dosing 
(see Section 6.5.2) 
Individualized dosing 
(see Section 6.5.3) 
Route of 
Administration 
Subcutaneous 
injection 
Subcutaneous 
injection 
Subcutaneous injection 
Frequency of 
Administration 
Once-weekly study 
basal insulin 
Once-daily study 
basal insulin 
Background prandial 
insulin therapy with 
meals and as needed 
Authorized as 
defined by EU 
Clinical Trial 
Regulation 
Not authorized in EU  Authorized and used 
according to 
authorization  
Authorized and used 
according to 
authorization 
 
LY3209590 frequency of administration and guidance for missed doses 
LY3209590 should be administered once weekly at approximately the same time and day each 
week. 
If a dose is missed, it should be administered as soon as possible if at least 3 days (72 hours) 
remain until the next scheduled dose. If less than 3 days remain before the next scheduled dose, 
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skip the missed dose and administer the next dose on the regularly scheduled day. In each case, 
participants can then resume their regular once-weekly dosing schedule.  
The day of weekly administration can be changed, if necessary, only if the last dose has been 
administered at least 3 days earlier.  
Insulin glargine frequency of administration  
Insulin glargine should be administered daily at approximately the same time each day. 
Anatomical location of injections  
For both LY3209590 and insulin glargine, participants should rotate injection sites from one 
injection to the next, even when injecting within the same region. Injections may be administered 
in the abdomen, thigh, arm, or buttock.  
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Medical Devices 
LY3209590 or insulin glargine, and insulin lispro will be provided in prefilled pen injectors.  
Instructions for device use will be provided. 
All Product Complaints, including malfunction, use error and inadequate labeling, shall be 
documented and reported by the investigator throughout the clinical investigation (see Section 
8.3) and appropriately managed by the sponsor. 
6.1.2. 
Background Therapy 
For patients with type 2 diabetes requiring MDI therapy, standard of care stipulates treatment 
with both basal and prandial bolus insulin. In this study, participants will be treated with 
LY3209590 or insulin glargine as study basal insulin intervention and insulin lispro as prandial 
bolus therapy.  
Insulin lispro is being used to standardize the prandial insulin therapy. 
6.1.3. 
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, that is, LY3209590 or insulin 
glargine, both in combination with prandial insulin lispro. Correction doses of insulin lispro can 
also be used.  
An additional antihyperglycemic medication should be considered as rescue therapy if a 
participant develops severe, persistent hyperglycemia after randomization, based on meeting one 
of the criteria in this table, and in the absence of intercurrent cause of the hyperglycemia.  
 
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Average Fasting Glucose over 2-week Period Timing of Events 
>270 mg/dL (15 mmol/L) 
From Visit 15 until Visit  17 (Weeks 12 to 16) 
>240 mg/dL (13 mmol/L) 
After Visit 17 until Visit 19 (Weeks 16 to 20) 
>200 mg/dL (11 mmol/L) 
After Visit 19 until Visit 23 (Weeks 20 to 26) 
Investigators should first confirm that the participant is fully compliant with the assigned 
therapeutic regimen and that the participant does not have an acute condition causing severe 
hyperglycemia. If study basal and prandial insulin therapy are fully optimized, the investigator 
will decide, in consultation with the participant, on an appropriate intensification of therapy after 
considering relevant clinical criteria. Therapy intensification may include adjustment of 
concomitant antihyperglycemic medication, addition of a concomitant antihyperglycemic 
medication if taking <3 concomitant medications as per Section 6.8.3, or addition of a non-study 
insulin. Participants who receive a new intervention for hyperglycemia management should also 
continue administering study insulin therapy for the remaining period in the trial. 
Participants who require a new non-study basal insulin intervention as rescue therapy for 
hyperglycemia management must discontinue study basal insulin therapy (LY3209590 or insulin 
glargine). The participant will remain in the study and follow procedures for the remaining study 
visits. 
The investigator should ensure that the participant met the criteria for severe or persistent 
hyperglycemia before initiating rescue medicine and document this in the source files. 
6.2. 
Preparation, Handling, Storage, and Accountability 
The investigator or designee must confirm appropriate storage conditions have been maintained 
during transit for all study intervention received and any discrepancies are reported and resolved 
before use of the study intervention. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized study personnel. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
Participant responsibilities 
In-use storage conditions are expected to be followed according to the instructions for use 
provided by the sponsor. Study participants will be trained on the proper storage and handling of 
the study intervention. 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization and stratification 
All participants will be centrally randomized and assigned to LY3209590 or insulin glargine 
using an IWRS. Before the study is initiated, the login information and directions for the IWRS 
will be provided to each site. 
Participants will be randomly assigned in a 1:1 ratio to LY3209590: insulin glargine. 
Participants will be stratified based on 
 country 
 HbA1c stratum (<8% and ≥8%) at Visit 1   
 Routine use of personal CGM or FGM at randomization (yes/no)  
Blinding 
This is an open-label study. Investigators and participants will be unblinded to the assigned 
treatment groups. 
The Lilly study team members who are closely involved in data interpretation and analysis 
planning will remain blinded throughout the course of the study. Only a minimum number of 
Lilly personnel will see the randomization table and treatment assignments before the study is 
complete. 
The investigator should make every effort to preserve the blinding when contacting the Lilly 
study team members, including the Lilly clinical research physician or scientist. 
Unblinded reviews 
External committees reviewing unblinded data during the study are described in Section 10.1.5. 
6.4. 
Study Intervention Compliance 
The investigator or trained designee will assess treatment compliance at each visit based on 
review of the participant glycemic control, e-diary completion, and adherence to prescribed dose 
and study procedures. 
If a participant is considered poorly compliant with their study procedures, for example, missed 
visits or specific diagnostic tests, they will be retrained as needed by designated study personnel. 
Study personnel will ensure participants enter in their e-diary  
 the dose amount and date of their basal insulin, and  
 prandial insulin dose amount and date, and 
o additional recording of insulin dosing can be requested throughout the study as 
clinically indicated. 
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The insulin dose e-diary entries differ by study period as described in this table. 
During study 
period… 
participants will 
record their dose 
for… 
during… 
at a frequency of… 
Screening and 
Lead-in 
pre-study basal insulin 
Week -1 to 0  
 
≥2 days per week. 
Pre-study prandial 
insulin 
Week -1 to 0 
 
≥2 days per week. 
Treatment 
LY3209590 or  
insulin glargine 
Week 0 to 26 
 
1 day per week  
prandial insulin lispro  
the week prior to the 
visits at 
Week 0-12, 16, 20, 24, 
and 26 
 
 
≥2 days per week. 
Safety Follow-
up 
basal insulin 
Week 26 to 31 
 
≥2 days per week. 
Prandial insulin 
Week 26 to 31 
 
≥2 days per week. 
Additional recording of insulin dosing can be requested throughout the study as clinically 
indicated. 
Study personnel will ensure participants perform 
 FBGs daily when possible or a minimum of 3 days per week 
 4-point SMBG profiles strongly encouraged to be at least 3 days per week (see Section 
8.1.1.1 for further information), and 
 SMBG to assess hypoglycemia and hyperglycemia as needed.  
6.5. 
Dose Modification 
The overall glycemic targets for study participants during the study treatment period are similar 
to those recommended by clinical guidelines (ADA 2022). The glycemic targets should be 
balanced with minimizing the risk of significant hypoglycemia. 
Glycemic target  
Target value 
Fasting glucose 
80 to 120 mg/dL or 4.4 to 6.6 mmol/L 
Nonfasting preprandial glucose 
80 to 130 mg/dL or 4.4 to 7.2 mmol/L 
Peak postprandial glucose 
<180 mg/dL or ≤10.0 mmol/L 
 
Dosing of basal insulin will be individualized based on FBG and hypoglycemia events. The FBG 
target is 80 to 120 mg/dL (4.4 to 6.6 mmol/L). Additional SMBG values, including 4-point 
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glucose profiles and the change from bedtime to fasting glucose values, should also be 
considered. 
Titration of the study basal insulin (LY3209590 or glargine) dose should be made at weekly 
intervals from Week 0 to 12 (titration period, Visit 3 to 15), and every 4 weeks thereafter (Visits 
17, 19, and 21) or more often as clinically indicated. 
Decreases to the basal insulin dose may be made at any time during the study based upon the 
judgment of the investigator (for example, in response to hypoglycemia). The basal insulin dose 
may be influenced by other clinical circumstances and safety considerations known to the 
investigator; thus, the prescribed basal insulin dose during the study is determined by, and the 
responsibility of, the investigator.   
Participants will measure FBG using the study-provided glucometer as described in Section 
8.1.1.1. The median FBG for basal insulin dose adjustment 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 week 
measurements were 132, 140, and 128, the median is 132.  
Note: If the participant has only 2 FBG readings for the week, then the lower 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. 
6.5.1. 
LY3209590 Dose Initiation and Adjustment 
This section outlines the LY3209590 
 dose initiation at Visit 3 (Week 0),  
 dose adjustment guidance based on hypoglycemia, and 
 dose adjustment guidance based on FBG. 
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6.5.1.1. 
LY3209590 General Dosing Information by Visit 
 
LY3209590 General Dosing Information 
Visit (Week) 
Dose 
Additional dosing instruction 
Visit 3 
(Week 0)  
Initial loading 
dose  
 FBG >120 mg/dL (6.6 mmol/dL): usual 
daily basal dose (U) × 7 × 3 
 FBG ≤120 mg/dL (6.6 mmol/dL): usual 
daily basal dose (U) × 7 
 Doses should be rounded to the nearest 10 
 If the participant’s pre-study basal insulin is 
glargine U-300 or twice daily NPH, the prior 
daily basal insulin dose should be reduced 
by 20% when determining usual daily basal 
dose.  
Visit 4 
(Week 1)  
Starting weekly 
dose  
 Usual daily basal dose (U) × 7 
 Doses should be rounded to the nearest 10 
 
 If the participant’s pre-study basal insulin is 
glargine U-300 or twice daily NPH, the prior 
daily basal insulin dose should be reduced 
by 20% when determining usual daily basal 
dose.  
 If a participant experiences nocturnal or 
fasting hypoglycemia in the previous week, 
then reduce the starting weekly dose by 10% 
or as clinically indicated (see Section 
6.5.1.2). 
 CAUTION: Do NOT repeat administration 
of the loading dose. 
Visits 5-15 
(Weeks 2-12) 
 Doses will be individualized based on 
FBG and hypoglycemia events (Section 
6.5.1.2) 
 Doses should be rounded to the nearest 10 
 
 Dose modifications may occur weekly. 
 Investigators should factor in 4-point SMBG 
profile and changes to prandial insulin doses 
as indicated. 
After Visit 15 
(Week 12) 
 Doses will be individualized based on 
FBG and hypoglycemia events (Section 
6.5.1.2) 
 Doses should be rounded to the nearest 10 
 
 Dose modifications may occur every 4 
weeks (Visits 17, 19, and 21) or as clinically 
indicated. 
 Investigators should factor in 4-point SMBG 
profile and changes to prandial insulin doses 
as indicated. 
 Dose may be adjusted at any time in 
response to hypoglycemia. 
 
Abbreviations: FBG = fasting blood glucose; NPH = Neutral Protamine Hagedorn; SMBG = self-monitoring blood 
glucose. 
Visit 3 (Week 0 – Randomization) loading dose 
At Visit 3 (Week 0), participants will stop their pre-study basal and prandial insulin therapy and 
initiate study basal and prandial insulin therapy.    
The LY3209590 loading dose is administered at the site and is based on the participant’s prior 
daily basal insulin dose and median FBG from the most recent 3 FBGs in the week prior to 
randomization (Visit 3 [Week 0]).   
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6.5.1.2. 
LY3209590 Dose Adjustment  
From Visit 5 until the end of treatment (Week 26), assess hypoglycemia events over the previous 
week, and reduce the LY3209590 dose if the participant meets a criterion for hypoglycemia dose 
reduction according to the table below.  
Hypoglycemia Dose Reduction Criteria 
Decrease the LY3209590 dose:  
1 nocturnal hypoglycemia event ≤70 mg/dL (3.9 
mmol/L) a 
to previous lower dose b 
1 fasting hypoglycemia event ≤70 mg/dL (3.9 
mmol/L) a 
Any confirmed severe hypoglycemia event 
by 20 to 40 units or as clinically 
indicated 
a Investigator should use discretion to adjust for daytime hypoglycemia that is not attributed to prandial insulin.  
b If there is no previous lower dose, then decrease basal insulin dose by 10% or as clinically indicated and round 
dose to the nearest 10 units. 
If the participant does not meet criteria for hypoglycemia dose reduction, determine the median 
fasting glucose and adjust the LY3209590 dose according to the table below.  
This table provides guidance for dose adjustments based on median FBG from the 3 most 
recently recorded FBG data from the previous week. Subject with lead-in FBG values ≤120 
mg/dL or ≤6.6 mmol/L may be titrated with the more gentle titration algorithm throughout the 
study. 
LY3209590 Dose Adjustment 
Median FBG mg/dL (mmol/L) 
Median Lead-In FBG ≤120 
mg/dL (6.6 mmol/L)a 
Median Lead-In FBG >120 
mg/dL (6.6 mmol/L) 
<80 (4.4) 
-10 to -20 units 
-20 units 
80–120 (4.4-6.6) 
No change 
No change 
121–140 (6.7-7.7) 
+10 units 
+20 units 
>140 (7.7) 
+20 units 
+40 units 
Abbreviations: FBG = fasting blood glucose. 
a Investigators may choose the more gentle titration algorithm for subjects with a pre-study basal insulin dose <20 
units and median FBG >120 mg/dL (6.6 mmol/L) 
Note: 120 mg/dL is rounded to 6.6 mmol/L and 121 mg/dL is rounded to 6.7 mmol/L to allow for distinct thresholds 
in consideration of glucose meters only displaying 1 significant digit after the decimal point. 
 
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6.5.2. 
Insulin Glargine Dose Initiation and Adjustment 
This section outlines the insulin glargine 
 dose initiation at Visit 3 (Week 0),  
 dose adjustment guidance based on hypoglycemia, and 
 dose adjustment guidance based on FBG. 
6.5.2.1. 
Insulin Glargine General Dosing Information by Visit 
At Visit 3 (Week 0), participants will stop their pre-study basal and prandial insulin therapy and 
initiate study basal and prandial insulin therapy.    
The first glargine dose is based on the participant’s prior daily basal insulin dose from the week 
prior to randomization (Visit 3 [Week 0]). If participant’s usual basal insulin dosing time 
overlaps with the visit, they should take the first dose at the site. If participant’s usual basal 
insulin dosing time does not coincide with the visit, they are not required to administer at the 
site.     
This table provides general dosing information across visits for all participants randomized to 
insulin glargine. 
Insulin Glargine General Dosing Information 
Visit 
Dose 
Additional dosing instruction 
Visit 3 (Week 0) starting 
dose  
Equivalent to pre-study 
usual daily basal insulin 
dose 
Note: If the participant’s pre-study basal 
insulin is glargine U-300 or twice daily 
NPH, the prior daily basal insulin dose 
should be reduced by 20% when 
determining usual daily basal insulin 
dose.  
 
Visits 4-15 (Weeks 1-12) 
Doses will be 
individualized based on 
FBG and hypoglycemia 
events 
Dose modifications may occur weekly. 
Investigators should factor in 4-point 
SMBG profile and changes to prandial 
insulin doses as indicated. Dose may be 
adjusted at any time in response to 
hypoglycemia. 
 
After Visit 15 (Week 12) 
Doses will be 
individualized based on 
FBG and hypoglycemia 
events 
 Dose modifications may occur every 4 
weeks (Visits 17, 19, and 21) or as 
clinically indicated. Investigators should 
factor in 4-point SMBG profile and 
changes to prandial insulin doses as 
indicated. 
 Dose may be adjusted at any time in 
response to hypoglycemia. 
Abbreviations: FBG = fasting blood glucose; NPH = neutral protamine Hagedorn; SMBG = self-monitoring blood 
glucose. 
 
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6.5.2.2. 
Insulin Glargine Dose Adjustment  
For Visit 4 until end of treatment (Week 26), assess hypoglycemia events over the previous 
week, and reduce the insulin glargine dose if the participant meets criterion for hypoglycemia 
dose reduction according to this table.  
Hypoglycemia Dose Reduction Criteria 
Decrease the glargine dose:  
1 nocturnal hypoglycemia event ≤70 mg/dL (3.9 
mmol/L) a 
to previous lower dose b 
1 fasting hypoglycemia event ≤70 mg/dL (3.9 
mmol/L) a 
Any confirmed severe hypoglycemia 
by 3 to 6 units or as clinically indicated 
a Investigator should use discretion to adjust for daytime hypoglycemia that is not attributed to prandial insulin.  
b If there is no previous lower dose, then decrease basal insulin dose by 10% or as clinically indicated. 
 
If the participant does not meet criteria for hypoglycemia dose reduction, determine the median 
fasting glucose and adjust the insulin glargine dose according to this table. This table provides 
guidance for dose adjustments based on median FBG from the 3 most recently recorded FBG 
data from the previous week. 
Insulin Glargine Dose Adjustment 
If the median FBG is… 
Then…  
mg/dL 
mmol/L 
 
<80 
<4.4 
reduce the dose by 3 U. 
80-120 
4.4-6.6 
do not change the dose. 
121-140 
6.7-7.7 
increase the dose by 3 U. 
>140 
>7.7 
increase the dose by 6 U. 
Abbreviations: FBG = fasting blood glucose; U = units. 
Note: 120 mg/dL is rounded to 6.6 mmol/L and 121 mg/dL is rounded to 6.7 mmol/L to allow for distinct thresholds 
in consideration of glucose meters only displaying 1 significant digit after the decimal point. 
 
6.5.3. 
Prandial Insulin Lispro Dose Initiation and Adjustment 
During the lead-in period (Visit 2 to 3), participants will continue their pre-study basal and 
prandial insulin therapy.  
During the treatment period (Visit 3 to 23), all participants will be treated with insulin lispro. The 
initial insulin lispro doses may be converted unit-for-unit from the pre-study prandial insulin 
regimen.  
Prandial insulin is titrated based on glucose and hypoglycemia data and other clinical factors. 
Decreases to the prandial insulin dose may be made at any time during the study based upon the 
judgment of the investigator (for example, in response to hypoglycemia). The prandial insulin 
dose may be influenced by other clinical circumstances and safety considerations known to the 
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investigator; thus, the prescribed prandial insulin dose during the study is determined by, and the 
responsibility of, the investigator. 
To facilitate prandial insulin dose titration, subjects should be strongly encouraged to check 4-
point glucose profiles for at least 3 days each week.  
 fasting 
 pre-midday meal 
 pre-evening meal, and 
 bedtime.  
See Section 8.1.1.1 for further information about 4-point SMBG. 
The investigator, in consultation with the participant, will determine the prandial dosing plan to 
use during the study. The following prandial dosing plans may be considered: 
 Carbohydrate-counting plan: If the participant performed flexible carbohydrate counting 
for prandial insulin dosing (insulin to carbohydrate ratio plan) prior to study enrollment, 
this plan may be continued during the study. The prandial insulin dose is based on the 
participant’s estimated carbohydrate content of the meal (such as unit insulin per grams 
carbohydrate). 
 Fixed-dose plan: The participant is prescribed a fixed dose or dose range of insulin for 
each meal. The fixed dose or dose range of insulin may be individualized for each meal. 
The participant should maintain the same prandial insulin dosing plan throughout the study. If 
participants enter the study not covering all meals with prandial insulin, investigators can choose 
to increase the numbers of meals covered by prandial insulin as needed to reach glycemic targets.   
Participants must remain on at least 2 injections of prandial insulin per day with one at the 
evening meal except if safety concerns require a decrease in the number of prandial insulin 
injections per day. 
A correction factor, for example, 1 unit of insulin per glucose (mg/dL or mmol/L) above target 
goal, may be implemented with either prandial insulin dosing plan. Implementation of the 
correction factor (for example, via an equation or a sliding scale) is per investigator discretion in 
consultation with the participant. 
For participants who are using the carbohydrate-counting plan: the insulin to carbohydrate 
ratio, and correction factor if applicable, should be reviewed and adjusted by the investigator, in 
discussion with the patient, based on SMBG, hypoglycemia data, and other clinical factors at 
clinic and telephone visits and as clinically indicated.  
For participants who are using the fixed-dose plan: the prandial insulin dose, and correction 
factor if applicable, should be reviewed and adjusted by the investigator, in discussion with the 
patient, based on SMBG, hypoglycemia data and other clinical factors at clinic and telephone 
visits and as clinically indicated.  
Assessment of the prandial insulin dose includes review of the SMBG levels in the previous 
week for the corresponding meal or bedtime as described in the table below.  
For example, if assessing the need to adjust the morning meal prandial insulin dose, review the 
glucose values from the pre-midday meal. 
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Prandial Insulin Dose Assessed 
Corresponding SMBG for Review 
Fasting or morning premeal 
Pre-midday meal glucose valuesa  
Midday premeal 
Pre-evening meal glucose valuesa  
Evening premeal 
Bedtime glucose valuesa  
Abbreviation: SMBG = self-monitored blood glucose. 
a Investigators can request 2-hour post-meal glucose values or other additional glucose values from participants to 
aid titration. 
 
The median SMBG profile from premeal or bedtime is used as the “adjustment value” and the 
change in insulin lispro dose (either increase or decrease) is based upon this value as described in 
the table below. 
If Mealtime Dose of 
Insulin Lispro is: 
Glucose Below 
Target Range 
Glucose at Target 
Range 
Glucose Above 
Target Range 
<10 units  
Decrease by 1 unit 
No change 
Increase by 1 unit 
11-19 units  
Decrease by 1-2 units 
No change 
Increase by 1-2 units 
>20 units  
Decrease by 2-3 units 
No change 
Increase by 2-3 units 
Source: Adapted from Bergenstal et al. 2008. 
 
For either prandial insulin dosing plan, the investigator may determine the appropriate correction 
factor for the participant to administer when premeal glucose levels are above target based on 
clinical judgment, taking into account the participant’s clinical history with previous/current 
insulin regimen and recent glucose profiles. Alternatively, the correction factor may initially be 
calculated as follows: 
correction factor = 1800/total daily insulin dose = estimated decrease in glucose (mg/dL) 
level per unit of prandial insulin administered, or 
correction factor = 100/total daily insulin dose = estimated decrease in glucose (mmol/L) 
level per unit of prandial insulin administered 
6.6. 
Continued Access to Study Intervention after the End of the Study 
The sponsor will not provide participants with any ongoing supplies of study intervention after 
they have completed the study treatment period or permanently discontinued the study 
intervention. 
6.6.1. 
Transitioning off of Study Basal Insulin  
At the last treatment visit (Visit 23 [Week 26] or ED visit), the investigator will prescribe a non-
study basal insulin for use during the safety follow-up period.  
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The investigator, in consultation with the participant, will decide on prandial insulin therapy for 
use during the safety follow-up period.  
Study participants treated with LY3209590  
Participants will administer their last dose of LY3209590 at Week 25 of the study and can begin 
the transition to the non-study insulin after Visit 23 (Week 26). At Visit 23 (Week 26), the 
investigator will review instructions for transitioning to the non-study insulin with the 
participant. The non-study daily basal insulin treatment should be started slowly and under 
regular review of glucose profiles after discontinuation of LY3209590.   
Since LY3209590 has a half-life of approximately 17 days, a slow up-titration of the non-study 
daily basal insulin is necessary to prevent hypoglycemia due to overlapping insulin action. Non-
study basal insulin would not be required until the study participant’s fasting glucose is above 
120 mg/dL (6.6 mmol/L), and then daily basal insulin would be initiated and adjusted based on 
fasting glucose, other SMBGs, hypoglycemia evaluation, and other clinical factors. The 
investigator should consider titration of the non-study basal insulin to reach 50% of the required 
daily basal insulin dose at approximately 2 weeks and 80% of the required daily basal insulin 
dose at approximately 4 weeks. In addition to Visit 801, unscheduled visits may occur during 
this time to facilitate the transition to non-study daily basal insulin. 
Study participants treated with insulin glargine 
Participants assigned to the insulin glargine treatment arm will transition to their non-study basal 
insulin after Visit 23 (Week 26) with dose adjustment per investigator discretion based on fasting 
glucose, other SMBGs, and hypoglycemia evaluation and in accordance with the local product 
label for the basal insulin.  
6.7. 
Treatment of Overdose 
An overdose of LY3209590 or insulin glargine, defined as a dangerously large amount of insulin 
compared to the protocol-prescribed dose, will be reported as per Section 10.3.1. In the event of 
an overdose, refer to the IB for LY3209590 or product label for insulin glargine depending on 
the participant treatment assignment.  
In the event of an overdose, the investigator or treating physician should: 
● contact the medical monitor immediately 
● evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced 
● consider holding non-insulin diabetes medications, if clinically appropriate 
● 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. 
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6.8. 
Concomitant Therapy 
Concomitant therapy regimens 
All participants should maintain their usual medication regimens for concomitant conditions or 
diseases throughout the study, unless those medications are specifically excluded in the protocol 
(see Section 5.2). 
Acceptable non-insulin diabetes treatments are described in Section 6.8.3 
Changing concomitant therapy 
Participants should consult with authorized study personnel before taking any new medications 
during the study, except when initiated for treatment of medical emergencies. Authorized study 
personnel should consult the sponsor’s medical monitor if there are any questions about 
concomitant therapies during the study. 
Concomitant therapy data collection 
For therapy that the participant is receiving at the time of enrollment or receives during the 
study, including over-the-counter medications, authorized study personnel should collect 
 the name of medication, vaccine, or therapy 
 the reason for use, and 
 dates of administration, including start and end dates. 
For diabetes and lipid-modifying medications, collect dosage information including dose and 
frequency. 
Non-study medications taken by study participants who have signed informed consent, but are not 
randomly assigned, will not be reported unless an SAE or AE occurs that the investigator believes 
may have been caused by a study procedure. 
6.8.1. 
Medications with Approved Weight Loss Indication 
Allowed usage of weight loss medication during the study 
A participant may use a medication that promotes weight loss if they are on stable therapy 90 
days prior to screening (Visit 1). 
Allowed medications include, but are not limited to 
 over-the-counter medications, including food supplements that promote weight loss 
 liraglutide 3.0 mg 
 orlistat 
 sibutramine 
 mazindol 
 phentermine 
 phentermine and topiramate combination 
 naltrexone and bupropion combination, or 
 semaglutide injection 2.4 mg. 
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Prohibited usage of weight loss medication during the study 
After screening (Visit 1), no prescription or over-the-counter medications that promote weight 
loss may be initiated or changes in dosage allowed. 
6.8.2. 
Chronic Systemic Glucocorticoid Medication 
Chronic systemic glucocorticoid therapy is allowed for no more than one 14-consecutive day 
period during study treatment period.  
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. 
6.8.3. 
Antihyperglycemic Medications 
This table shows the conditions for use of other antihyperglycemic medications. 
Drug Class 
Use during 
Screening or 
Lead-In 
Conditions for Use after Randomization 
 
Y = yes, if on 
stable therapy 
90 days prior to 
screening. 
N = No 
During 
Treatment 
Period 
Acute Therapy 
Treatment for 
up to 14 days 
Rescue 
Therapy 
During 
Safety 
Follow-
Up 
Period 
Metformin
a 
Y 
Yes, if on stable 
therapy 90 days 
prior to 
screening 
N/A 
Yb 
Yc 
GLP-1 Ras 
Y 
N/A 
Yb 
Yc 
DPP-4 inhibitors 
Y 
N/A 
Yb 
Yc 
SGLT2 inhibitors 
Y 
N/A 
Yb 
Yc 
Non-study daily 
basal insulins 
Y 
N 
Yes, only if study 
basal insulin is 
temporarily 
discontinued 
See Noted 
Y 
Non-study 
prandial insulin 
Y 
N 
Yes, only if study 
prandial insulin is 
temporarily 
discontinued 
Y 
Y 
Insulin mixtures 
N 
N 
N 
N 
N 
Meglitinides 
N 
N 
N/A 
N 
N 
Alpha-glucosidase 
inhibitors 
N 
N 
N/A 
N 
N 
Sulfonylureas 
N 
N 
N/A 
N 
N 
Thiazolidinediones 
N 
N 
N/A 
N 
N 
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; N = no; N/A 
= not applicable; SGLT2 = sodium-glucose cotransporter 2; Y = yes. 
a Switching metformin manufacturer is allowed if the dosage is the same. Changing to a metformin formulation 
with a different action profile (that is, from short-acting to long-acting metformin) is not permitted. 
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b   For rescue therapy, concomitant antihyperglycemic medication doses may be increased if the dose is below 
maximum approved dose per country-specific label. 
c Participants can continue on these therapies but should not start a new class of therapy during the 5-week safety 
follow-up period. 
d Participants who require a non-study basal insulin as rescue therapy must discontinue study basal insulin therapy 
(LY3209590 or insulin glargine). The participant will remain in the study and follow procedures for the 
remaining study visits.  
Dose adjustments of allowable non-insulin antihyperglycemic medications are permitted after 
randomization under the following circumstances: 
 situations that require short-term treatment interruption consistent with the product 
labeling for each respective country 
 situations that require dose adjustment or discontinuation per country-specific label, for 
example, in the case of reduced estimated glomerular filtration rate 
 in the case of increased hypoglycemia risk during the treatment period (as described in 
Section 8.3.6), and  
 for safety reasons at the discretion of the investigator. 
Any changes in dose should be documented. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
7.1. 
Discontinuation of Study Intervention 
When necessary, a participant may be permanently discontinued from LY3209590 or insulin 
glargine. If so, the participant will remain in the study and follow procedures for remaining study 
visits, as shown in the SoA. 
Participants who stop LY3209590 or insulin glargine permanently may receive another glucose-
lowering medication. The new glucose-lowering medication will be recorded on the appropriate 
CRF. 
A participant should be permanently discontinued from LY3209590 or insulin glargine if 
 the participant becomes pregnant during the study 
 the participant requests to discontinue LY3209590 or insulin glargine  
 the participant is diagnosed with an active or untreated malignancy, except for 
successfully treated basal or squamous cell carcinoma 
 the participant did not take insulin glargine for more than 21 consecutive days or 
missed more than 3 consecutive doses of LY3209590 at any time during the study, or 
 in the opinion of the investigator, the participant should permanently discontinue 
LY3209590 or insulin glargine for safety reasons. 
7.1.1. 
Liver Chemistry Stopping Criteria 
The study drug should be interrupted or discontinued if one or more of these conditions occur.  
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or 
INR >1.5  
In participants with Gilbert’s 
syndrome, doubling of direct 
bilirubin should be used for 
LY3209590 or insulin glargine 
interruption or discontinuation 
decisions rather than TBL>2x 
ULN. 
ALT or AST >3x ULN with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
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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 
LY3209590 or insulin glargine 
interruption or discontinuation 
decisions rather than TBL >2x 
ULN. 
ALP >2.5x ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited, non-drug etiology is identified.   
7.1.2. 
Hypersensitivity Reactions 
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the sponsor’s designated medical monitor should be notified. 
If the investigator is uncertain about whether a systemic hypersensitivity reaction has occurred 
and whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor. 
7.1.3. 
Temporary Discontinuation 
Criteria for temporary discontinuation of LY3209590 or insulin glargine 
The investigator may temporarily interrupt study treatment, due to an AE, clinically significant 
laboratory value, hospital visits, travel, or shortage of study treatment supply. 
This will be allowed for up to 21 consecutive days for insulin glargine or 3 consecutive doses for 
LY3209590 at any time during the study. This information should be documented by the 
investigator. 
Guidance when temporary discontinuation of LY3209590 or insulin glargine occurs 
Every effort should be made by the investigator to maintain participants in the study and to 
restart LY3209590 or insulin glargine promptly, as soon as it is safe to do so. 
Participants will continue their study visits and follow-up according to the SoA. 
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Participants should resume the dose prescribed before the temporary dosing interruption at the 
discretion of the investigator. 
Recording temporary discontinuation of LY3209590 or insulin glargine  
The dates of LY3209590 or insulin glargine interruption and restart must be documented in 
source documents and entered on the CRF. 
Participant noncompliance should not be recorded as interruption of LY3209590 or insulin 
glargine on the CRF. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study 
● at any time at the participant’s own request 
● at the request of the participant’s designee, for example, parents or legal guardian 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if 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 posttreatment follow-up, as shown in the SoA. 
If the participant has not already discontinued the LY3209590 or insulin glargine, the participant 
will be permanently discontinued from the LY3209590 or insulin glargine 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.  
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
8.1. 
Efficacy Assessments 
Efficacy will be measured by 
 HbA1c 
 Time in glucose ranges measured during the CGM session prior to Week 26 
 Fasting glucose, and 
 Patient-reported outcomes questionnaires 
o EQ-5D-5L  
o DID-EQ 
o Basal Insulin Experience: Preference 
o Basal Insulin Experience: Likelihood of incorporating into routine 
 
See Section 3 for specific efficacy endpoints. 
This section will outline glucose monitoring and PRO.  
8.1.1. 
Glucose Monitoring 
Participants must use only the study-provided glucometer during the study. 
8.1.1.1. 
Self-Monitoring of Blood Glucose (SMBG) 
Glucometer for participant use during the study 
Participants will receive a sponsor-approved glucometer and related testing supplies for use 
during the study. 
Site personnel will train the participant on correct use of the glucometer for self-monitoring 
blood glucose and reporting of hypoglycemia data in the e-diary. 
Participants should use the glucometer 
 whenever hypoglycemia is experienced or suspected 
 when there is awareness of increased risk related to changes in dietary intake, physical 
activity, or inadvertent or atypical insulin dosing 
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 at meals in order to aid in prandial insulin dosing 
 to check for hyperglycemic events  
 at their own discretion, or 
 as directed by the investigator. 
When to measure fasting blood glucose during the study 
Site personnel will train the participant to measure FBG daily when possible, and a minimum of 
3 times per week using the study-provided glucometer. 
The FBG should be measured upon waking in the morning, prior to food or caloric beverage 
intake. 
When to measure 4-point self-monitored blood glucose profile during the study 
Site personnel will train the participant to measure a 4-point SMBG profile using the study-
provided glucometer. 
The 4-point SMBG profile should be measured 
 upon waking in the morning, prior to food or caloric beverage intake (FBG) 
 ahead of the midday meal 
 ahead of the evening meal, and 
 at bedtime.  
Subjects are strongly encouraged to perform 4-point SMBG ≥3 days per week. Subjects should 
be encouraged to perform 4-point SMBG profiles on consecutive days of the week so that the 
change from bedtime glucose to fasting glucose can be assessed by the investigator. In addition, 
subjects should be encouraged to measure an SMBG ahead of administration of all prandial 
insulin and at bedtime to assist in insulin dosing decisions throughout the study. Investigators 
may request 2-hour postprandial glucose readings, overnight glucose readings, or other 
additional glucose readings at their discretion. 
Glucometer data transfer 
The study-provided glucometer will wirelessly transmit blood glucose measurements to the 
participant’s e-diary. Site personnel will be able to view SMBG data that have been transmitted 
to the e-diary through a web-based portal as well as any reported events of hypoglycemia. 
8.1.1.2. 
Continuous Glucose Monitoring Systems 
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 according to the SoA. Participants will be trained on the CGM system before use and 
will be required to replace the sensor at designated intervals per the investigator instruction. A 
CGM Participant User Guide that provides an overview of device components and study specific 
instructions is available for at-home use. 
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Participants are not allowed to connect the transmitter of the Dexcom G6 system to a personal 
smartphone, smartphone application, or other system. 
CGM data compliance 
At the end of each CGM session, participants will return the CGM system to the site. Site 
personnel will upload the CGM data to a vendor-hosted online portal to view data capture 
compliance using the available reports and visualization tools. The compliance threshold of 80% 
for each session is defined as the percentage of actual data versus expected data collected during 
a session. Site personnel will re-educate participants on CGM operation and requirements when 
session compliance is <80%. 
To minimize data loss, the CGM service vendor will review site uploads and notify site users 
when sessions do not meet the compliance threshold. CGM compliance reports will also be 
provided to the sponsor and site monitors during the study for review and to determine if further 
mitigation is necessary. 
Participants may continue to use their personal CGM in addition to the study provided CGM if 
they were using CGM before screening (Visit 1). Participants who use a personal CGM must 
also check FBGs, 4-point SMBGs, and BGs for hypoglycemia events as specified in the 
protocol. Subjects must check a BG prior to treatment for hypoglycemia even if personal CGM 
values indicate hypoglycemia unless it would be unsafe to do so. 
8.1.2. 
Patient-reported Outcomes 
The self-administered questionnaires will be translated into the native language of the region and 
administered at the site during the designated visits in the SoA. 
Order of administering the questionnaires during the visit 
If the participant is not adversely affected by their fasting condition, the questionnaires should be 
completed before the participant has discussed their medical condition or progress in the study 
with the investigator or study personnel. 
Preferred administration order of these questionnaires is 
1. EQ-5D-5L 
2. Diabetes Injection Device Experience Questionnaire 
3. Basal Insulin Experience: Preference, and 
4. Basal Insulin Experience: Likelihood of incorporating into routine. 
8.1.2.1. 
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 
 
self-care 
 
usual activities 
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 
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. 
A total of 3125 health states is possible. 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). In addition, the EQ 
Visual Analog Scale records the respondent’s self-rated health status on a vertical graduated (0 to 
100) visual analog scale. 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. 
8.1.2.2. 
Diabetes Injection Device Experience Questionnaire 
Description of DID-EQ 
The DID-EQ (Matza et al. 2018) is a self-administered, 10-item questionnaire designed to assess 
participants’ perceptions of  diabetes injection delivery systems for T2D.  
Scoring for DID-EQ 
Each item is rated on a 4-point scale with higher scores indicating more positive perceptions of 
the injection device.  
Items 1 to 7 focus on specific characteristics of diabetes injection device, and these 7 items 
comprise the Device Characteristics subscale.  
In addition, there are 3 global items:  
 Item 8 assessing overall satisfaction  
 Item 9 ease of use, and  
 Item 10 convenience of diabetes injection devices. 
These 3 global items are each scored separately. 
8.1.2.3. 
Basal Insulin Experience: Preference 
The Basal Insulin Experience: Preference is a self-report scale consisting of a single 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. 
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8.1.2.4. 
Basal Insulin Experience: Likelihood of Incorporating into Routine 
The Basal Insulin Experience: Likelihood of Incorporating into Routine is a self-report scale 
consisting of a single 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.”  
8.2. 
 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
Physical examination at screening 
The complete physical examination will include, at a minimum, assessments of these systems 
 cardiovascular 
 respiratory 
 gastrointestinal, and 
 neurologic. 
Height and weight will be measured and recorded. 
Additional assessments include clinical signs and symptoms related to T2D, T2D-related 
illnesses, and injection-site reactions. 
8.2.2. 
Vital Signs 
Blood pressure and pulse rate will be measured as specified in the SoA and as clinically 
indicated. Additional vital signs may be measured during study visits if warranted, as determined 
by the investigator. 
8.2.3. 
Electrocardiograms 
Local and single 12-lead ECG will be obtained as outlined in the SoA.  
Electrocardiograms will initially be interpreted by the investigator or qualified designee at the 
site as soon after the time of ECG collection as possible, and ideally while the participant is still 
present, to determine whether the participant meets entry criteria and for immediate participant 
management, should any clinically relevant findings be identified.  
The investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document their review of the ECG printed at the time of 
evaluation.  
 
8.2.4. 
Clinical Safety Laboratory Tests 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency. 
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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 medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments, as defined in 10.2, must be conducted in 
accordance with the SoA, standard collection requirements, and laboratory manual. 
If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE.  
8.2.5. 
Hepatic Monitoring 
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests (Section 10.5), including ALT, AST, ALP, TBL, direct bilirubin, GGT, and 
creatine kinase, should be repeated within 48 to 72 hours to confirm the abnormality and to 
determine if it is increasing or decreasing, if 1 or more of these conditions occur.  
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 aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
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What to do if the abnormal condition persists or worsens 
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. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including 
 symptoms 
 recent illnesses, for example, heart failure, systemic infection, hypotension, or seizures 
 recent travel 
 history of concomitant medications, including over-the-counter, herbal and dietary 
supplements, and 
 history of alcohol drinking and other substance abuse.  
Frequency of monitoring 
Initially, monitoring of symptoms and 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 
When to perform a comprehensive evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 1 
or more of 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 or symptomsa, or 
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs or symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s 
syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; 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%. 
What a comprehensive evaluation should include 
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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 patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for 
 hepatitis D virus 
 cytomegalovirus 
 Epstein-Barr virus 
 acetaminophen levels 
 acetaminophen protein adducts 
 urine toxicology screen 
 Wilson’s disease 
 blood alcohol levels 
 urinary ethyl glucuronide, and 
 blood phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a hepatologist or 
gastroenterologist consultation, magnetic resonance cholangiopancreatography (MRCP), 
endoscopic retrograde cholangiopancreatography (ERCP), cardiac echocardiogram, or a liver 
biopsy.   
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Collect additional hepatic safety data collection in the hepatic safety CRFs if a participant  
 develops a hepatic event considered to be an SAE 
 discontinues study intervention due to a hepatic event, or 
 has changes in laboratory results described in this table. 
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If a participant 
with baseline 
develops the following 
elevations… 
Then… 
Elevated serum ALT 
Collect additional hepatic safety 
data in the hepatic safety CRF. 
ALT <1.5x ULN 
ALT to ≥5x ULN on 2 or more 
consecutive blood tests 
ALT ≥1.5x ULN 
ALT ≥3x baseline on 2 or more 
consecutive blood tests 
Elevated TBL 
TBL <1.5x ULN 
TBL ≥2x ULN, except for 
participants with Gilbert’s 
syndrome 
TBL ≥1.5x ULN 
TBL ≥2x baseline  
Elevated ALP 
ALP <1.5x ULN 
ALP ≥2x ULN on 2 or more 
consecutive blood tests 
ALP ≥1.5x ULN 
ALP ≥2x baseline on 2 or more 
consecutive blood tests 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; CRF = case report form; TBL = total 
bilirubin; ULN = upper limit of normal. 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
See Section 10.5 for hepatic laboratory tests. 
8.2.6. 
Pregnancy Testing  
Pregnancy testing will occur as outlined in the SoA. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected as outlined in Sections 8.3.1 and 8.3.2. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Section 10.3, Appendix 3: 
 Adverse events (AEs) 
 Serious adverse events (SAEs), and 
 Product complaints (PCs). 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
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After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
For product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Section 10.3.  
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 
Signing of 
the informed 
consent form 
(ICF) 
The last 
safety follow-
up visit 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
The last 
safety follow-
up visit 
Within 24 hours of 
awareness 
SAE CRF  
SAE paper 
form 
SAEa – after 
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  
(see Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; PC = product 
complaint; SAE = serious adverse event.  
a SAEs 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 LY3209590 or insulin glargine. 
After learning of a pregnancy in the female partner of a study participant, the investigator will 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female participants who become pregnant 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant’s 
pregnancy.  
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
gestational age, fetal status (presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring at ≥20 
weeks gestational age) is always considered to be an SAE and will be reported as such.  
Any post-study 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. 
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.   
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8.3.3. 
Adjudicated Events: Cerebrocardiovascular Events 
A blinded external Clinical Event Committee will adjudicate potential cerebrocardiovascular 
events in a consistent and unbiased manner. 
Events include 
 death 
 myocardial infarction 
 coronary revascularization procedure 
 hospitalization for unstable angina 
 hospitalization for heart failure, and 
 stroke or transient ischemic attack. 
8.3.4. 
Systemic Hypersensitivity Reactions 
Many drugs, including biologic agents, carry the risk of systemic hypersensitivity reactions. If 
such a reaction occurs, additional data should be provided to the sponsor in the designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory.  
8.3.5. 
Injection-Site Reactions 
Symptoms and signs of a local injection-site reaction may include erythema, induration, pain, 
pruritus, lipodystrophy, and edema. 
If an injection-site reaction is reported by a participant or study personnel, additional information 
about this reaction will be collected in the CRF. 
8.3.6. 
Hypoglycemia 
Participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia and how to treat hypoglycemia. Hypoglycemia events entered into the participant 
e-diary will be available for review through a web-based portal that can be accessed by 
designated investigative site personnel at any time. 
Hypoglycemia classification and definitions 
Level 1   
Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L)   
Level 1 hypoglycemia can alert a person to take action such as treatment with fast-acting 
carbohydrates. Providers should continue to counsel participants to treat hypoglycemia at this 
glucose alert value. 
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Level 2  
Glucose <54 mg/dL (3.0 mmol/L)   
Level 2 hypoglycemia is also referred to as documented or blood glucose confirmed 
hypoglycemia. The glucose threshold is clinically relevant regardless of the presence or absence 
of symptoms of hypoglycemia.  
Level 3 Severe 
A severe hypoglycemic event is characterized by altered mental or physical status requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions for the treatment of hypoglycemia.   
The determination of an episode of severe hypoglycemia is made by the investigator based on 
the medical need of the participant to have required assistance and is not predicated on the report 
of a participant simply having received assistance. 
Examples of severe hypoglycemia in adults are 
 altered mental status and the inability to assist in their own care  
 semiconscious or unconscious, or  
 coma with or without seizures.  
Glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of glucose concentration to normal is considered sufficient 
evidence that the event was induced by a low glucose concentration. 
Nocturnal hypoglycemia  
Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, that occurs at 
night and presumably during sleep between midnight and 0600 (6:00 am).   
Reporting of severe hypoglycemic events 
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE CRF and report it to Lilly as an SAE.   
The investigator should also determine if repeated or prolonged episodes of hypoglycemia 
occurred prior to the severe event.  
8.4. 
Pharmacokinetics 
At the visits and times specified in the SoA (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. 
Sample retention is described in Section 10.1.12.  
8.5. 
Pharmacodynamics 
Pharmacodynamic parameters are described in Section 8.1. 
8.6. 
Genetics 
Genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Serum and plasma samples will be used for exploratory biomarker research, where local 
regulations allow. See Clinical Laboratory Tests in Section 10.2, and the SoA for sample 
collection information. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3209590, pathways associated with T2D, mechanisms of action of LY3209590 or research 
methods, or in validating diagnostic tools or assay(s) related to T2D. 
Samples may be used for research to develop methods, assays, prognostics, and/or companion 
diagnostics related to the intervention target, disease state, pathways associated with disease, 
and/or the mechanism of action of the study intervention. 
Sample retention is described in Section 10.1.12.  
8.8. 
Immunogenicity Assessments 
At the visits and times specified in the SoA, venous blood samples from all study participants 
will be collected to determine antibody production against LY3209590. Antibodies may be 
further characterized for cross-reactive binding to endogenous insulin. 
To interpret the results of immunogenicity, a corresponding venous blood sample will be 
collected at the same visits to determine the concentrations of LY3209590 (PK sample). At 
Visit 3, the sample for immunogenicity should be taken before dosing and the PK sample for 
LY3209590 after dosing. 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
Treatment-emergent anti-drug antibody (TE ADA) is defined in Section 9.3.6.2. 
Immunogenicity will be assessed by a validated assay designed to detect and characterize ADA 
in the presence of LY3209590 at a laboratory approved by the sponsor. 
Sample retention is described in Section 10.1.12. 
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8.9. 
Health Economics 
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations 
The first version of the SAP will be finalized prior to 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 glargine on glycemic control as measured by change in HbA1c from baseline at Week 26 
in participants with T2D currently on basal insulin and at least 2 injections per day of prandial 
insulin. 
The null hypothesis (H0) to be tested is the difference in the change in HbA1c (LY3209590 – 
insulin glargine) from baseline at Week 26 is greater than the noninferiority margin (NIM). 
The NIMs of 0.4% and 0.3% will both be tested to meet different regulatory requirements. Each 
NIM will have its own familywise error rate. The upper bound of the 2-sided 95% CI will be 
used for testing the noninferiority hypothesis.  
Secondary hypotheses 
The key secondary (multiplicity adjusted) objectives are to test the hypotheses that LY3209590 
is superior to insulin glargine with respect to 
 change from baseline in HbA1c at Week 26 
H0: the difference (LY3209590 – insulin glargine) ≥0.0 
 The percentage of participants achieving HbA1c <7% at Week 26 without nocturnal 
hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during treatment phase up to Week 
26 
H0: the odds ratio (LY3209590 vs insulin glargine) ≤1 
 the event rate of nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during 
treatment period up to Week 26 
H0: the relative event rates (LY3209590 vs insulin glargine) ≥1 
These hypotheses and the primary hypothesis will be tested using a strategy to control the overall 
type 1 error (see Section 9.1.1). 
9.1.1. 
Multiplicity Adjustment 
A graphical approach (Bretz et al. 2009, 2011) for multiple comparisons will be used to ensure 
the strong control of overall type I error rate for testing the primary and key secondary 
(multiplicity adjusted) objectives. 
The overall significance level (α) will be set to 0.05. The total α will be used for the primary 
objective first, then the α will be allocated and transitioned to other key secondary objectives 
once the primary objective is met. The testing procedure and α allocation will be established 
according to the clinical importance and statistical power of the endpoints in this study 
population. 
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The details of graphical testing scheme will be described in the SAP. 
9.2. 
Analyses Sets 
This table defines the populations for the purpose of analysis. 
Analysis Populations or 
Datasets 
Description 
Entered Population 
All participants who sign the informed consent form. 
Randomized Population 
All randomized participants. Participants will be analyzed 
according to the treatment they were assigned. 
Modified Intent-to-Treat 
(mITT) Population  
All randomized participants who took at least 1 dose of 
LY3209590 or insulin glargine. Participants will be 
analyzed according to the treatment they were assigned. 
Efficacy Analysis Set 1 (EAS1) 
for treatment regimen estimand 
The data will include  
 mITT Population excluding participants 
discontinuing the study treatment due to inadvertent 
enrollment 
 all measurement regardless of the use of study 
treatment or rescue medications.  
Efficacy Analysis Set 2 (EAS2) 
for efficacy estimand 
The data will include 
 mITT Population excluding participants 
discontinuing the study treatment due to inadvertent 
enrollment 
 measurement up to the discontinuation of study 
treatment or the initiation of rescue medications.    
Safety Analysis Set (SS) 
The data will include 
 mITT Population 
 all measurement regardless of the use of study 
treatment or rescue medications. 
9.3. 
Statistical Analyses 
9.3.1. General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designees. Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol. Any other changes to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
SAP or the clinical study report. Additional exploratory analyses of data will be conducted as 
deemed appropriate. 
Unless otherwise stated, the efficacy and safety analyses will be conducted on either EAS1 or 
EAS2, and the safety analyses will be conducted on the 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. 
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Unless otherwise specified, the other secondary and tertiary efficacy measures will be analyzed 
using the data up to the discontinuation of study treatment (EAS2), defined by the date of last 
study dose + 10 days or the initiation of rescue therapy, whichever is earlier.  
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis 
The primary objective is to demonstrate noninferiority of LY3209590 compared to insulin 
glargine on the HbA1c change from baseline at Week 26 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 as defined in Section 3 of this 
protocol. 
Treatment regimen estimand 
The treatment regimen estimand will be estimated using the HbA1c data at baseline and Week 
26 for the EAS1 regardless of the use of study treatment or rescue therapy. 
Missing measures 
The missing measures at the primary endpoint will be imputed using multiple imputation by the 
retrieved dropout approach. The retrieved dropout participants are those who discontinue 
LY3209590 or insulin glargine prior to Week 26 but have non-missing measures at Week 26. 
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 will be imputed by return-to-
baseline approach. 
Analysis model 
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 use of personal CGM or FGM), and 
baseline HbA1c value. The statistical inference will be based on the multiple imputation 
framework by Rubin (1987). 
Efficacy estimand 
The efficacy estimand is the treatment differences in the change in HbA1c from baseline to 
Week 26 if all participants would adhere to the treatment without intercurrent events. 
The HbA1c collected at all planned postbaseline visits from the EAS2 will be used in the 
analysis. 
Missing measures 
There may be missing values due to the early discontinuation of study treatment or use of rescue 
therapy. 
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The mixed-model for repeated measures (MMRM) will be used, and the missing values will be 
handled in the MMRM analysis under the assumption of missing at random. 
Analysis model 
The MMRM model will include treatment, strata (country and use of personal CGM or FGM), 
visit and treatment-by-visit interaction as fixed effects, and baseline HbA1c value 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, and  
6. compound symmetry without heterogeneous variances. 
 
The 2-sided 95% CI of the LS mean for individual treatment groups, treatment LS mean 
difference (LY3209590 – insulin glargine) in the HbA1c change from baseline to Week 26 will 
be estimated. For both estimands, LY3209590 will be declared noninferior to insulin glargine if 
the upper limit of the 2-sided 95% CI for the LS mean difference in the HbA1c change from 
baseline is below the NIM (+0.4% or +0.3% depending on 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 (NGSP IFCC Standardization of HbA1c page 
[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 glargine for  
1) change in HbA1c from baseline at Week 26  
2) the percentage of participants achieving HbA1c <7% at Week 26 without nocturnal 
hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during treatment phase up to Week 
26 
3) the event rate of participant-reported clinically significant nocturnal hypoglycemia 
(<54 mg/dL [3.0 mmol/L] or severe) during treatment period up to Week 26  
 
The superiority test in change from baseline at Week 26 in HbA1c will be based on the same 
primary endpoint analysis described above. 
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The percentage of participants achieving HbA1c <7% at Week 26 without nocturnal 
hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) will be analyzed by logistic regression model 
including treatment, strata (country and use of personal CGM or FGM), baseline HbA1c value, 
and baseline incidence of nocturnal hypoglycemia as independent variables.   
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. 
9.3.3.2. 
Other Secondary Endpoints 
Other secondary endpoints include various measures for efficacy, patient-reported outcome 
measures and safety. Efficacy and patient-reported outcome measures will be analyzed using 
EAS2 unless otherwise noted. Safety measures will be analyzed using the SS regardless of 
treatment discontinuation and use of rescue therapy. 
Analysis details will be provided in the SAP. 
9.3.4. 
Tertiary Endpoint(s) Analysis 
Refer to the SAP for analyses related to tertiary endpoints. 
9.3.5. 
Safety Analyses 
Safety measures include 
 treatment exposure 
 AE 
 vital signs 
 weight 
 hypoglycemia 
 laboratory measures, and 
 immunogenicity. 
All safety analyses will be based on the SS. 
Events that are newly reported after the first dose of LY3209590 or insulin glargine, or reported 
to worsen in severity from baseline, will be considered as 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. 
Summary statistics will be provided for incidence of 
 TEAEs 
 SAEs 
 study discontinuation due to AEs 
 intervention discontinuation due to AEs, and 
 deaths. 
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Hypoglycemia analysis 
The participant-reported hypoglycemia will be analyzed using data from e-diary by 
 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. 
The analysis periods of 0-6, 0-12, 0-26, 12-26 weeks of treatment will be considered. 
Documented hypoglycemia will be defined as 
 All documented hypoglycemia - episodes for the 24-hour period 
 Non-nocturnal hypoglycemia - episodes during 6 AM to midnight, and 
 Nocturnal hypoglycemia - episodes during midnight to 6 AM.  
The incidence and rate of hypoglycemia will be summarized by treatment and analysis period for 
different types of hypoglycemia. 
For continuous safety variables (for example, laboratory measures, vital signs and weight), 
MMRM or ANCOVA models will be used. For categorical safety variables (for example, AEs, 
incidence of hypoglycemia, 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, sex, and renal function on PK and/or PD 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-drug antibody (ADA) status (detected or not detected) against LY3209590 will 
be summarized by treatment for the participants evaluable for treatment-emergent (TE) ADA 
defined as participants with non-missing baseline and at least 1 non-missing postbaseline 
measurement. 
The number and percentage of participants who are TE ADA positive (TE ADA+) will be 
summarized by treatment group. 
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The frequency of cross-reactive binding to endogenous insulin may also be summarized for the 
participants with TE ADA+. 
The relationship between the presence of TE ADA and the safety and efficacy measures may be 
assessed. 
Definition of TE ADA+ 
A participant is considered TE ADA+ if either treatment-induced ADA or treatment-boosted 
ADA occur. 
Treatment-induced ADA is defined as 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 is defined as 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.  
9.3.6.3. 
Subgroup Analysis 
Detailed description of the subgroup variables will be provided in the SAP. 
9.4. 
Interim Analysis  
A program level safety review using selected efficacy and safety data will be conducted on a 
periodic basis across all ongoing Phase 3 clinical trials evaluating LY3209590. The analysis 
will be performed using the unblinded data and be reviewed by the DMC consisting of 
experienced members external to Lilly (Section 10.1.5). 
Study team personnel will remain blinded. Detailed information for the data review and the 
unblinding is specified in the DMC Charter or a separate unblinding plan document. 
9.5. 
Sample Size Determination 
Approximately 670 participants will be randomly assigned to LY3209590 and insulin glargine in 
a 1:1 ratio. With the assumption of 15% dropout at Week 26, approximately 284 participants on 
LY3209590 and 284 participants on insulin glargine will complete 26 weeks of treatment. 
The primary objective of this study is to test the hypothesis that LY3209590 is noninferior to 
insulin glargine on glycemic control as measured by change from baseline at Week 26 in HbA1c 
in participants with T2D currently on basal insulin and at least 2 injections per day of prandial 
insulin.  
Assuming an NIM of 0.4%, no true difference between treatment groups, and a SD of 1.1%, 568 
completers (284 on each of LY3209590 and insulin glargine) will provide greater than 99% 
statistical power to show noninferiority of LY3209590 compared to insulin glargine using the 
upper limit of a 2-sided 95% CI of (LY3209590 – insulin glargine). This sample size also has at 
least 90% statistical power to show noninferiority of LY3209590 compared to insulin glargine 
using a 0.3% NIM at Week 26. 
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The 568 completers will provide 90% statistical power to demonstrate the superiority 
(LY3209590 vs insulin glargine) of change in HbA1c from baseline at Week 26 (assuming a SD 
of 1.1% and true mean difference is -0.3%) using t-test at alpha of 0.05.  
The 568 completers will provide 90% statistical power to demonstrate the superiority 
(LY3209590 vs insulin glargine) on percentage of participants achieving HbA1c <7% at Week 
26 without nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during treatment phase 
up to Week 26 using a Fisher’s Exact test assuming 28.7% of insulin glargine patients achieve 
this target and 42% of LY3209590 patients achieve this target.  
The 568 participants will provide approximately 83% 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 26 (assuming event rate of 0.55 [SD = 2.6] and 1.1 
[SD = 2.6] events per participant per year for LY3209590 and insulin glargine, respectively, 
representing a 50% decrease in event rate for LY3209590 over insulin glargine) 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 Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
○ International Organization for Standardization (ISO) 14155 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
○ Reporting significant issues related to participant safety, participant rights, or 
data integrity 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
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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 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
Regulations 50, local regulations, ICH guidelines, privacy and data protection requirements, 
where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant and is kept on file. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets 
or tissue samples that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that the participant’s personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.  
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor has processes in place to ensure data protection, information security, and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach. 
10.1.5. 
Committees Structure 
10.1.5.1. Internal Safety Review Team 
Participant safety will be continuously monitored by the sponsor’s internal review team, which 
includes safety signal detection at any time during the study. 
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All safety data collected will be summarized and reviewed by the sponsor’s internal safety team 
for agreement of next steps. 
10.1.5.2. Clinical Event Committee for Adjudication of Events 
A blinded Clinical Event Committee, external to Lilly, will adjudicate all deaths and 
cerebrocardiovascular events. The committee will include physicians external to Lilly with 
cardiology expertise. 
10.1.5.3. Data Monitoring Committee 
An independent, external DMC will be responsible for reviewing unblinded data during the 
study. 
The committee will include, at a minimum, a medical physician with appropriate expertise and a 
statistician. 
Access to the unblinded data will be limited to the DMC and the external Statistical Analysis 
Center statisticians who are providing the analysis of the data. These statisticians will be 
independent from the study team. The study team will not have access to the unblinded data. 
Only the DMC is authorized to evaluate unblinded interim analyses. 
Details about the membership, purpose, responsibilities, and operation will be included in the 
DMC charter. 
 
10.1.6. 
Dissemination of Clinical Study Data 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
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Data and documents, including the study protocol, SAP, clinical study report, and blank or 
annotated case report forms, will be provided in a secure data sharing environment for up to 2 
years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance 
Investigator responsibilities 
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (for example, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Data monitoring and management 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These pre-defined parameters will be 
monitored during the study and important excursions from the 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 transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement (CTA) 
unless local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
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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. 
Electronic data capture system 
An EDC 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, caregiver, or study personnel, into an 
instrument, for example, hand-held smart phone or tablet. The eCOA data will serve as the 
source documentation and the investigator does not maintain a separate written or electronic 
record of these data. 
Data storage and access 
Data collected via the sponsor-provided data capture systems will be stored at third parties. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture systems. Prior to decommissioning, the investigator will 
receive or access an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on or entered in the CRF and are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definition of what constitutes source data can be found in 10.1.7. 
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10.1.9. 
Study and Site Start and Closure 
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to 
 study termination 
o discontinuation of further study intervention development 
 site termination 
o failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
o inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, or 
o total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information 
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
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10.1.12. 
Sample Retention 
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3209590 or after LY3209590 become(s) commercially available. 
Sample Type 
Custodian 
Maximum Retention Period after Last Patient Visita 
Pharmacokinetic 
Sponsor or designee 
1 year 
Exploratory biomarker 
Sponsor or designee 
15 years 
Immunogenicity  
Sponsor or designee 
15 years 
a 
Sample retention periods may differ dependent upon local regulations. 
 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in the table below will be performed by the Lilly-designated laboratory or by 
the local laboratory as specified in the table below. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded. 
In circumstances where the sponsor approves local laboratory testing in lieu of central laboratory 
testing (in the table below), the local laboratory must be qualified in accordance with applicable 
local regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
 
 
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Clinical Laboratory Tests  
Comments 
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs - red blood cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs - white blood cells)  
  
Differential 
  
Percent and absolute count of: 
  Neutrophils, segmented 
  
  Lymphocytes 
  
  Monocytes 
  
  Eosinophils 
  
  Basophils 
  
Platelets 
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
Alanine aminotransferase (ALT) 
  
Aspartate aminotransferase (AST) 
  
Gamma-glutamyl transferase (GGT) 
  
Blood urea nitrogen (BUN) 
  
Creatinine  
  
Uric acid 
  
Total protein 
  
Albumin 
  
Calcium 
  
Phosphorus 
  
Glucose  
Fasting or random (Refer to SoA) 
Cholesterol  
  
Triglycerides 
  
Lipid Panel 
Assayed by Lilly-designated laboratory  
High-density lipoprotein (HDL) 
  
Low-density lipoprotein (LDL-C) 
This value will be calculated. If triglycerides >400 mg/dL, 
the direct LDL will be assayed  
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Very-low-density lipoprotein (VLDL-C) 
  
Urinalysis 
Assayed by Lilly-designated laboratory 
Specific gravity 
  
pH 
  
Protein 
  
Glucose 
  
Ketones 
  
Bilirubin 
  
Urobilinogen 
  
Blood 
  
Nitrite 
  
Urine leukocyte esterase 
  
Microscopic examination of sediment 
  
Hormones (female) 
  
Serum pregnancy  
Assayed by Lilly-designated laboratory  
Urine pregnancy 
Evaluated locally  
Follicle-stimulating hormone (FSH)  
Assayed by Lilly-designated laboratory. Performed as 
needed to confirm participant’s postmenopausal status 
Urine Chemistry 
Assayed by Lilly-designated laboratory 
Albumin 
 
Creatinine 
 
Calculations 
Generated by Lilly-designated laboratory 
eGFR (CKD-EPI)  
  
Urinary albumin/creatinine ratio (UACR) 
  
Pharmacokinetic Samples  
LY3209590 concentration 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites 
Additional Testing 
Assayed by Lilly-designated laboratory  
C-Peptide 
  
HbA1c 
  
Glucose 
Fasting per SoA 
Exploratory Biomarker Storage Samples 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites 
Serum 
  
Plasma (EDTA) 
  
Immunogenicity Samples 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites 
Anti-LY3209590 antibodies  
  
 
 
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10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event 
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory test results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection, 
ideally prior to the next dose after the event, to assess post-event return-to-baseline values. 
Timing 
Sample Type 
Laboratory Testa 
Collect from 30 min to 4 hr after 
the start of the event. 
Note: The optimal collection time 
is from 1 to 2 hr after the start of 
event. 
Serum 
Total tryptase 
Serum/Plasma 
Complements (C3, C3a, and C5a) 
Serum 
Cytokine panel (IL-6, IL‐1β, IL‐10, or any cytokine 
panel that includes these 3 cytokines)  
Collect samples on the same day as 
the event. 
If samples were already collected 
per the SoA on the same day as the 
event, then duplicate samples are 
not collected. 
Note: The optimal collection time 
is up to 12 hr after the start of the 
event. 
Serum 
LY3209590 ADAs 
Plasma 
LY3209590 concentration 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
Information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
 The definitions and procedures detailed in this appendix are in accordance with ISO 
14155. 
 Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list of 
sponsor medical devices). 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This 
definition includes events related to the investigational medical device or comparator 
and events related to the procedures involved except for events in users or other 
persons, which only include events related to investigational devices. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. See definitions in Section 10.9. 
 
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 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/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, 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, 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 product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
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 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (for example, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate CRF page and 
product complaint information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
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 Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB for LY3209590 and Product Information for 
insulin glargine and insulin lispro 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. 
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 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on an SAE paper form (see next 
section) or to the sponsor by telephone. 
 Contacts for SAE reporting can be found in site training documents. 
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in site training documents. 
10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
● Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
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● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Females of childbearing potential 
Females are considered a woman of childbearing potential if 
 
they have had at least 1 cycle of menses, or 
 
they have Tanner 4 breast development. 
Any amount of spotting should be considered menarche.   
Females not of childbearing potential 
Females are considered women not of childbearing potential if 
 
absence of a uterus including having a congenital condition such as Mullerian agenesis  
 
they are infertile due to surgical sterilization, or  
 
they are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-oophorectomy, bilateral 
salpingectomy, or bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state should be defined as 
 
a woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note 
or  
 
a woman at least 40 years of age and up to 55 years old with an intact uterus, not on hormone 
therapya, who has had cessation of menses for at least 12 consecutive months without an 
alternative medical cause, AND with a follicle-stimulating hormone >40 mIU/mL 
or  
 
a woman 55 or older not on hormone therapy, who has had at least 12 months of spontaneous 
amenorrhea 
or 
 
a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone 
replacement therapy. 
 
a Women should not be taking medications during amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor modulators (SERMs), or 
chemotherapy that could induce transient amenorrhea. 
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10.4.2. 
Contraception Guidance 
Guidance for women of childbearing potential 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as 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 NOT in a 
same-sex relationship as their preferred and usual lifestyle, must do the following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative urine 
and serum result at randomization. See the protocol Schedule of Activities for 
subsequent pregnancy testing requirements. 
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. 
 
Guidance for all men 
No male contraception is required except in compliance with specific local government study 
requirements. 
 
Examples of different forms of contraception:  
 
Methods 
Examples 
Highly effective 
contraception (less than 
1% failure rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
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 
contraceptive patch (only women <198 pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception 
 
barrier method with use of a spermicide 
o male condom with spermicide 
o diaphragm with spermicide or cervical sponge, or 
o female condom with spermicide 
 
Note: The barrier method must include use of a spermicide (that is, condom 
with spermicide, diaphragm with spermicide, or female condom with 
spermicide) to be considered effective. 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical 
mucus, or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Hepatic evaluation testing 
See protocol Section 8.2.5 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
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    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
    HBV 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 
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 
 
 
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 for definitions and procedures for recording, evaluating, follow-up, and 
reporting of all events. 
 
 
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10.7. 
Appendix 7: Country-specific Requirements 
10.7.1. 
Germany 
This section describes protocol changes applicable for adult participants in study sites in 
Germany. 
10.7.1.1. Provisions for Changes in Study Conduct During Exceptional Circumstances 
In Germany, the temporary measures described in the “Provisions for Changes in Study Conduct 
During Exceptional Circumstances” (Section 10.8, Appendix 8) are applicable only to “the 
COVID-19 pandemic.”  
10.7.1.2. Changes Related to “Legally Authorized Representative,” “Legal Guardian,” 
“Parents” 
This table describes the changes and provides a rationale for the changes. 
Protocol Section Number and Name 
Description of the Change 
Brief Rationale 
7.2. 
Participant Discontinuation/Withdrawal 
from the Study 
 
8.3. 
Adverse Events, Serious Adverse 
Events, and Product Complaints 
 
10.9. Appendix 9: Abbreviations and 
Definitions 
 
Deleted references to “legally 
authorized representative,” 
“legal guardian,” “parents”  
The German Drug Law 
(Arzneimittelgesetz – AMG) with 
reference to EU Regulation 
536/2014 requires that adult 
participants act on their own behalf 
and provide their own written 
informed consent. If written consent 
is not possible, verbal consent with 
a witness is acceptable. No legal 
representative consent is accepted. 
 
The revised text in the following sections show the changes applicable to adult participants at 
study sites in Germany. Deletions are identified by strikethrough format. 
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 
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● 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. 
 
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). 
 
10.9. 
Appendix 9: Abbreviations and Definitions 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
 
 
 
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10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local ERBs, regulatory bodies, and any other relevant local authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific requirements in which notification is 
required, for example, upon implementation and suspension of changes. All approvals and 
notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
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The following changes in study conduct will not be considered protocol deviations: 
Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments according to the SoA, if written approval is provided by the 
sponsor. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor. 
Other alternative locations: Laboratory draws may be done at an alternate location in exceptional 
circumstances, if written approval is provided by the sponsor. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing, except for HbA1c 
and serum glucose testing. Lilly-designated laboratory testing must be retained for HbA1c and 
serum glucose. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Obtain local labs for safety hematology, chemistry, hormone panel, and urinalysis, when 
applicable, per the SoA. Safety labs should be obtained as specified in the SoA. 
All labs will be reviewed by the investigators. Sign and date review of local labs per normal 
process and follow-up with the participant as needed. Results will not be recorded in the CRF. 
Lilly Medical should be informed of any labs that meet criteria for temporary or permanent study 
intervention discontinuation. 
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Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken. 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site, for example, 
participant’s home, the investigator, sponsor, or both, should ensure oversight of the 
shipping process to ensure accountability and product quality, that is, storage 
conditions maintained and intact packaging upon receipt. 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening or the lead-in visits are valid for a maximum of 24 days. The following rules will be 
applied for active, nonrandomized participants whose participation in the study must be paused 
due to exceptional circumstances: 
 If screening is paused for less than 24 days from the signing of the ICF to the 
randomization visit, the participant will proceed to the next study visit per the usual 
SoA, provided that the randomization visit is conducted within 30 days from first 
screening. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 24 days from signing of the ICF to the 
randomization visit, the participant must be discontinued because of screening 
interruption due to an exceptional circumstance. This is documented as a screen 
failure in the CRF. The participant can reconsent and be rescreened as a new 
participant. The screening procedures per the usual SoA should be followed, starting 
at the screening visit to ensure participant eligibility by the randomization visit. 
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Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
The primary endpoint visit, Visit 23 (Week 26), should be completed per original schedule 
whenever possible and safe to do so. However, the visit windows should be within ±7 days 
relative to the target visit date. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
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10.9. 
Appendix 9: Abbreviations and Definitions 
 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
blinding 
A single-blind study is one in which the investigator and/or the investigator’s 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/the investigator’s 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. 
CGM 
continuous glucose monitoring: can refer to study procedure or analysis of 
representative CGM derived variables including but not limited to:   
 
Time in Range  
 
Time Below Range  
 
Time Above Range  
 
Daily Average Glucose  
 
Glucose Management Indicator  
 
Between- and Within-Day Glucose Variability  
 
Low Blood Glucose Index; High Blood Glucose Index; Blood Glucose Risk 
Indicator 
 
Ambulatory Glucose Profiles with interquartile ranges 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
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. 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CT 
computed tomography 
CV 
cardiovascular 
Device deficiencies 
equivalent to product complaint 
DID-EQ 
Diabetes Injection Device Experience Questionnaire 
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. 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
EAS 
Efficacy Analysis Set 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
ED 
Early Discontinuation 
EDC 
electronic data capture 
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. 
EQ-5D-5L 
EuroQol 5 dimensions 5 levels 
FBG 
fasting blood glucose 
FGM 
Flash glucose monitoring 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
HbA1c 
hemoglobin A1c 
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IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. See also “IMP.” 
IP 
investigational product 
IRB 
Institutional Review Board 
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 
LLT 
lowest level term 
LS 
least-squares 
MDI 
multiple daily injection 
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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. 
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 
mITT 
Modified Intent-to-Treat 
MMRM 
mixed-model for repeated measures 
NAFLD 
nonalcoholic fatty liver disease 
NIM 
noninferiority margin 
NIMP 
Non-investigational Medicinal Product 
NPH 
neutral protamine Hagedorn 
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 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
PT-INR 
prothrombin time, INR 
QTLs 
quality tolerance limits 
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.  
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SMBG 
self-monitoring of blood glucose 
SoA 
schedule of activities 
SS 
Safety Analysis Set 
T1D 
type 1 diabetes 
T2D 
type 2 diabetes  
TBL 
total bilirubin 
TE 
treatment emergent 
TE ADA 
treatment-emergent anti-drug antibody 
TEAE 
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
 
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10.10. Appendix 10: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]: (10-May-2022) 
Overall Rationale for the Amendment: 
The primary rationale for the current amendment is to address regulatory feedback regarding 
exclusionary ALT and AST thresholds and rescue medication. These changes are detailed in the 
table below. Minor error correction and formatting changes are not reflected in the table. 
Section # and Name 
Description of Change 
Brief Rationale 
3. Objectives, Endpoints, 
and Estimands 
Added initiation of rescue therapy to 
primary and secondary estimands. 
Added “2” intercurrent events in the 
description for remaining intercurrent 
events under efficacy regimen estimand 
attribute. 
Replaced “targeted study” with “study 
eligible” participants in the primary 
clinical question of interest for United 
States registration. 
Addressing regulator 
feedback. 
For clarity. 
5.1. Inclusion Criteria 
In inclusion criterion 5, added “as 
determined by the central laboratory”. 
For clarity. 
In inclusion criterion 7, removed “stable 
regimen” and added “any” 
5.2. Exclusion Criteria 
In exclusion criterion 22, added 
cirrhosis as a liver disease. 
ALT and AST thresholds were 
increased from 2.5x ULN to 3x ULN. 
For clarity. 
Addressing regulator 
feedback. 
In exclusion criterion 37, added 
wording “after having signed the 
informed consent form (ICF)” and 
“after receiving at least 1 dose of the 
study basal insulin”. 
For clarity. 
6.1. Study Intervention(s) 
Administered 
Added dose formulation and unit dose 
strength for study interventions used in 
this study. 
For clarity. 
6.1.3. Rescue Therapy 
for Management of 
Participants with Severe, 
Persistent Hyperglycemia 
Added new subsection and content for 
rescue therapy. 
Addressing regulator 
feedback. 
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Section # and Name 
Description of Change 
Brief Rationale 
during the Treatment 
Period 
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Revised “use of personal CGM or 
FGM” to “Routine use of personal 
CGM or FGM at randomization  
(yes/no)”. 
For clarity. 
6.8.3. Antihyperglycemic 
Medications 
Added rescue therapy in the table for 
use of other antihyperglycemic 
medications and a footnote.  
Related to addition of 
rescue therapy. 
8.1.1.2. Continuous 
Glucose Monitoring 
Systems 
Updated the type of continuous glucose 
monitoring (CGM) to be utilized in the 
study along with training and initiation 
and CGM data compliance. 
For clarity. 
9.2. Analyses Sets 
Updated the analysis populations or 
datasets for anticipated requirement for 
some countries. 
To meet the anticipated 
requirement for 
excluding inadvertently 
enrolled participants in 
some countries. 
9.3. Statistical Analyses 
Updated according to the changes made 
in analyses sets. 
Added use of rescue therapy 
Aligned with analyses 
sets and for clarity. 
10.9. Appendix 9: 
Abbreviations and 
Definitions 
Added CGM parameters. 
To address regulator 
feedback. 
Added Modified Intent-to-Treat 
(mITT), Efficacy Analysis Set (EAS) 
and Safety Analysis Set (SS). 
Editorial consistency. 
 
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11. 
References 
[ADA] American Diabetes Association. Clinical Practice Guidelines 2022. Diabetes Care. 
2022;45 (Suppl 1):S1-S264. 
Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of 
a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. 
Diabetes Care. 2008;31(7):1305-1310. https://doi.org/10.2337/dc07-2137 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28:586-604. https://doi.org/10.1002/sim.3495 
Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison procedures 
using weighted Bonferroni, Simes, or parametric tests. Biom J. 2011;53(6):894-913. 
https://doi.org/10.1002/bimj.201000239 
EuroQol Research Foundation. EQ-5D-5L user guide, version 3.0. Updated September 2019.  
Accessed March 15, 2022. https://euroqol.org/publications/user-guides 
Matza LS, Boye KS, Stewart KD, et al. Development of the Diabetes Injection Device 
Experience Questionnaire (DID-EQ) and Diabetes Injection Device Preference Questionnaire 
(DID-PQ). J Patient Rep Outcomes. 2018;2:43. https://doi.org/10.1186/s41687-018-0068-z 
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(11):3080-3086. 
https://doi.org/10.2337/diacare.26.11.3080 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley; 1987. 
 
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