A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Study to Evaluate the Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared With Insulin Degludec in Participants With Type 1 Diabetes Treated With Multiple Daily Injection Therapy
Phase: PHASE3
Conditions: Type 1 Diabetes, Diabetes
Sponsor: Eli Lilly and Company

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CONFIDENTIAL 
I8H-MC-BDCY(c) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3209590, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Study to Evaluate the 
Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared with Insulin Degludec 
in Participants with Type 1 Diabetes Treated with Multiple Daily Injection Therapy 
Protocol Number: I8H-MC-BDCY 
Amendment Number: c 
Compound: LY3209590 
Brief Title: 
Efficacy and Safety of LY3209590 Compared with Insulin Degludec in Participants with Type 1 
Diabetes Treated with Multiple Daily Injection Therapy 
Study Phase: Phase 3 
Acronym: QWINT-5 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): 
IND: 129390 
EudraCT: 2021-005892-38 
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-074455 
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I8H-MC-BDCY(c) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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I8H-MC-BDCY(c) 
3 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment b 
21-Jun-2022 
Amendment a 
10-May-2022 
Original Protocol 
08-Mar-2022 
Amendment [c]  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary rationale for the current amendment is to add continuous glucose monitoring 
(CGM) download and review at Visits 20 and 22 in the Schedule of Activities. 
These and other 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 
1.3. Schedule of 
Activities 
Added information for visit interval at the 
beginning of the section 
For clarification 
An “X” has been added at Visits 20 and 22 
for “Download and review CGM data in 
study vendor portal” 
Added for study CGM 
download and review to 
be performed at all in-
office visits 
Comment for Pharmacokinetic (PK) 
samples was revised to include the 
following, 
“Visit 3: Collect sample at least 15 min 
after dosing. For participants randomized 
to degludec who are not dosed onsite 
during Visit 3, the sample may be collected 
at any time during Visit 3.”   
For clarification 
5.1. Inclusion 
Criteria 
Inclusion Criterion #6 has been updated to 
clarify BMI must be ≤35.0 kg/m2 at the 
time of screening 
For clarification 
5.2. Exclusion 
Criteria 
Exclusion Criterion #36 has been updated 
to clarify “study basal insulin” refers to 
LY3209590 or comparator 
For clarification 
8.1.1.1. Self-
Monitoring of Blood 
Glucose (SMBG) 
Added “if the participants can safely do 
this” for participants advised to check 
SMBG readings for suspected 
hypoglycemia 
For clarification 
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I8H-MC-BDCY(c) 
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8.1.1.2. Continuous 
Glucose Monitoring 
(CGM) System  
Added a note for participants to not 
manually calibrate the study CGM with 
fingerstick blood glucose readings 
For clarification 
  
 
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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 
1.3.1. 
Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3-16 ......................................14 
1.3.2. 
Treatment Visits 17-29, Early Discontinuation, Unscheduled 
Visits, and Safety Follow-Up Visits 801 and 802...........................................................22 
2. 
Introduction ...................................................................................................................28 
2.1. 
Study Rationale ...............................................................................................................28 
2.2. 
Background .....................................................................................................................28 
2.3. 
Benefit/Risk Assessment ................................................................................................29 
2.3.1. 
Risk Assessment .............................................................................................................29 
2.3.2. 
Benefit Assessment .........................................................................................................30 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................30 
3. 
Objectives, Endpoints, and Estimands .......................................................................31 
4. 
Study Design ..................................................................................................................36 
4.1. 
Overall Design ................................................................................................................36 
4.2. 
Scientific Rationale for Study Design ............................................................................37 
4.3. 
Justification for Dose ......................................................................................................38 
4.4. 
End of Study Definition ..................................................................................................39 
5. 
Study Population ...........................................................................................................40 
5.1. 
Inclusion Criteria ............................................................................................................40 
5.2. 
Exclusion Criteria ...........................................................................................................41 
5.3. 
Lifestyle Considerations .................................................................................................44 
5.4. 
Screen Failures ................................................................................................................44 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................44 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................45 
6.1. 
Study Intervention(s) Administered................................................................................45 
6.1.1. 
Medical Devices..............................................................................................................46 
6.1.2. 
Background Therapy .......................................................................................................46 
6.1.3. 
Rescue Therapy for Management of Participants with Severe, 
Persistent Hyperglycemia during the Treatment Period .................................................47 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................47 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................48 
6.4. 
Study Intervention Compliance ......................................................................................48 
6.5. 
Dose Modification ..........................................................................................................49 
6.5.1. 
Glycemic Targets and Goals ...........................................................................................49 
6.5.2. 
Basal Insulin Therapy .....................................................................................................50 
6.5.3. 
Prandial Insulin Therapy .................................................................................................55 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................56 
6.6.1. 
Transitioning off of Study Basal Insulin .........................................................................56 
6.7. 
Treatment of Overdose ...................................................................................................57 
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6.8. 
Concomitant Therapy .....................................................................................................58 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................59 
7.1. 
Discontinuation of Study Intervention ............................................................................59 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................59 
7.1.2. 
Hypersensitivity Reactions .............................................................................................60 
7.1.3. 
Temporary Discontinuation of LY3209590 or Insulin Degludec ...................................60 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................61 
7.3. 
Lost to Follow up ............................................................................................................61 
8. 
Study Assessments and Procedures.............................................................................62 
8.1. 
Efficacy Assessments .....................................................................................................62 
8.1.1. 
Glucose Monitoring ........................................................................................................62 
8.1.2. 
Patient-Reported Outcomes ............................................................................................64 
8.2. 
Safety Assessments .........................................................................................................67 
8.2.1. 
Physical Examinations ....................................................................................................67 
8.2.2. 
Vital Signs .......................................................................................................................67 
8.2.3. 
Electrocardiograms .........................................................................................................68 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................68 
8.2.5. 
Hepatic Monitoring .........................................................................................................69 
8.2.6. 
Pregnancy Testing ...........................................................................................................71 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................71 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................72 
8.3.2. 
Pregnancy ........................................................................................................................74 
8.3.3. 
Cardiovascular Events ....................................................................................................75 
8.3.4. 
Systemic Hypersensitivity Reactions ..............................................................................75 
8.3.5. 
Injection Site Reactions ..................................................................................................75 
8.3.6. 
Hypoglycemia .................................................................................................................75 
8.4. 
Pharmacokinetics ............................................................................................................77 
8.5. 
Pharmacodynamics .........................................................................................................77 
8.6. 
Genetics ..........................................................................................................................77 
8.7. 
Biomarkers ......................................................................................................................77 
8.8. 
Immunogenicity Assessments.........................................................................................77 
8.9. 
Health Economics ...........................................................................................................78 
9. 
Statistical Considerations .............................................................................................79 
9.1. 
Statistical Hypotheses .....................................................................................................79 
9.1.1. 
Multiplicity Adjustment ..................................................................................................79 
9.2. 
Analyses Sets ..................................................................................................................80 
9.3. 
Statistical Analyses .........................................................................................................80 
9.3.1. 
General Considerations ...................................................................................................80 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................81 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................82 
9.3.4. 
Tertiary Endpoints Analysis ...........................................................................................83 
9.3.5. 
Safety Analyses ...............................................................................................................83 
9.3.6. 
Other Analyses ................................................................................................................84 
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I8H-MC-BDCY(c) 
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9.4. 
Interim Analysis ..............................................................................................................85 
9.5. 
Sample Size Determination ............................................................................................85 
10. 
Supporting Documentation and Operational Considerations ..................................87 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................87 
10.1.1. Regulatory and Ethical Considerations ...........................................................................87 
10.1.2. Financial Disclosure........................................................................................................88 
10.1.3. Informed Consent Process ..............................................................................................88 
10.1.4. Data Protection................................................................................................................88 
10.1.5. Committees Structure......................................................................................................89 
10.1.6. Dissemination of Clinical Study Data.............................................................................89 
10.1.7. Data Quality Assurance ..................................................................................................90 
10.1.8. Source Documents ..........................................................................................................91 
10.1.9. Study and Site Start and Closure ....................................................................................92 
10.1.10. Publication Policy ...........................................................................................................92 
10.1.11. Investigator Information .................................................................................................93 
10.1.12. Sample Retention ............................................................................................................94 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................95 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................97 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................99 
10.3.1. Definition of AE .............................................................................................................99 
10.3.2. Definition of SAE .........................................................................................................100 
10.3.3. Definition of Product Complaints .................................................................................101 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ....................................................................................................................102 
10.3.5. Reporting of SAEs ........................................................................................................104 
10.3.6. Regulatory Reporting Requirements .............................................................................104 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ........................................................106 
10.4.1. Definitions.....................................................................................................................106 
10.4.2. Contraception Guidance................................................................................................107 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ..................................................................................................................109 
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 ..........................................................................111 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................112 
10.8. 
Appendix 8: Abbreviations and Definitions .................................................................116 
10.9. 
Appendix 9: Protocol Amendment History ..................................................................120 
11. 
References ....................................................................................................................125 
 
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I8H-MC-BDCY(c) 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
A Phase 3, Multicenter, Randomized, Parallel-Design, Open-Label Study to Evaluate the 
Efficacy and Safety of LY3209590 as a Weekly Basal Insulin Compared with Insulin Degludec 
in Participants with Type 1 Diabetes Treated with Multiple Daily Injection Therapy  
Brief Title:  
Efficacy and Safety of LY3209590 Compared with Insulin Degludec in Participants with Type 1 
Diabetes Treated with Multiple Daily Injection Therapy 
Regulatory Agency Identifier Number(s):  
IND: 129390 
EudraCT: 2021-005892-38 
Rationale: 
This Phase 3 study will evaluate the efficacy and safety of once-weekly administration of 
LY3209590 on glycemic control compared with daily administration of insulin degludec in adult 
participants with type 1 diabetes (T1D) treated with multiple daily injection (MDI) therapy. This 
study will inform the clinical development of LY3209590. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
To demonstrate that LY3209590 is 
noninferior to insulin degludec for the 
treatment of T1D in adults 
 Change in HbA1c from baseline to 
Week 26  
Key Secondary (multiplicity adjusted) 
To demonstrate superiority of LY3209590 to 
insulin degludec 
 Change in HbA1c from baseline to 
Week 26 
 Time in glucose range between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) 
inclusive, measured by CGM 4 weeks 
prior to Week 26 
 Event rate of participant-reported 
clinically significant nocturnal 
hypoglycemia (<54 mg/dL [3.0 
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I8H-MC-BDCY(c) 
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mmol/L] or severe) during treatment 
phase up to Week 52 
Other Secondary 
To investigate the effect of LY3209590 
compared with insulin degludec in additional 
parameters of glycemic control 
 Change in HbA1c from baseline to 
Week 52 
 Change from baseline to Weeks 26 
and 52 in fasting glucose as measured 
by SMBG  
 Glucose variability, measured by 
CGM 4 weeks prior to Weeks 26 and 
52 
 Time in glucose range between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) 
inclusive, measured by CGM 4 weeks 
prior to Week 52 
 Insulin dose at Weeks 26 and 52 
o basal  
o bolus  
o total, and  
o basal/total insulin dose ratio. 
To compare the safety of LY3209590 to 
insulin degludec 
 Rate of composite of Level 2 and 3 
hypoglycemia events during treatment 
period 
 Body weight change from baseline to 
Weeks 26 and 52 
 Time in hypoglycemia range with 
glucose <54 mg/dL (3.0 mmol/L), 
measured by CGM 4 weeks prior to 
Weeks 26 and 52 
 Time in hyperglycemia range defined 
as glucose >180 mg/dL (10.0 
mmol/L), measured by CGM 4 weeks 
prior to Weeks 26 and 52 
To compare treatment satisfaction and health-
related quality of life between LY3209590 
and degludec as assessed by patient-reported 
outcome questionnaires 
 DTSQ change from baseline to Weeks 
26 and 52 
 Change in SF-36 v2 acute form 
domain scores from baseline to Weeks 
26 and 52 
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Abbreviations: CGM = continuous glucose monitoring; DTSQ = Diabetes Treatment Satisfaction Questionnaire; 
HbA1c = hemoglobin A1c; PK/PD = pharmacokinetics/pharmacodynamics; SMBG = self-monitoring of blood 
glucose; SF-36 = Short Form-36 Version 2 Health Survey Acute Form; T1D = type 1 diabetes.  
Overall Design: 
This is a Phase 3, open-label, 2-arm, parallel-design, randomized control study to evaluate the 
efficacy and safety of once-weekly basal insulin LY3209590 compared to insulin degludec in 
adult participants with T1D who are treated with basal-bolus insulin MDI therapy.  
Brief Summary: 
The study consists of a 1-week screening period, a 2-week lead-in period, a 52-week treatment 
period, and a 5-week safety follow-up period.  
All participants will use a study-provided, unblinded 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 HbA1c from baseline to Week 26. 
Study Population: 
In general, participants may take part in the study if they 
 are 18 years of age or older 
 have a diagnosis of T1D for at least 1 year  
 have HbA1c value of 7.0% to 10.0% 
 have received treatment with allowed basal-bolus insulin analog MDI therapy for at least 
90 days prior to screening, and 
 are reliable and willing to make themselves available for the duration of the study and are 
willing and able to follow study procedures as required. 
In general, participants may not take part in the study if they 
 have a diagnosis of Type 2 diabetes mellitus, latent autoimmune diabetes, or specific 
types of diabetes other than T1D  
 are women who are pregnant, lactating, or breastfeeding, or 
 have a history or presence of an underlying disease, or surgical, physical, or medical 
condition that, in the opinion of the investigator, would potentially affect participant 
safety within the study or interfere with the interpretation of data. 
Number of Participants: 
Approximately 670 participants will be randomly assigned to LY3209590 and insulin degludec 
in a 1:1 ratio. With the assumption of 15% dropout at Week 26, approximately 284 and 284 
participants will complete 26 weeks of treatment on LY3209590 and insulin degludec, 
respectively. 
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I8H-MC-BDCY(c) 
11 
Intervention Groups and Duration: 
Participants who meet entry criteria will be randomly assigned in a 1:1 ratio to LY3209590 or 
insulin degludec basal insulin treatment. LY3209590 will be administered once-weekly. Insulin 
degludec will be administered once-daily. 
Participants will also be treated with insulin lispro as prandial insulin.  
The study treatment period duration is 52 weeks. 
Ethical Considerations of Benefit/Risk: 
Considering the data that are available to date from previous clinical studies, and the measures 
taken to ensure the safety of the participants in this study, the potential risks related to 
LY3209590 are justified by the anticipated benefits a participant with T1D may experience in the 
study. 
Data Monitoring Committee: Yes 
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1.2. 
Schema 
 
Abbreviations: CGM = continuous glucose monitoring; V = visit. 
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I8H-MC-BDCY(c) 
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1.3. 
Schedule of Activities (SoA) 
Two tables describe the schedule of activities. 
Table 1 (Section 1.3.1) describes procedures for Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3 to 16. 
Table 2 (Section 1.3.2) describes Treatment Visits 17-29, early discontinuation, unscheduled visits, and safety follow-up Visits 801 
and 802. 
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 11-17 days after Visit 2. 
 
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1.3.1. 
Screening Visit 1, Lead-In Visit 2, and Treatment Visits 3-16 
Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
The ICF must be signed before any 
protocol-specific tests or procedures are 
performed. See Section 10.1.3 for 
additional details. 
Inclusion 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 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
Substance use 
(recreational drugs, 
alcohol, caffeine, and 
tobacco use)  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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I8H-MC-BDCY(c) 
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Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
Adverse events (AEs) 
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 
Clinical assessment based on participant 
history, e-diary entries, and CGM data. 
Physical evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Participant should remove shoes. 
Weight 
X 
X 
X 
X 
X 
  
X 
  
X 
  
 X 
 
 
  
X 
  
Vital signs 
X 
X 
X 
X 
X 
  
X 
  
X 
  
 X 
 
 
  
X 
 
Include blood pressure and pulse rate. 
Measure 3 times using the same arm, after 
participant has been sitting at least 5 min. 
The recordings should be taken at least 1 
min apart. Vital signs should be taken 
before ECG tracing and collection of blood 
samples. Additional vital signs may be 
measured as necessary at investigator 
discretion. 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional physical examinations may be 
completed as necessary at investigator 
discretion. 
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16 
Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
12-lead ECG (local) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect prior to collection of blood 
samples. Participants should be supine for 
approximately 5 to 10 min before ECG 
collections and remain supine but awake 
during the ECG collection.  
ECGs may be repeated at the investigator’s 
discretion at any visit. 
Unblinded continuous 
glucose monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense CGM system 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense CGM supplies as needed after 
Visit 2. 
Download and review 
CGM data in study vendor 
portal  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Discuss CGM and 
hypoglycemia data 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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, and 
CGM training 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
After Visit 3, conduct as needed. 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
17 
Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
Electronic participant 
diary and glucometer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense e-diary and 
glucometer 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucometer supplies as needed 
after Visit 2. 
Diary compliance check 
 
 
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. See Sections 6.4 and 8.1.1 for 
additional details. 
Electronic patient-
reported outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes Treatment 
Satisfaction Questionnaire 
– Status (DTSQs) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 v2 acute form 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests and 
sample collections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hemoglobin A1c 
(HbA1c) 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
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CONFIDENTIAL 
I8H-MC-BDCY(c) 
18 
Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
Clinical chemistry  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Glucose 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Lipid panel 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect for WOCBP only. 
Urine pregnancy (local) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
The result must be available prior to first 
dose of intervention.  
Perform additional pregnancy tests if a 
menstrual period is missed, if there is 
clinical suspicion of pregnancy, or as 
required by local law or regulation. 
Follicle-stimulating 
hormone (FSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perform as needed to confirm 
postmenopausal status. See Section 10.4. 
C-Peptide 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR (CKD-EPI)  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urinary 
albumin/creatinine ratio 
(UACR) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
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CONFIDENTIAL 
I8H-MC-BDCY(c) 
19 
Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
Pharmacokinetic (PK) 
samples 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Visit 3: Collect sample at least 15 min after 
dosing. For participants randomized to 
degludec who are not dosed onsite during 
Visit 3, the sample may be collected at any 
time during Visit 3.  
For all other visits, collect at any time 
during the visit (see Section 8.4). 
Immunogenicity (ADA) 
samples 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Visit 3: Collect samples before dosing. 
If an immediate or nonimmediate systemic 
drug hypersensitivity reaction occurs, 
collect an additional unscheduled sample as 
detailed in Section 10.2.1.  
Stored samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory biomarker 
samples  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
Randomization using 
IWRS 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
Basal and prandial insulin 
dose assessment and 
documentation  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 6.5. 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
20 
Study I8H-MC-BDCY 
Table 1 
Screen-
ing and 
Lead-In 
Treatment 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
Randomization 
-3 
-2 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
 
Visit Interval Tolerance 
(days) 
 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Visit Detail 
 
 
F 
 
 
 
F 
 
 
 
 
 
 
 
F 
T 
T = telehealth visit 
F = fasting visit 
Dispense ancillary 
supplies as needed  
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Dispense study 
intervention 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Training regarding study 
basal insulin. LY3209590 
loading dose administered 
at site 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 3: LY3209590 loading dose will be 
administered during the study visit. The 
loading dose may be administered by study 
personnel or by the participant under 
observation of study personnel. The 
LY3209590 loading dose and time is 
entered in the e-diary by the participant at 
the study visit.  
Observe participant 
administer LY3209590 
study intervention  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 4: Weekly dose of LY3209590 will 
be administered by the participant during 
the study visit under observation of study 
personnel. The insulin dose amount and 
time is recorded for all LY3209590 doses. 
Assess study intervention 
compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant returns unused 
intervention  
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Abbreviations: ADA = antidrug antibody; BG = blood glucose; CGM = continuous glucose monitoring; ECG = electrocardiogram; eGFR (CKD-EPI) = 
estimated glomerular filtration rate (chronic kidney disease epidemiology collaboration); FSH = follicle-stimulating hormone; ICF = informed consent form; 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
21 
IWRS = interactive web-response system; SF-36 v2 acute = Short Form-36 Version 2 Health Survey Acute Form; UACR = urinary albumin/creatinine ratio; 
WOCBP = women of childbearing potential. 
 
 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
22 
1.3.2. 
Treatment Visits 17-29, Early Discontinuation, Unscheduled Visits, and Safety Follow-Up Visits 801 and 802 
Study I8H-MC-BDCY 
Table 2 
Treatment 
Safety 
Follow-Up 
Comments 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
E
D 
U
V 
801 
802 
ED = early discontinuation 
UV = unscheduled visit 
801 and 802 = safety follow-up visits 
Weeks from 
Randomization 
16 
18 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
 
T 
 
 
 
F 
 
 
F 
 
 
 
F 
F 
 
 
F 
T = telehealth visit  
F = fasting visit  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
Clinical assessment based on 
participant history, e-diary entries, and 
CGM data. 
Physical evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Vital signs 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Include blood pressure and pulse rate. 
Measure 3 times using the same arm, 
after participant has been sitting at least 
5 min. The recordings should be taken 
at least 1 min apart. Vital signs should 
be taken before ECG tracing and 
collection of blood samples. Additional 
vital signs may be measured as 
necessary at investigator discretion. 
Physical examination 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
Additional physical examinations may 
be completed as necessary at 
investigator discretion. 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
23 
Study I8H-MC-BDCY 
Table 2 
Treatment 
Safety 
Follow-Up 
Comments 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
E
D 
U
V 
801 
802 
ED = early discontinuation 
UV = unscheduled visit 
801 and 802 = safety follow-up visits 
Weeks from 
Randomization 
16 
18 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
 
T 
 
 
 
F 
 
 
F 
 
 
 
F 
F 
 
 
F 
T = telehealth visit  
F = fasting visit  
12-lead ECG (local) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Collect prior to collection of blood 
samples. Participants should be supine 
for approximately 5 to 10 min before 
ECG collections and remain supine but 
awake during the ECG collection.  
ECGs may be repeated at the 
investigator’s discretion at any visit. 
Unblinded continuous 
glucose monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense CGM supplies 
as needed 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Download and review 
CGM data in study 
vendor portal 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Discuss CGM and 
hypoglycemia data  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Return CGM receiver 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
The CGM receiver must be returned at 
the last participant visit. 
Participant education 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes counseling, 
training, and education as 
needed after Visit 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
24 
Study I8H-MC-BDCY 
Table 2 
Treatment 
Safety 
Follow-Up 
Comments 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
E
D 
U
V 
801 
802 
ED = early discontinuation 
UV = unscheduled visit 
801 and 802 = safety follow-up visits 
Weeks from 
Randomization 
16 
18 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
 
T 
 
 
 
F 
 
 
F 
 
 
 
F 
F 
 
 
F 
T = telehealth visit  
F = fasting visit  
e-diary, glucometer, and 
CGM training as needed 
after Visit 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electronic participant 
diary and glucometer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucometer 
supplies as needed 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
e-Diary compliance 
check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review entries of BG, hypoglycemia 
events, and insulin dose. If participant 
is not compliant, study personnel will 
re-educate the participant on study 
requirements for continued study 
participation. See Sections 6.4 and 
8.1.1 for additional details. 
e-diary return 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
The e-diary must be returned at the last 
participant visit. 
Electronic patient-
reported outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes Treatment 
Satisfaction 
Questionnaire – Change 
(DTSQc)  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
SF-36 v2 acute form  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
25 
Study I8H-MC-BDCY 
Table 2 
Treatment 
Safety 
Follow-Up 
Comments 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
E
D 
U
V 
801 
802 
ED = early discontinuation 
UV = unscheduled visit 
801 and 802 = safety follow-up visits 
Weeks from 
Randomization 
16 
18 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
 
T 
 
 
 
F 
 
 
F 
 
 
 
F 
F 
 
 
F 
T = telehealth visit  
F = fasting visit  
Basal insulin experience: 
Likelihood of 
incorporating into routine 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Basal insulin experience: 
Preference 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
EQ-5D-5L 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Laboratory tests and 
sample collections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Hemoglobin A1c 
(HbA1c) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
Clinical chemistry  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Glucose 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Lipid panel 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Urinalysis  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Urine pregnancy (local) 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
26 
Study I8H-MC-BDCY 
Table 2 
Treatment 
Safety 
Follow-Up 
Comments 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
E
D 
U
V 
801 
802 
ED = early discontinuation 
UV = unscheduled visit 
801 and 802 = safety follow-up visits 
Weeks from 
Randomization 
16 
18 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
 
T 
 
 
 
F 
 
 
F 
 
 
 
F 
F 
 
 
F 
T = telehealth visit  
F = fasting visit  
C-Peptide 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
eGFR (CKD-EPI)  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Urinary 
albumin/creatinine ratio 
(UACR) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Pharmacokinetic (PK) 
samples 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
Collect at any time during the visit. See 
Section 8.4. 
Immunogenicity (ADA) 
samples 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
If an immediate or nonimmediate 
systemic drug hypersensitivity reaction 
occurs, collect an additional 
unscheduled sample as detailed in 
Section 10.2.1 
Stored samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory biomarker 
samples  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Randomization and 
dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Process visit using IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
Basal and prandial 
insulin dose assessment 
and documentation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
See Section 6.5. 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
27 
Study I8H-MC-BDCY 
Table 2 
Treatment 
Safety 
Follow-Up 
Comments 
Visit Number 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
E
D 
U
V 
801 
802 
ED = early discontinuation 
UV = unscheduled visit 
801 and 802 = safety follow-up visits 
Weeks from 
Randomization 
16 
18 
20 
22 
24 
26 
28 
32 
36 
40 
44 
48 
52 
— 
— 
54 
57 
 
Visit Interval Tolerance 
(days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
— 
— 
+7 
±7 
 
Visit Detail 
 
T 
 
 
 
F 
 
 
F 
 
 
 
F 
F 
 
 
F 
T = telehealth visit  
F = fasting visit  
Assessment for post 
study basal and prandial 
insulin treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
See Section 6.6.1. 
Dispense ancillary 
supplies as needed  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Dispense study 
intervention  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Assess study intervention 
compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Participant returns 
unused intervention and 
supplies 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Abbreviations: ADA = antidrug antibody; BG = blood glucose; CGM = continuous glucose monitoring; eGFR (CKD-EPI) = estimated glomerular filtration rate 
(chronic kidney disease epidemiology collaboration); ECG = electrocardiogram; IWRS = interactive web-response system; SF-36 v2 acute = Short Form-36 
Version 2 Health Survey Acute Form; UACR = urinary albumin/creatinine ratio; WOCBP = women of childbearing potential. 
 
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
28 
2. 
Introduction 
LY3209590 is a long-acting insulin receptor agonist in development for the once-weekly 
treatment of patients with T1D and T2D. 
2.1. 
Study Rationale 
This Phase 3 study will evaluate the efficacy and safety of once-weekly administration of 
LY3209590 on glycemic control compared with daily administration of insulin degludec in adult 
participants with T1D treated with MDI therapy. This study will inform the clinical development 
of LY3209590. 
2.2. 
Background 
Current state of diabetes care 
There have been many advances in the treatment of T1D; however, reaching and maintaining 
glycemic goals while managing the risk of hypoglycemia remain challenging.  
Potential for improved treatment regimens 
Once-weekly basal insulins with a lower peak-to-trough profile during the week and a nearly flat 
insulin profile could 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 patients with T1D and T2D. LY3209590 was designed as a divalent 
(dimer) insulin receptor agonist consisting of a single-chain insulin analog (comprised of an 
insulin B-chain analog, a short peptide linker, and an insulin A-chain analog) fused to a second 
peptide linker that is fused to an unmodified human IgG2 Fc domain.  
A detailed description of the chemistry, pharmacology, non-clinical and clinical efficacy, and 
safety of LY3209590 is provided in the Investigator’s Brochure. 
Summary of clinical results 
Phase 1 and Phase 2 studies have been completed to assess the PK/PD, safety, and efficacy of 
LY3209590. The results thus far support continued development of LY3209590 as a treatment 
for diabetes mellitus. 
Phase 1 study results  
LY3209590 pharmacokinetics show a low peak-to-trough ratio and extended mean half-life of 17 
days 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.  
Approved on 12 Oct 2022 GMT

CONFIDENTIAL 
I8H-MC-BDCY(c) 
29 
Phase 2 study BDCM results comparing LY3209590 to insulin degludec in patients with T2D  
Study BDCM was a randomized, open-label, Phase 2 study to evaluate the safety and efficacy of 
LY3209590 in participants with T2D previously treated with basal insulin.  
LY3209590 was noninferior to degludec for glycemic control as measured by change in HbA1c 
from baseline to Week 32 with significant improvement in HbA1c in all treatment groups with a 
lower risk of hypoglycemia with LY3209590.  
The overall adverse event profile from Study BDCM showed no increased safety risk with 
LY3209590 compared with degludec treatment. 
Phase 2 study BDCP comparing LY3209590 to insulin degludec in patients with T1D  
Study BDCP was a randomized, open-label, Phase 2 study to evaluate the safety and efficacy of 
LY3209590 in patients with T1D treated with MDI therapy.  
LY3209590 was noninferior to degludec as measured by change in HbA1c from baseline to 
Week 26, although participants treated with LY3209590 had higher fasting glucose at study 
endpoint. Over 26 weeks of study treatment, the rate of Level 2 hypoglycemia and nocturnal 
hypoglycemia as well as time below range from CGM were not significantly different between 
groups.  
The overall adverse event profile from Study BDCP in patients with T1D showed no increased 
safety risk with LY3209590 compared with degludec treatment. 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of LY3209590 may be found in the Investigator’s Brochure, and that of insulin 
degludec may be found in the local product package insert. 
2.3.1. 
Risk Assessment 
Potential risks for this study 
The potential risks associated with LY3209590 include 
 hypoglycemia 
 hyperglycemia 
 hypersensitivity reaction 
 injection site reactions, for example, injection site rash, erythema, pruritus, or 
lipohypertrophy 
 immunogenicity, and 
 cardiovascular risks. 
It is expected that the known risks would be similar to other insulins. 
Safety data available to date suggest that there is no increased risk to participants’ safety with 
LY3209590 treatment compared to insulin degludec. 
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Management of risks 
Sections 5.1, 5.2, 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 
hypoglycemia events. 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 CGM and blood glucose levels 
All participants will use the study-provided, unblinded CGM system to facilitate diabetes and 
hypoglycemia management and for data collection throughout the study. A web interface will be 
available for site personnel to download and review CGM data.  
Each participant will have a study-provided glucometer that will wirelessly transfer participant 
SMBG to their study-provided e-diary. Participants should check glucose values with the 
glucometer when 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 basal insulin dosing algorithm used in the study requires consideration and adjustment of 
insulin dosing by the investigator based on participant FBG, CGM data, 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 during the study by frequent engagement and support from health care 
providers for diabetes management and safety assessments with the potential to improve 
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 T1D. 
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3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
To demonstrate that LY3209590 is 
noninferior to insulin degludec for the 
treatment of T1D in adults 
 Change in HbA1c from baseline to 
Week 26 
Key Secondary (multiplicity adjusted) 
To demonstrate superiority of LY3209590 to 
insulin degludec 
 Change in HbA1c from baseline to 
Week 26 
 Time in glucose range between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) 
inclusive, measured by CGM 4 weeks 
prior to Week 26 
 Event rate of participant-reported 
clinically significant nocturnal 
hypoglycemia (<54 mg/dL [3.0 
mmol/L] or severe) during treatment 
phase up to Week 52 
Other Secondary 
To investigate the effect of LY3209590 
compared with insulin degludec in additional 
parameters of glycemic control 
 Change in HbA1c from baseline to 
Week 52 
 Change from baseline to Weeks 26 
and 52 in fasting glucose as measured 
by SMBG 
 Glucose variability, measured by 
CGM 4 weeks prior to Weeks 26 and 
52 
 Time in glucose range between 70 and 
180 mg/dL (3.9 and 10.0 mmol/L) 
inclusive, measured by CGM 4 weeks 
prior to Week 52 
 Insulin dose at Weeks 26 and 52 
o basal  
o bolus  
o total, and  
o basal/total insulin dose ratio 
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To compare the safety of LY3209590 to 
insulin degludec 
 Rate of composite of Level 2 and 3 
hypoglycemia events during treatment 
period 
 Body weight change from baseline to 
Weeks 26 and 52 
 Time in hypoglycemia range with 
glucose <54 mg/dL (3.0 mmol/L), 
measured by CGM 4 weeks prior to 
Weeks 26 and 52 
 Time in hyperglycemia range defined 
as glucose >180 mg/dL (10.0 
mmol/L), measured by CGM 4 weeks 
prior to Weeks 26 and 52 
To compare treatment satisfaction and health-
related quality of life between LY3209590 
and degludec as assessed by patient-reported 
outcome questionnaires 
 DTSQ change from baseline to Weeks 
26 and 52 
 Change in SF-36 v2 acute form 
domain scores from baseline to Weeks 
26 and 52 
Tertiary 
To investigate the effect of LY3209590 
compared with insulin degludec on other 
measures of efficacy, safety, and patient-
reported outcomes 
Efficacy 
 Percentage of participants achieving 
HbA1c < 7% at Weeks 26 and 52  
 Percentage of participants achieving 
HbA1c ≤ 6.5% at Weeks 26 and 52  
 Change from baseline to Weeks 26 
and 52 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 
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Patient-reported outcomes 
 Frequency of responses to “Basal 
Insulin Experience: Likelihood of 
incorporating into routine” at Weeks 
26 and 52 
 Frequency of responses to “Basal 
Insulin Experience: Preference” at 
Weeks 26 and 52 
 Change in EQ-5D-5L from baseline to 
Weeks 26 and 52 
To characterize the PK/PD of LY3209590 
 LY3209590 PK and concentration 
response relationships to key safety 
and efficacy measures. 
Abbreviations: CGM = continuous glucose monitoring; DTSQ = Diabetes Treatment Satisfaction Questionnaire; 
HbA1c = hemoglobin A1c; PK/PD = pharmacokinetics/pharmacodynamics; SF-36 = Short Form-36 Version 2 
Health Survey Acute Form; SMBG = self-monitoring of blood glucose; T1D = Type 1 diabetes. 
 
Primary estimand 
United States registration 
The primary clinical question of interest is 
What is the treatment difference between LY3209590 and insulin degludec in HbA1c 
change from baseline after 26 weeks of treatment, in study eligible participants with T1D 
treated with MDI therapy, regardless of treatment discontinuation for any reason and 
regardless of initiation of rescue medication? 
Treatment regimen estimand attributes 
This table describes the treatment regimen estimand attributes. 
Treatment Regimen Estimand Attributes 
Description 
Population 
Targeted study population (see table in Section 9.2).  
Endpoint 
HbA1c change from baseline to Week 26. 
Remaining intercurrent events 
None. The 2 intercurrent events, treatment 
discontinuation for any reason and initiation of rescue 
medication, are both addressed by the treatment 
condition of interest attribute. 
Treatment condition 
The randomized treatment regardless of treatment 
discontinuation and use of rescue medications. 
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Population-level summary 
Difference in mean changes between treatment 
conditions. 
Rationale for the treatment regimen estimand 
The treatment regimen estimand estimates how participants with T1D are treated in clinical 
practice and considers both efficacy and safety. 
Registration for countries outside the United States 
The primary clinical question of interest is 
What is the treatment difference between LY3209590 and insulin degludec in HbA1c 
change from baseline after 26 weeks of treatment, in study eligible participants with T1D 
treated with MDI therapy and adhere to the randomized treatment without an intercurrent 
event during the study treatment period? 
Efficacy estimand attributes 
This table describes the efficacy estimand attributes. 
Efficacy Regimen Estimand Attribute 
Description 
Population 
Targeted study population. (see table in Section 9.2). 
Endpoint 
HbA1c change from baseline to Week 26. 
Remaining intercurrent events 
None. The 2 intercurrent events, treatment 
discontinuation for any reason and initiation of rescue 
medication, are both addressed by the hypothetical 
strategy, for example, the potential outcome for those 
participants if the intercurrent events have not occurred 
will be estimated.  
Treatment condition 
The randomized treatment. 
Population-level summary 
Difference in mean changes between treatment 
conditions. 
 
Rationale for the efficacy estimand 
The efficacy estimand supports the interpretation of the treatment effect as participants adhere to 
study treatment and free from the confounding effect of rescue medications. 
Secondary estimands for multiplicity-adjusted objectives 
The superiority test in change from baseline to Week 26 (Visit 22) in HbA1c will also be based 
on the primary estimand described above. 
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The time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L), inclusive, 
measured by CGM in the 4 weeks prior to Visit 22 (Week 26) will use treatment regimen 
estimated for US registration and efficacy estimand for other countries. 
The participant-reported clinically significant nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] 
or severe) is one of the safety measures for the study. The event rate will be based on all 
available data during the specific analysis period. Relative rate between randomized treatment 
groups will be used for treatment comparison. 
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4. 
Study Design 
4.1. 
Overall Design 
This is a Phase 3, open-label, 2-arm, parallel-design, randomized control study to investigate if 
LY3209590 is noninferior to insulin degludec in adult participants with T1D who are treated 
with basal-bolus insulin MDI therapy.  
The study consists of a 1-week screening period, a 2-week lead-in period, a 52-week treatment 
period, and a 5-week safety follow-up period.  
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 glucometer, electronic study diary, and unblinded CGM system.  
Participants will receive training on 
 diabetes self-monitoring and management 
 unblinded CGM system  
 glucometer and e-diary, and 
 study requirements. 
Starting with Visit 2, participants will use the study-supplied glucometer, e-diary, and unblinded 
CGM system for diabetes management and data collection throughout the study. 
Participants will continue with their current basal-bolus insulin therapy until randomization. 
Treatment period 
Visit 3 (Week 0): Randomization 
This is the general flow for Visit 3 
 study personnel confirm enrollment criteria 
 participants are randomly assigned to an intervention group (LY3209590 or insulin 
degludec) 
 study personnel complete baseline procedures and sample collection 
 study personnel will provide study insulin dosing training  
o For participants randomized to LY3209590, the first dose of LY3209590 will be 
administered at the site by study personnel or by the participant under observation 
of study personnel. Insulin dose information will be entered in the e-diary.  
o For participants randomized to insulin degludec, the first dose of degludec can be 
administered at the site or after the visit, depending upon the usual time of basal 
insulin dosing.  
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 study personnel complete all visit procedures. 
Participants assigned to insulin degludec will be treated with daily dosing of degludec after 
Visit 3. 
Participants will be treated with insulin lispro as prandial insulin throughout the treatment period 
as described in Section 6.5.3. 
Visit 4 (Week 1) 
Participants complete all visit procedures described in the SoA. 
Study personnel will provide dosing training and observe participants administer their second 
dose of LY3209590. 
Visit 5 through Visit 29 (Week 2 through Week 52) 
Study personnel and participants complete all visit procedures described in the SoA. 
The participant’s BG and CGM data will be used to titrate basal and prandial insulin dosing as 
described in Section 6.5.  
The investigator or study staff will review participant e-diary compliance for 
 SMBG 
 hypoglycemia events, including related signs and symptoms, and 
 study intervention compliance, including insulin dose data. 
Last study treatment visit: either V29 (Week 52) or ED visit 
Participants complete all visit procedures described in the SoA. 
Participants will return any unused study intervention to the investigative site. 
The investigator will determine the participant’s basal and prandial insulin treatment during the 
safety follow-up period as described in Section 6.6.1. 
Safety follow-up visits 801 and 802 
Study personnel and participants complete all visit procedures described in the SoA. 
The investigator will follow up on the participant’s transition to non-study basal and prandial 
insulin 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. 
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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 degludec. 
The follow-up visits after the last dose is designed to capture any additional safety signals and to 
monitor the transition from study treatment to non-study insulins. 
Comparator 
Insulin degludec was chosen as the comparator because it is widely accepted as the best-in-class 
basal insulin. It has the longest half-life among other marketed basal insulins. 
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 and/or 
efficacy based on race or ethnicity. This question can be answered only if all the relevant data are 
collected. 
4.3. 
Justification for Dose 
The dosing guidance for starting doses and dose titrations of LY3209590 and insulin degludec is 
derived from findings from Phase 2 studies and model-based simulations. These data informed 
the development of titration algorithms to safely and efficiently initiate and guide LY3209590 
and insulin degludec dose adjustments to achieve the same glycemic goal of FBG between 80 
and 120 mg/dL (4.4 and 6.6 mmol/L), while minimizing hypoglycemia risk. 
See Section 6.5.2 for study basal insulin therapy details. 
LY3209590  
Following a once-weekly subcutaneous administration of LY3209590, the time to reach steady-
state PK without a loading dose is estimated to be between 8 and 10 weeks, based on the long 
half-life of LY3209590. With a loading dose, the estimated time to reach steady state is 
estimated to be 2 to 3 weeks. For this reason, all participants randomly assigned to LY3209590 
will receive a single loading dose of LY3209590 (see Section 6.5.2.1). This strategy was 
designed to minimize loss of glycemic control when transitioning from the shorter duration once-
daily basal insulins to a weekly insulin. This approach is supported by findings in the Phase 2 
Study BDCP and model-based simulations. 
Directions for conversion of the prior daily basal insulin dose to the LY3209590 weekly dose 
and the titration algorithm are described in Section 6.5.2.1.  
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Insulin degludec  
The starting dose for insulin degludec is based on the daily dose of basal insulin the participant 
was taking prior to Visit 3 (Week 0). The insulin degludec algorithm is based on well-established 
algorithms while balancing efficacy and hypoglycemia with the same FBG targets as 
LY3209590 (see Section 6.5.2.2). 
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 at least 18 years of age at screening, or older per local regulations. 
Type of participant and disease characteristics 
2. Have a clinical diagnosis of T1D for at least 1 year prior to screening. 
3. Have HbA1c value of 7.0% to 10.0%, inclusive, as determined by the central laboratory 
at screening. 
4. Have received treatment with basal-bolus insulin analog MDI therapy according to the 
local product label for at least 90 days prior to screening 
 Allowed basal insulin analogs (includes biosimilars) 
 
insulin glargine U-100 
 
insulin glargine U-300 
 
insulin degludec U-100 or U-200, or 
 
insulin detemir 
 Allowed bolus insulin analogs (includes biosimilars) 
 
insulin lispro U-100 or U-200 
 
insulin aspart  
 
insulin glulisine  
 
fast acting insulin aspart (Fiasp® [Novo Nordisk A/S., Bagsvaerd, 
Denmark]), or 
 
insulin lispro-aabc U-100 or U-200 (Lyumjev™ [Eli Lilly and Co., 
Indianapolis, IN]). 
5. Are reliable and willing to make themselves available for the duration of the study and 
are willing and able to follow study procedures as required, including 
 adhere to the study basal-bolus insulin MDI regimen and use of study insulins 
according to injection instructions and protocol  
 use the CGM system supplied for this study for glucose monitoring, diabetes 
management, and data collection per protocol  
 maintain an electronic study diary and use the glucometer supplied for use in the 
study 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. 
Weight 
6. have a body mass index ≤ 35.0 kg/m2 at the time of screening. 
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Contraceptive/barrier requirements 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
7. Female participants: for the contraception requirements of this protocol, see 
Section 10.4. 
Male participants: no male contraception required except in compliance with specific 
local government requirements. 
Informed consent 
8. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
Diabetes related 
9. Have a diagnosis of T2D, latent autoimmune diabetes, or specific types of diabetes other 
than T1D, for example, monogenic diabetes, diseases of the exocrine pancreas, and drug-
induced or chemical-induced diabetes. 
10. Have a history of more than 1 episode of severe hypoglycemia, defined as requiring 
assistance due to neurologically disabling hypoglycemia, within the 6 months prior to 
screening. 
11. Have hypoglycemia unawareness, in the opinion of the investigator. 
12. Have a history of more than 1 episode of diabetic ketoacidosis or hyperosmolar state or 
coma requiring hospitalization within the 6 months prior to screening. 
13. Have excessive insulin resistance, defined as having received a total daily dose of insulin 
>1.5 units/kg at the time of screening. 
Cardiovascular 
14. Have had New York Heart Association Class IV heart failure or any of the following 
cardiovascular conditions within 90 days prior to screening 
 acute myocardial infarction 
 cerebrovascular accident (stroke), or 
 coronary bypass surgery. 
Gastrointestinal 
15. Have undergone gastric bypass (bariatric) surgery, restrictive bariatric surgery, for 
example, Lap-Band© or sleeve gastrectomy within 1 year prior to screening. 
16. Have presence of clinically significant gastroparesis, in the opinion of the investigator. 
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Hepatic 
17. Have acute or chronic hepatitis, cirrhosis, or obvious clinical signs or symptoms of any 
other liver disease, except nonalcoholic fatty liver disease (that is, study participants with 
nonalcoholic fatty liver disease are eligible for participation), or have elevated liver 
enzyme measurements as determined by the central laboratory at screening:  
 total bilirubin >2x ULN except for participants with Gilbert’s syndrome 
 ALT or serum glutamic pyruvic transaminase >3x ULN 
 AST or serum glutamic oxaloacetic transaminase >3x ULN, or 
 ALP >2.5x ULN. 
Renal 
18. 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. 
Hematologic 
19. Have had a blood transfusion or severe blood loss within 90 days prior to screening.  
20. Have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or any other 
hemoglobin abnormalities known to interfere with the measurement of HbA1c in the 
opinion of the investigator. 
Malignancy 
21. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy within 5 years prior to screening. 
Exceptions: 
 basal cell or squamous cell skin cancer. 
22. Are at increased risk for developing cancer or a recurrence of cancer. 
General 
23. Have had a significant weight gain or loss in the past 3 months in the investigator’s 
opinion, for example, ≥5%. 
24. Have known hypersensitivity or allergy to any of the study medications or their 
excipients. 
25. 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. 
26. Are women who test positive for pregnancy or intend to become pregnant. 
27. Are women who are lactating or breastfeeding. 
Prior or concomitant therapy 
28. Have been on an insulin treatment regimen, including NPH insulin, U-500 insulin, 
regular human insulin, or any premixed insulins within 90 days prior to screening. 
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29. Have used insulin human inhalation powder (Afrezza) within 90 days prior to screening. 
30. Have used continuous subcutaneous insulin infusion therapy within 90 days prior to 
screening. 
31. Are receiving any oral or injectable medication intended for the treatment of diabetes 
mellitus other than insulins as specified in Inclusion Criterion 4 in the 90 days prior to 
screening. 
32. Are receiving chronic (>14 days) systemic glucocorticoid therapy or have received such 
therapy for >14 days within 30 days prior to screening. 
Exceptions: 
 replacement therapy for adrenal insufficiency, and 
 topical, intraocular, intranasal, or inhaled preparations or intra-articular injection 
33. Have used any weight loss drugs within 90 days prior to screening. 
Examples: 
 glucagon-like peptide-1 (GLP-1) receptor agonists 
 lorcaserin 
 orlistat 
 phentermine 
 phentermine and topiramate combination 
 naltrexone and bupropion combination, or 
 over-the-counter weight loss medications. 
Prior or concurrent clinical study experience 
34. Are currently enrolled in any other clinical study involving an intervention or any other 
type of medical research, judged not to be scientifically or medically compatible with this 
study. 
35. Have participated, within the last 30 days in a clinical trial involving an intervention. If 
the previous intervention has a long half-life, 3 months or 5 half-lives, whichever is 
longer, should have passed. 
36. 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 (LY3209590 or comparator). 
Other exclusions 
37. Have evidence of any substance abuse disorder of any severity defined by the Diagnostic 
and Statistical Manual of Mental Disorders-5, within 6 months prior to screening. 
Exceptions: nicotine or caffeine. 
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. 
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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. Diabetes self-management counseling may be reviewed throughout the study, as 
needed. 
Dietary and exercise considerations 
Study participants should generally follow a healthy meal plan and continue their usual exercise 
habits throughout the course of the study. 
Dietary and exercise restrictions 
Study participants should not initiate an intensive diet or exercise program with the intent of 
reducing body weight at any time during the study, other than the lifestyle and dietary measures 
for diabetes treatment. 
Blood donation 
Study participants should not donate blood or blood products during the study or for 4 weeks 
following their last study visit. 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (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.  
6.1. 
Study Intervention(s) Administered 
This table lists the interventions used in this clinical study. 
Intervention 
Name 
LY3209590 
Insulin Degludec 
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 6.5.2.1) 
Individualized dosing 
(see Section 6.5.2.2) 
Individualized dosing (see 
Section 6.5.3) 
Frequency of 
Administration 
Once-weekly study 
basal insulin 
Once-daily study 
basal insulin 
Background prandial 
insulin therapy with meals 
and as needed 
Route of 
Administration 
Subcutaneous 
injection 
Subcutaneous 
injection 
Subcutaneous injection 
Authorized as 
defined by EU 
Clinical Trial 
Regulation 
No 
Yes 
Yes 
 
 
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LY3209590 frequency of administration and guidance for missed doses 
LY3209590 should be administered once weekly at approximately the same time and day each 
week.  
If a dose is missed, it should be administered as soon as possible if at least 3 days (72 hours) 
remain until the next scheduled dose. If less than 3 days remain before the next scheduled dose, 
skip the missed dose and administer the next dose on the regularly scheduled day. In each case, 
participants can then resume their regular once-weekly dosing schedule. 
The day of weekly administration can be changed, if necessary, only if the last dose has been 
administered at least 3 days earlier.  
Insulin degludec frequency of administration 
Insulin degludec should be administered once daily at approximately the same time each day. 
Anatomical location of injections 
For both LY3209590 and insulin degludec, participants should rotate injection sites from one 
injection to the next, even when injecting within the same region. Injections may be administered 
in the abdomen, thigh, arm, or buttock. Refer to the Instructions for Use for complete 
instructions on dose administration. 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Medical Devices 
LY3209590, insulin degludec, and insulin lispro will be provided as a solution in a prefilled pen 
injector for the administration of either LY3209590 or insulin degludec and insulin lispro. 
Instructions for device use will be provided. 
All Product Complaints, including malfunctions, use error, and inadequate labelling, shall be 
documented and reported by the investigator throughout the clinical investigation (see Section 
8.3.1) and appropriately managed by the sponsor. 
6.1.2. 
Background Therapy 
For patients with T1D, standard of care stipulates treatment with both basal and bolus insulin. In 
this study, participants will be treated with LY3209590 or insulin degludec as study basal insulin 
intervention and insulin lispro as prandial bolus background therapy.  
Insulin lispro is being used to standardize the prandial insulin therapy. 
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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 
degludec, in combination with prandial insulin lispro. Correction doses of insulin lispro can also 
be used.  
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, 
rescue therapy with an additional therapeutic intervention should be considered.  
 
Average Fasting Glucose over 2-week Period 
Timing of events 
>270 mg/dL (15 mmol/L) 
Weeks 12 to 16 (from Visit 15 until Visit 17) 
>240 mg/dL (13 mmol/L) 
Weeks 16 to 20 (after Visit 17 until Visit 19)   
>200 mg/dL (11 mmol/L) 
Weeks 20 to 52 (after Visit 19 until Visit 29)  
 
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 is fully optimized, the investigator 
will decide, in consultation with the participant, on an appropriate intensification of insulin 
therapy after considering relevant clinical criteria. 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 degludec). The participant will remain in the 
study and follow procedures for the remaining study visits. 
The investigator should ensure that the participant met the criteria for severe or persistent 
hyperglycemia before initiating rescue medicine and document this in the source files. 
 
6.2. 
Preparation, Handling, Storage, and Accountability 
The investigator or designee must confirm appropriate storage conditions have been maintained 
during transit for all study intervention received and any discrepancies are reported and resolved 
before use of the study intervention. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized study personnel. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records). 
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Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
Participant responsibilities 
In-use storage conditions are expected to be followed according to the instructions for use 
provided by the sponsor. Study participants will be trained on the proper storage and handling of 
the study intervention. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization and stratification 
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, the log-in 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 degludec. 
Participants will be stratified based on 
 country 
 HbA1c stratum (<8% and ≥8%) at screening Visit 1 
 CGM use prior to study entry (yes/no), and 
 carbohydrate counting for prandial insulin dosing (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 
Study personnel will ensure participants enter in their e-diary  
 the dose amount and date of their daily or weekly basal insulin dose, and  
 prandial insulin dose.  
o Note: Record all prandial insulin doses injected each day with meals and 
additional doses if applicable. 
The minimum required insulin dose e-diary entries differ by study period as described in the 
table below. 
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During study period… 
participants will record 
their dose for… 
during… 
at a minimum frequency 
of… 
Lead in 
prestudy basal insulin 
Weeks -1 to 0  
Visits 2 to 3 
2 days per week 
prestudy prandial insulin 
Weeks -1 to 0 
Visits 2 to 3 
2 days per week 
Treatment 
LY3209590 or insulin 
degludec 
Weeks 0 to 52 
Visits 3 to 29 
1 day per week 
prandial insulin lispro  
Weeks 0 to 12 
Visits 3 to 15 
2 days per week 
the week prior to 
Weeks 16, 20, 24, 26, 28, 
32, 36, 40, 44, 48, and 52 
Visits 17, 19, 21, 22, 23, 
24, 25, 26, 27, 28, and 29 
2 days per week 
Safety follow-up 
basal insulin 
Weeks 52 to 57 
Visits 29 to 802 
1 day per week 
prandial insulin 
Weeks 52 to 57 
Visits 29 to 802 
1 day per week 
Additional recording of insulin dosing can be requested throughout the study as clinically 
indicated. 
The investigator or trained designee will assess treatment compliance at each visit based on 
review of the participant’s 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, specific diagnostic tests, or e-diary entries, they will be retrained as needed by designated 
study personnel. 
6.5. 
Dose Modification 
6.5.1. 
Glycemic Targets and Goals 
The overall glycemic targets and goals for study participants during the study treatment period 
are similar to those recommended by the American Diabetes Association and the European 
Association for the Study of Diabetes (Holt et al. 2021). The glycemic targets and goals should 
be balanced with minimizing the risk of significant hypoglycemia.  
Glucose Timepoint 
Glucose Target Range  
Fasting or preprandial glucose 
80-120 mg/dL or 4.4-6.6 mmol/L 
 
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CGM Time in Ranges  
Overall CGM Goals 
Time in range (TIR) 70-180 mg/dL (3.9-10.0 
mmol/L) 
>70%  
Time below range (TBR)  
Readings and time < 54 mg/dL  
(3.0 mmol/L; Level 2 hypoglycemia)  
 
<1% 
 
Readings and time < 70 mg/dL  
(3.9 mmol/L; Level 1 and Level 2 
hypoglycemia) 
<4%  
 
Time above range (TAR) 
Readings and time >250 mg/dL (13.9 
mmol/L) 
 
<5%  
 
Readings and time >180 mg/dL (10.0 
mmol/L) 
<25% 
6.5.2. 
Basal Insulin Therapy 
During the lead-in period (Visits 2 to 3), participants will continue their prestudy basal and 
prandial insulin therapy.  
At Visit 3, participants will be randomized to study basal insulin LY3209590 or degludec. Basal 
insulin is titrated based on the FBG target of 80 to 120 mg/dL (4.4 to 6.6 mmol/L) and 
hypoglycemia evaluation. CGM data including 24-hour glucose profiles and additional SMBG 
monitoring (if applicable) should also be considered. 
Titration of the study basal insulin (LY3209590 or degludec) dose should be made at weekly 
intervals from Weeks 0 to 12 (titration period, Visits 3 to 15), and then at a minimum of every 4 
weeks from Weeks 12 to 52 (Visits 16 to 29) 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 e-diary-linked, 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. Investigators should also consider 
CGM data for basal insulin dose titration.  
Note: If the participant has only 2 FBG readings for the week, then the lesser of the readings 
should be used to determine the dose adjustments. If only 1 FBG measurement is available, 
determination if dose is changed using only a single FBG value is at the discretion of the 
investigator.  
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6.5.2.1. 
LY3209590 Dose Initiation and Modification 
This section outlines LY3209590  
 loading dose (Week 0)  
 starting weekly dose (Week 1)  
 weekly dose (Weeks 2 to 52)  
 dose modification guidance based on hypoglycemia, and 
 dose modification guidance based on FBG.  
Visit 3 (Week 0 – Randomization) loading dose 
At Visit 3 (Week 0), participants randomized to LY3209590 will start study basal 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 week prior to randomization (Visit 3 [Week 
0]).  
Note: If the participant’s prestudy basal insulin is glargine U-300, the prior daily basal 
insulin dose should be reduced by 20% when determining usual daily basal insulin dose.  
For participants with median FBG ≤ 140 mg/dL (7.8 mmol/L), follow instructions in this table 
to calculate the LY3209590 Loading Dose.  
LY3209590 Loading Dose – Participants with Median FBG ≤ 140 mg/dL (7.8 mmol/L) 
 
Step 
Action 
Example Participant A 
FBG ≤ 140 mg/dL (7.8 mmol/L) 
1 
Determine usual daily basal insulin dose from the 
lead-in period 
24 units/day 
2 
Calculate Starting Weekly Dose (daily basal dose 
multiplied by 7 and round to nearest 10) 
170 units/week 
3 
Multiply Starting Weekly Dose by 3 to determine the 
Loading Dose 
510 units Loading Dose 
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For participants with FBG > 140 mg/dL (7.8 mmol/L), an incremental addition to the prior daily 
basal insulin dose was instituted to reduce transient hyperglycemia while LY3209590 achieves 
steady state. 
For participants with median FBG 141 to 160 mg/dL (>7.8 to 8.9 mmol/L), the prior daily 
basal insulin dose should be increased by 10 to 20%. Follow instructions in this table to 
calculate the LY3209590 Loading Dose.  
LY3209590 Loading Dose – Participants with Median FBG 141 to 160 mg/dL (7.8 to 8.9 mmol/L) 
 
Step 
Action 
Example Participant B 
FBG 141 to 160 mg/dL (>7.8 to 
8.9 mmol/L) 
1 
Determine usual daily basal insulin dose from the 
lead-in period 
24 units/day  
2 
Increase the usual daily basal insulin dose by 10 to 
20% to determine the adjusted daily basal dose 
26 units/day 
3 
Calculate Starting Weekly Dose (adjusted daily basal 
dose multiplied by 7 and round to nearest 10) 
180 units/week 
4 
Multiply Starting Weekly Dose by 3 to determine the 
Loading Dose 
540 units Loading Dose 
 
For participants with median FBG >160 mg/dL (8.9 mmol/L), the prior daily basal insulin dose 
should be increased by 20 to 30%. Follow instructions in this table to calculate the LY3209590 
Loading Dose.  
LY3209590 Loading Dose – Participants with Median FBG >160 mg/dL (8.9 mmol/L) 
 
Step 
Action 
Example Participant C 
FBG >160 mg/dL (>8.9 mmol/L) 
1 
Determine usual daily basal insulin dose from the 
lead-in period 
24 units/day  
2 
Increase the usual daily basal insulin dose by 20 to 
30% to calculate the adjusted daily basal dose 
30 units/day 
3 
Calculate Starting Weekly Dose (adjusted daily basal 
dose multiplied by 7 and round to nearest 10) 
210 units/week 
4 
Multiply Starting Weekly Dose by 3 to determine the 
Loading Dose 
630 units Loading Dose 
Visit 4 (Week 1) starting weekly dose 
The Starting Weekly Dose (Week 1) is administered at the site at Visit 4 
If the participant experienced hypoglycemia in the previous week and met any of the criteria for 
a dose reduction as listed in the hypoglycemia dose reduction for LY3209590 table below, the 
Visit 4 starting weekly dose may be reduced by 10% or as clinically indicated.  
CAUTION: Do NOT repeat administration of the loading dose. 
 
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Visits 5 to 29 (Weeks 2 to 52) weekly dosing 
Titration of the study basal insulin LY3209590 dose should be made at weekly intervals from 
Weeks 0 to 12 (titration period, Visits 3 to 15), and then at a minimum of every 4 weeks from 
Weeks 12 to 52 (Visits 16 to 29) or more often as clinically indicated.  
Assess hypoglycemia events over the previous week.  
Reduce the LY3209590 dose if the participant meets criterion for hypoglycemia dose reduction 
according to this table.  
Hypoglycemia Dose Reduction Criteria 
Decrease the LY3209590 Dose  
2 nocturnal hypoglycemia events ≤70 mg/dLa (3.9 
mmol/L) 
to previous lower doseb 
2 fasting hypoglycemia events ≤70 mg/dLa (3.9 mmol/L) 
1 nocturnal and 1 fasting hypoglycemia event ≤70 mg/dLa 
(3.9 mmol/L) 
Any confirmed severe hypoglycemia 
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. 
 
If the participant does not meet criteria for hypoglycemia dose reduction, determine the median 
fasting glucose and adjust the LY3209590 dose according to this table.  
LY3209590 Dose Adjustment 
Median FBG (mg/dL) 
Median FBG (mmol/L) 
LY3209590 Dose 
 <100 Units per Week 
LY3209590 Dose 
≥100 Units per Week 
<80 
<4.4 
Decrease to previous 
lower dosea 
Decrease to previous 
lower dosea 
80-120 
4.4-6.6 
No change 
No change 
121-150 
6.7-8.3 
Increase by 5 units 
Increase by 10 units 
151-180 
8.4-10.0 
Increase by 10 units 
Increase by 20 units 
>180 
>10.0 
Increase by 20 units 
Increase by 30 units 
a  If there is no previous lower dose, then decrease basal insulin dose by 10% or as clinically indicated. 
 
6.5.2.2. 
Insulin Degludec Dose Initiation and Modification 
This section outlines insulin degludec 
 dose initiation at Visit 3 (Week 0) 
 dose modification guidance based on hypoglycemia, and 
 dose modification guidance based on FBG.  
 
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Visit 3 (Week 0 – Randomization) 
At Visit 3 (Week 0), participants randomized to insulin degludec will start study basal insulin 
therapy.  
The initial degludec dose may be unit-for-unit of the prior basal insulin regimen.  
Note: If the participant’s prestudy basal insulin is glargine U-300, reduce the prior basal 
insulin dose by 20%.  
Visits 4 to 29 (Weeks 1 to 52)  
Titration of the study basal insulin degludec dose should be made at weekly intervals from 
Weeks 0 to 12 (titration period, Visits 3 to 15), and then at a minimum of every 4 weeks from 
Weeks 12 to 52 (Visits 16 to 29) or more often as clinically indicated.  
Assess hypoglycemia events over the previous week.  
Reduce the insulin degludec dose if the participant meets criterion for hypoglycemia dose 
reduction according to this table.  
Hypoglycemia Dose Reduction Criteria 
Decrease the Insulin Degludec Dose 
2 nocturnal hypoglycemia events ≤70 mg/dLa (3.9 
mmol/L) 
to previous lower doseb 
2 fasting hypoglycemia events ≤70 mg/dLa (3.9 mmol/L) 
1 nocturnal and 1 fasting hypoglycemia event ≤70 mg/dLa 
(3.9 mmol/L) 
Any confirmed severe hypoglycemia 
by 2 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 degludec dose according to this table. 
Insulin Degludec Dose Adjustment 
Median FBG (mg/dL) 
Median FBG (mmol/L) 
Degludec Dose 
<15 Units per Day 
Degludec Dose 
≥15 Units per Day 
<80 
<4.4 
Decrease to previous 
lower dosea 
Decrease to previous 
lower dosea 
80-120 
4.4-6.6 
No change 
No change 
121-150 
6.7-8.3 
Increase by 1 unit 
Increase by 2 units 
151-180 
8.4-10.0 
Increase by 2 units 
Increase by 3 units 
>180 
>10.0 
Increase by 3 units 
Increase by 4 units 
a If there is no previous lower dose, then decrease basal insulin dose by 10% or as clinically indicated. 
Source: Adapted from Bartley et al. 2008 and Bolli et al. 2009. 
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6.5.3. 
Prandial Insulin Therapy 
During the lead-in period (Visits 2 to 3), participants will continue their prestudy basal and 
prandial insulin therapy.  
During the treatment period (Visits 3 to 29), all participants will be treated with insulin lispro. 
The initial insulin lispro doses may be unit-for-unit of the prestudy prandial insulin regimen.  
Prandial insulin is titrated based on glucose and hypoglycemia data from CGM and SMBG. 
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 
investigator; thus, the prescribed prandial insulin dose during the study is determined by, and the 
responsibility of, the investigator.  
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.  
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.  
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 CGM, SMBG, and hypoglycemia data at clinic and 
telephone visits and as clinically indicated. Twenty-four-hour glucose profiles, including premeal 
glucose and postprandial glucose levels, from CGM can be evaluated.  
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 CGM, SMBG, and hypoglycemia data at clinic and telephone visits and as 
clinically indicated. Twenty-four-hour glucose profiles, including premeal glucose and 
postprandial glucose levels, from CGM can be evaluated.  
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In the fixed-dose plan, assessment of the prandial insulin dose may include review of the pattern 
of CGM glucose levels from the previous week or as clinically indicated 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 CGM glucose values from the previous week pre-mid-day meal. 
Prandial Insulin Dose Assessed 
Corresponding CGM Glucose for Review 
Fasting or morning premeal 
Pre-midday meal glucose values  
Midday premeal 
Pre-evening meal glucose values  
Evening premeal 
Bedtime glucose values  
Abbreviation: CGM = continuous glucose monitoring. 
The pattern of CGM glucose values from the premeal or bedtime is used as the “adjustment 
value” and the change in dose, either increase or decrease, is based upon this value as described 
in the table below. 
If Meal Time Dose of 
Insulin Lispro is 
Pattern of CGM Glucose 
Below Target Range 
Pattern of CGM Glucose 
at Target Range 
Pattern of CGM 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, 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 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 29 [Week 52] or ET visit), the investigator will prescribe a non-
study basal insulin for use during the safety follow-up period.  
The investigator, in consultation with the participant, will decide on prandial insulin therapy for 
use during the safety follow-up period.  
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Study participants treated with LY3209590  
Participants will administer their last dose of LY3209590 at Week 51 of the study and can begin 
the transition to the non-study insulins after Visit 29 (Week 52). At Visit 29 (Week 52), the 
investigator will review instructions for transitioning to the non-study insulins 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 
100 mg/dL (5.5 mmol/L), and then daily basal insulin would be initiated and adjusted based on 
fasting glucose, CGM profile, and hypoglycemia evaluation. 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. An unscheduled visit in addition to Visit 801 may occur during this time to facilitate the 
transition to non-study daily basal insulin. 
Study participants treated with insulin degludec 
Participants assigned to the insulin degludec treatment arm will transition to their non-study 
basal insulin after Visit 29 (Week 52) with dose adjustment per investigator discretion based on 
fasting glucose, CGM profile, and hypoglycemia evaluation and in accordance with the local 
product label for the basal insulin.  
6.7. 
Treatment of Overdose 
Study intervention overdose, dangerously large amount of insulin compared to the protocol-
prescribed dose, will be reported as per Section 10.3.1. In the event of an overdose, refer to the 
IB for LY3209590 or product label for insulin degludec depending on the participant treatment 
assignment. 
In the event of an overdose, the investigator/treating physician should 
● Contact the 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. 
● Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until study intervention no longer has a clinical effect  
● Obtain a plasma sample for PK analysis if the participant is assigned to 
LY3209590. 
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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 
(Section 5.2). 
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. 
Non-study medications taken by study participants who have signed informed consent, but are 
not randomized to study insulin, will not be reported unless an SAE or AE occurs that the 
investigator believes may have been caused by a study procedure. 
Excluded concomitant medications 
The following concomitant therapies will not be allowed during the study: 
 any oral or injectable medication intended for the treatment of diabetes mellitus other 
than study insulins 
Exception: Short-term use of non-study insulins is permissible as outlined in Section 7.1.3.   
Note: Participants who require treatment with non-study basal insulins as rescue therapy for 
management of severe or persistent hyperglycemia as outlined in Section 6.1.3., must 
discontinue study basal insulin therapy (LY3209590 or insulin degludec). The participant 
will remain in the study and follow procedures for the remaining study visits.  
 chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy 
excluding topical, intraocular, intranasal, inhaled, or intraarticular preparations, and 
 weight loss drugs, for example, prescription drugs: glucagon-like peptide-1 (GLP-1) 
receptor agonists, lorcaserin, orlistat, phentermine, phentermine and topiramate 
combination, naltrexone and bupropion combination, or over-the-counter weight loss 
medications. 
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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 
degludec. 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 degludec permanently will receive another non-
study basal insulin (see Section 6.6.1). The new insulin will be recorded on the CRF. 
A participant should be permanently discontinued from LY3209590 or insulin degludec if 
● the participant becomes pregnant during the study 
● the participant requests to discontinue intervention 
 the participant is diagnosed with an active or untreated malignancy, except for 
successfully treated basal or squamous cell skin carcinoma 
 the participant has not taken insulin degludec for more than 21 consecutive days or 
missed more than 3 consecutive doses of LY3209590, or 
● in the opinion of the investigator, the participant should permanently discontinue 
LY3209590 or insulin degludec for safety reasons. 
7.1.1. 
Liver Chemistry Stopping Criteria 
The study intervention should be interrupted or discontinued if 1 or more of these conditions 
occur. 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for intervention interruption or 
discontinuation decisions rather than TBL 
>2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL > 2x ULN  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for intervention interruption or 
discontinuation decisions rather than TBL 
>2x ULN. 
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ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) 
 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited, non-intervention etiology is identified.  
7.1.2. 
Hypersensitivity Reactions 
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the sponsor’s designated medical monitor should be notified. 
If the investigator is uncertain about whether a systemic hypersensitivity reaction has occurred 
and whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor. 
7.1.3. 
Temporary Discontinuation of LY3209590 or Insulin Degludec 
Criteria for temporary discontinuation of LY3209590 or insulin degludec 
The investigator may temporarily interrupt study treatment, due to an AE, clinically significant 
laboratory value, hospital visits, travel, or shortage of study treatment supply. 
This will be allowed for up to 3 consecutive weeks for degludec or 3 consecutive doses for 
LY3209590. During this time, non-study insulins may have been used. This information should 
be documented by the investigator. 
Guidance when temporary discontinuation of LY3209590 or insulin degludec occurs 
Every effort should be made by the investigator to maintain participants in the study and to 
restart LY3209590 or insulin degludec promptly, as soon as it is safe to do so.  
Participants will continue their study visits and follow up according to the SoA. 
Participants should resume the dose prescribed before the temporary dosing interruption at the 
discretion of the investigator.  
Recording temporary discontinuation of LY3209590 or insulin degludec 
The dates of LY3209590 or insulin degludec 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 
degludec on the CRF. 
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7.2. 
Participant Discontinuation/Withdrawal from the Study 
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
● at any time at the participant’s own request 
● at the request of the participant’s designee (for example, parents or legal 
guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
● if the participant, for any reason, requires treatment with a therapeutic agent that 
is prohibited by the protocol and has been demonstrated to be effective for 
treatment of the study indication. In this case, discontinuation from the study 
occurs prior to introduction of the new agent, and 
 if a study participant is diagnosed with any type of diabetes mellitus other than 
T1D. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and post-treatment follow-up, if applicable, as shown in the 
SoA.  
If the participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
If a participant withdraws from the study, the participant may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA.  
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 range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L), inclusive, and 
 patient-reported outcomes questionnaires 
o Diabetes Treatment Satisfaction Questionnaire - Status 
o Diabetes Treatment Satisfaction Questionnaire - Change 
o SF-36v2 acute form 
o EQ-5D-5L 
o Basal Insulin Experience: Preference, and 
o Basal Insulin Experience: Likelihood of incorporating into routine. 
See Section 3 for specific efficacy endpoints. 
This section will outline glucose monitoring and patient-reported outcome measures. 
8.1.1. 
Glucose Monitoring  
Participants must use only the study-provided glucose monitors during the study. 
8.1.1.1. 
Self-Monitoring of Blood Glucose (SMBG) 
Glucometer for participant use during the study 
Participants will receive a study-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. 
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Fasting blood glucose (FBG) measurement  
The FBG should be measured upon waking in the morning, prior to food or caloric beverage 
intake.  
This table describes when participants will measure their FBG using the study-provided 
glucometer. 
The participant must measure their FBG during… 
At a frequency of… 
Weeks -1 to 0  
Visits 2 to 3 
3 days per week 
Weeks 0 to 12 
Visits 3 to 15 
the week prior to 
Weeks 16, 20, 24, 26, 28, 32, 36, 40, 44, 48, and 52 
Visits 17, 19, 21, 22, 23, 24, 25, 26, 27, 28, and 29 
Additional FBG and SMBG measurements can be obtained as clinically indicated.  
SMBG for suspected hypoglycemia 
Participants will be advised to check SMBG readings when they experience signs and symptoms 
of hypoglycemia and for CGM glucose < 70 mg/dL (3.9 mmol/L) prior to treatment with 
carbohydrates (if the participants can safely do this). 
The participant’s SMBG readings and hypoglycemia events in conjunction with CGM data will 
be used to determine insulin dosing during the study (Section 6.5). 
Glucometer data transfer 
The study-provided glucometer will wirelessly transmit blood glucose measurements to the 
participant’s e-diary. Site personnel will be able to view SMBG data that have been transmitted 
to the e-diary through a web-based portal as well as any reported events of hypoglycemia. 
8.1.1.2. 
Continuous Glucose Monitoring (CGM) System 
The unblinded Dexcom G6® CGM system will be used continuously throughout the stud y to 
facilitate diabetes management and for data collection. The Dexcom G6 CGM system includes 
the sensor, transmitter, and receiver.  
Training and initiation 
At Visit 2, participants will receive the study supplied CGM system and training on its use and 
study requirements. The sensor can be worn for up to 10 days. Participants will be instructed to 
change the sensor and transmitter before they expire according to the product label information 
and to keep the transmitter within 20 feet (6 meters) of the receiver during use. Study 
participants will use the receiver to review CGM data during the study. A CGM participant user 
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guide that provides an overview of device components and study-specific instructions will be 
available for at-home use.   
Site personnel will download the CGM data from the receiver to a vendor online portal where 
data can be reviewed as per the SoA and as clinically indicated. 
Notes:  
 Participants are not allowed to connect the transmitter of the study supplied Dexcom G6 
system to a personal smartphone, smartphone application, or other system.  
 The sensor code must be entered into the CGM receiver. Participants are not allowed to 
manually calibrate the study CGM with fingerstick blood glucose readings. 
 Participants may not use their own personal CGM device.  
In the CGM receiver, a hypoglycemia alert at 70 mg/dL (3.9 mmol/L) will be required. 
Participants will be advised to check SMBG readings when they experience signs and symptoms 
of hypoglycemia and for CGM glucose <70 mg/dL (3.9 mmol/L) prior to treatment with 
carbohydrates (if the participant can safely do this). 
CGM data compliance 
Sites will be required to review data capture compliance following CGM data downloads using 
the available vendor portal reports and visualization tools. A compliance threshold of 80% will 
be used to assess minimum CGM data capture requirements are met and is defined as the 
percentage of actual data versus expected data collected in between data downloads. Site 
personnel will re-educate participants on CGM requirements when download compliance is 
<80%. 
To minimize data loss, the CGM service vendor will review site downloads 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. 
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 (Section 1.3). 
Order of administering the questionnaires during the visit 
The questionnaires should be completed before the participant has discussed their medical 
condition or progress in the study with the investigator or study personnel, if the participant is 
not adversely affected by their fasting condition. 
The order of administration of these questionnaires, where applicable, is 
 Diabetes Treatment Satisfaction Questionnaire - Status 
 Diabetes Treatment Satisfaction Questionnaire - Change 
 SF-36v2 acute form  
 EQ-5D-5L 
 Basal Insulin Experience: Preference, and 
 Basal Insulin Experience: Likelihood of incorporating into routine. 
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8.1.2.1. 
Diabetes Treatment Satisfaction Questionnaire – Status 
The Diabetes Treatment Satisfaction Questionnaire-Status Version (Bradley and Lewis 1990; 
Bradley 1994) is a diabetes-specific patient-reported outcome instrument that assesses the overall 
treatment satisfaction and perceived frequency of hyperglycemia and hypoglycemia. It is 
appropriate for use in both T1D and T2D. 
The Diabetes Treatment Satisfaction Questionnaire-Status Version consists of 8 items that assess 
treatment satisfaction as well as concerns about hyperglycemia and hypoglycemia over the past 
few weeks, prior to the visit.  
Each item is rated on a 7-point Likert scale. Items 1, 4, 5 to 7, and 8 are rated from 0 (very 
dissatisfied) to 6 (very satisfied) and can be summed up to produce a treatment satisfaction score. 
Items 2 and 3 evaluate the perceived frequency of hyperglycemia and hypoglycemia and are 
rated from 0 (none of the time) to 6 (most of the time). 
8.1.2.2. 
Diabetes Treatment Satisfaction Questionnaire – Change 
The Diabetes Treatment Satisfaction Questionnaire-Change Version (Bradley 1999) was 
designed to overcome potential ceiling effects in the status version. The Diabetes Treatment 
Satisfaction Questionnaire-Change Version has the same 8 items as the status version but is 
reworded slightly to measure the change in treatment satisfaction rather than absolute treatment 
satisfaction. 
Each item is scored on a scale of -3 to +3. For all items except Item 2 (perceived frequency of 
hyperglycemia) and Item 3 (perceived frequency of hypoglycemia):  
 the higher the score, the greater the improvement in treatment satisfaction 
 the lower the score, the greater the deterioration in treatment satisfaction, and 
 a score of 0 represents no change.  
For Items 2 and 3: the lower the score, the better the perception. 
8.1.2.3. 
Short Form-36 Version 2 Health Survey Acute Form 
Description of SF-36v2 
The SF-36 v2 Health Survey Acute form is a participant self-administered measure designed to 
assess these 8 domains 
 Physical Functioning 
 Role Physical 
 Bodily Pain 
 General Health 
 Vitality 
 Social Functioning 
 Role Emotional, and 
 Mental Health. 
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The Physical Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Participants answer each item using Likert 3-
point, 5-point, or 6-point scales for the responses.  
Scoring 
Each domain is scored individually and information from these 8 domains is further aggregated 
into 2 health component summary scores, the Physical Component Summary and Mental 
Component Summary.  
Scoring of each domain and both summary scores are norm based and presented in the form of 
T-scores, with a mean of 50 and standard deviation of 10.  
Higher scores indicate better levels of function and/or better health (Maruish 2011).  
8.1.2.4. 
EQ-5D-5L 
Description of EQ-5D-5L 
The EQ-5D-5L (EuroQol Research Foundation 2019) is a standardized, 5-item, self-administered 
instrument for use as a measure of health outcome. It provides a simple, descriptive health 
profile and a single health state index value that can be used in the clinical and economic 
evaluation of health care as well as population health surveys. 
The EQ-5D-5L assesses 5 dimensions of health 
 mobility 
 self-care 
 usual activities 
 pain/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.  
Scoring 
The scores on the 5 dimensions can be presented as a health profile or converted to a single 
health state index value.  
The single health state index value can be derived based on a formula that attaches weights to 
each of the levels in each dimension. This index value ranges between less than 0 to 1, where 
negative values are valued as worse than dead, 0 is a health state equivalent to death, and 1 
represents perfect health.  
EQ Visual Analog Scale 
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The EQ Visual Analog Scale records the respondent’s self-rated health status on a vertical 
graduated visual analog scale from 0 to 100, where 0 represents the worst imaginable health and 
100 represents the best imaginable health.  
In conjunction with the health state data, this provides a composite picture of the respondent’s 
health status.  
8.1.2.5. 
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. 
8.1.2.6. 
Basal Insulin Experience: Likelihood of Incorporating into Routine 
Description of questionnaire 
The Basal Insulin Experience: Likelihood of incorporating into routine is a self-reported scale 
consisting of a single question to understand the participant’s likelihood of incorporating their 
study insulin into their diabetes management routine.  
Scoring 
The question is rated on a 5-point scale with responses ranging from “very unlikely” to “very 
likely.” 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
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 T1D, T1D-related 
illnesses, and injection site reactions. 
8.2.2. 
Vital Signs 
Blood pressure and pulse rate will be measured when specified in the SoA and as clinically 
indicated. Additional vital signs may be measured during study visits if warranted, as determined 
by the investigator.  
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8.2.3. 
Electrocardiograms 
Local and single 12-lead ECG will be obtained as outlined in the SoA.  
Electrocardiograms will initially be interpreted by the investigator or qualified designee at the 
site as soon after the time of ECG collection as possible, and ideally while the participant is still 
present, to determine whether the participant meets entry criteria and for immediate participant 
management, should any clinically relevant findings be identified.  
The investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document their review of the ECG printed at the time of 
evaluation.  
8.2.4. 
Clinical Safety Laboratory Tests 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA for 
the timing and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE.  
The laboratory results must be retained with source documents unless a Source Document 
Agreement or comparable document cites an electronic location that accommodates the 
expected retention duration.  
Clinically significant abnormal laboratory findings are those which are not associated 
with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 weeks after the last dose of intervention should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the SoA, standard collection requirements, and laboratory 
manual. 
If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE. 
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8.2.5. 
Hepatic Monitoring 
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests, including ALT, AST, ALP, TBL, direct bilirubin, GGT, and creatine kinase, 
should be repeated within 48 to 72 hours to confirm the abnormality and to determine if it is 
increasing or decreasing, if 1 or more of these conditions occur. This table shows when to repeat 
laboratory tests. 
If a participant with baseline results 
of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants with 
Gilbert’s syndrome) 
What to do if the abnormal condition persists or worsens 
If the abnormal liver test result persists or worsens, clinical and laboratory monitoring, and 
evaluation for possible causes of abnormal liver tests should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including  
1. symptoms  
2. recent illnesses, for example, heart failure, systemic infection, hypotension, or seizures  
3. recent travel  
4. history of concomitant medications, including over-the-counter, herbal and dietary 
supplements, and  
5. history of alcohol drinking and other substance abuse.  
Frequency of monitoring 
Initially, monitoring of symptoms and liver tests should be done 1 to 3 times weekly, based on 
the participant’s clinical condition and liver test results.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize.  
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return to 
approximate baseline levels. 
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Comprehensive hepatic evaluation 
When to perform a comprehensive evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of the conditions in this table occur. 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs or symptomsa, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs or symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s syndrome)  
a  Hepatic signs or symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
What a comprehensive evaluation should include 
At a minimum, this evaluation should include  
 physical examination and a thorough medical history, as outlined above  
 tests for 
o PT-INR  
o viral hepatitis A, B, C, or E, and 
o autoimmune hepatitis, and  
 an abdominal imaging study, for example, ultrasound or computed tomography scan.  
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for  
 hepatitis D virus  
 cytomegalovirus  
 Epstein-Barr virus  
 acetaminophen levels  
 acetaminophen protein adducts  
 urine toxicology screen  
 Wilson’s disease  
 blood alcohol levels  
 urinary ethyl glucuronide, and  
 blood phosphatidylethanol.  
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a hepatologist or 
gastroenterologist consultation, magnetic resonance cholangiopancreatography, endoscopic 
retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
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Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Collect additional hepatic safety data collection in the hepatic safety CRFs if a participant  
 develops a hepatic event considered to be an SAE, or 
 discontinues study intervention due to a hepatic event, or  
 has changes in laboratory results described in this table. 
If a participant with 
baseline results of...  
develops the following elevations… 
Then… 
Elevated serum ALT 
Collect additional hepatic safety data in 
the hepatic safety CRF. 
ALT <1.5x ULN 
ALT to ≥5x ULN on 2 or more 
consecutive blood tests 
ALT ≥1.5x ULN 
ALT ≥3x baseline on 2 or more 
consecutive blood tests 
Elevated TBL 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants 
with Gilbert’s syndrome) 
TBL ≥1.5x ULN 
TBL ≥2x baseline  
Elevated ALP 
ALP <1.5x ULN 
ALP ≥2x ULN on 2 or more consecutive 
blood tests 
ALP ≥1.5x ULN 
ALP to ≥2x baseline on 2 or more 
consecutive blood tests 
Note: The interval between the 2 consecutive blood tests should be at least 2 days.  
See Section 10.5 for hepatic laboratory tests. 
8.2.6. 
Pregnancy Testing 
Pregnancy testing will occur as outlined in the SoA. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected as outlined in Sections 8.3.1 and 8.3.2. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3: 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 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). 
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Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs 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 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
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 
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 
Product Complaint 
form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product Complaint 
form 
 
a Serious adverse events should not be reported unless the investigator deems them to be possibly 
related to study treatment or study participation. 
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8.3.2. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
After learning of a pregnancy in the female partner of a study participant, the investigator 
will obtain a consent to release information from the pregnant female partner directly, 
and within 24 hours after obtaining this consent will record pregnancy information on the 
appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of gestational 
age, fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
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. 
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Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. If the participant is discontinued from the study, follow 
the standard discontinuation process and continue directly to the follow-up phase. The 
follow-up on the pregnancy outcome should continue independent of intervention or 
study discontinuation.  
8.3.3. 
Cardiovascular Events 
A blinded external Clinical Event Committee will adjudicate potential cerebrocardiovascular 
events in a consistent and unbiased manner. 
Events include 
 death 
 myocardial infarction 
 coronary revascularization procedure 
 hospitalization for unstable angina 
 hospitalization for heart failure, and 
 stroke or transient ischemic attack. 
8.3.4. 
Systemic Hypersensitivity Reactions 
Many drugs, including biologic agents, carry the risk of systemic hypersensitivity reactions. If 
such a reaction occurs, additional data should be provided to the sponsor in the designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.5. 
Injection Site Reactions 
Symptoms and signs of a local injection site reaction may include erythema, induration, pain, 
pruritus, 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. CGM data will be available for site personnel 
to download and review through a web-based portal. 
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Hypoglycemia classification and definitions 
Level 1 
Glucose <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 mmol/L)  
Level 1 hypoglycemia can alert a person to take action such as treatment with fast-acting 
carbohydrates. Providers should continue to counsel participants to treat hypoglycemia at this 
glucose alert value. 
Level 2  
Glucose <54 mg/dL (3.0 mmol/L)  
Level 2 hypoglycemia is also referred to as documented or blood glucose-confirmed 
hypoglycemia. The glucose threshold is clinically relevant regardless of the presence or absence 
of symptoms of hypoglycemia.  
Level 3 Severe 
A severe hypoglycemic event is characterized by altered mental or physical status requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions for the treatment of hypoglycemia.  
The determination of an episode of severe hypoglycemia is made by the investigator based on 
the medical need of the participant to have required assistance and is not predicated on the report 
of a participant simply having received assistance. 
Examples of severe hypoglycemia in adults are 
 altered mental status and the inability to assist in their own care  
 semiconscious or unconscious, or  
 coma with or without seizures.  
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. 
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8.4. 
Pharmacokinetics 
At the visits and times specified in the SOA, blood samples will be collected for all 
participants. Only samples from participants assigned to treatment with LY3209590 will 
be analyzed for drug concentration.  
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sampling will be recorded. 
Bioanalytical 
Samples will be analyzed at a laboratory designated by the sponsor and stored at a facility 
designated by the sponsor. Concentrations of LY3209590 will be assayed using a validated 
bioanalytical method. 
Sample retention is described in Section 10.1.12. 
8.5. 
Pharmacodynamics 
Pharmacodynamic parameters are described in Section 8.1. 
8.6. 
Genetics 
Genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Serum and plasma samples will be used for exploratory biomarker research, where local 
regulations allow. See Clinical Laboratory Tests, 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 T1D, mechanisms of action of LY3209590 or research 
methods, or in validating diagnostic tools or assay(s) related to T1D. 
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 (Section 1.3), venous blood samples from all study 
participants will be collected for analysis to determine antibody production against LY3209590. 
Antibodies may be further characterized for cross-reactive binding to endogenous insulin.  
To interpret the results of immunogenicity, a corresponding venous blood sample will be 
collected at the same visits to determine the concentrations of LY3209590 (PK sample). At Visit 
3, the sample for immunogenicity should be taken before dosing and the PK sample for 
LY3209590 after dosing.  
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
Treatment-emergent ADAs are defined in Section 9.3.6.2.  
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Immunogenicity will be assessed by a validated assay designed to detect and characterize ADA 
in the presence of LY3209590 at a laboratory approved by the sponsor. 
Sample retention is described in Section 10.1.12. 
8.9. 
Health Economics 
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations 
The first version of the SAP will be finalized prior to first participant visit, and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
Primary hypothesis 
The primary objective of this study is to test the hypothesis that LY3209590 is noninferior to 
insulin degludec on glycemic control as measured by change in HbA1c from baseline to Week 
26 (Visit 22) in adults with T1D currently on basal-bolus insulin.  
The null hypothesis (H0) is the difference between LY3209590 and insulin degludec in the 
change in HbA1c from baseline to Week 26 (Visit 22) is greater than the NIM. 
The NIMs of 0.4% and 0.3% will both be tested to meet different regulatory requirements. The 
2-sided 95% CI will be used for testing the noninferiority. 
Secondary hypotheses 
The key secondary (multiplicity adjusted) objectives are to test the hypotheses that LY3209590 
is superior to insulin degludec with respect to 
• change in HbA1c from baseline to Week 26 (Visit 22) 
H0: the difference (LY3209590 – insulin degludec) ≥ 0.0 
• time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive 
measured by CGM 4 weeks prior to Week 26 (Visit 22) 
H0: the difference (LY3209590 – insulin degludec) ≤ 0.0 
• the event rate of nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during 
treatment period up to Week 52 (Visit 29) 
H0: the relative event rate (LY3209590 vs. insulin degludec) ≥ 1 
These hypotheses and the primary hypothesis will be tested using a strategy to control the overall 
Type I 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 key secondary objectives once the 
primary objective is met. The testing procedure and α allocation will be established according to 
the clinical importance and statistical power of the endpoints in this study population.  
The details of graphical testing scheme will be described in the SAP. 
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9.2. 
Analyses Sets 
For the purposes of analysis, this table defines the analysis sets for this study. 
Analysis Populations/Sets 
Description 
Entered population 
All participants who sign the informed consent form. 
Randomized population 
All randomized participants. Participants will be analyzed according to the 
treatment they were assigned. 
Modified Intent-to-Treat 
(mITT) Population 
All randomized participants who took at least 1 dose of LY3209590 or insulin 
degludec. 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 measurements regardless of the use of study treatment or rescue 
medications 
Efficacy Analysis Set 2 (EAS2) 
for efficacy estimand 
The data will include 
 
mITT Population excluding participants discontinuing the study 
treatment due to inadvertent enrollment 
 
measurement up to discontinuation of study treatment or the 
initiation of rescue medication 
Safety Analysis Set (SS) 
The data will include 
 
mITT Population 
 
all measurements regardless of the use of study treatment or rescue 
medications 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designees.  
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other changes to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or the clinical study report. Additional exploratory analyses of data will be conducted 
as deemed appropriate. 
Unless otherwise stated, the efficacy analyses will be conducted on either EAS1 or EAS2, and 
the safety analysis 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. 
Unless otherwise stated, the other secondary and tertiary efficacy measures will be analyzed on 
EAS2 using the data up to the discontinuation of LY3209590 or insulin degludec, defined by the 
date of last study dose +10 days or the initiation of rescue medication whichever is earlier. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
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9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis 
The primary objective is to compare the HbA1c change from baseline to Week 26 (Visit 22) 
between LY3209590 and insulin degludec and will be based on either of the 2 estimands  
treatment regimen estimand for the US FDA submission, and  
efficacy estimand for registrations in other countries 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 (Visit 22) from the EAS1 regardless of the use of LY3209590 or insulin degludec or rescue 
medication.  
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 degludec prior to Week 26 (Visit 22) but have non-missing measures at 
Week 26 (Visit 22).  
If there are only a limited number of retrieved participants that leads to a failure in performing 
the multiple imputation analysis, such as the model cannot converge, or the number of retrieved 
dropout participants is small, the missing HbA1c at Week 26 (Visit 22) will be imputed by 
return-to-baseline multiple imputations.  
Analysis model 
After the imputation, the observed and imputed data will be analyzed by the ANCOVA.  
The model will include treatment, strata (country, CGM use prior to study entry [yes/no], and 
carbohydrate counting for prandial insulin dosing [yes/no]), and baseline value of the dependent 
variable (HbA1c). 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 (Visit 22) 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 LY3209590 or insulin degludec 
or use of rescue medication. The MMRM model will be used, and the missing values will be 
handled implicitly in the MMRM analysis under the assumption of missing at random.  
Analysis model 
The MMRM model will include treatment, strata (country, CGM use prior to study entry 
[yes/no], and carbohydrate counting for prandial insulin dosing [yes/no]), visit and treatment-by-
visit interaction as fixed effects, and baseline of the dependent variable (HbA1c) as a covariate.  
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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 and treatment LS mean 
difference for the HbA1c change from baseline to Week 26 (Visit 22) will be estimated. For both 
estimands, LY3209590 will be declared noninferior to insulin degludec if the upper limit of the 
2-sided 95% CI for the LS mean difference in the HbA1c change from baseline is below NIM 
(+0.4% or +0.3% for different regulatory requirements). 
The HbA1c is reported in % units and will be converted to mmol/mol using this 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 degludec for  
 change in HbA1c from baseline to Week 26 (Visit 22) 
 time in normal glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) 
inclusive, measured by CGM 4 weeks prior to Week 26 (Visit 22), and 
 event rate of participant-reported clinically significant nocturnal hypoglycemia (<54 
mg/dL [3.0 mmol/L] or severe) during treatment phase up to Week 52 (Visit 29). 
The superiority test in change from baseline to Week 26 (Visit 22) in HbA1c will be based on the 
same primary endpoint analysis methods as described above. 
The rate of nocturnal hypoglycemia will be analyzed by a negative binomial regression with 
treatment, baseline HbA1c, baseline incidence of nocturnal hypoglycemia, and carbohydrate 
counting for prandial insulin dosing (yes/no) as independent variables, and log (exposure in year) 
as the offset. 
The time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive measured 
by CGM will be analyzed using an ANCOVA model for treatment regimen estimand (using data 
from EAS1) and an MMRM model for efficacy estimand (using data from EAS2).  
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In the ANCOVA model, treatment, strata (country, baseline HbA1c stratum [<8.0%, ≥8.0%], 
CGM use prior to study entry [yes/no], and carbohydrate counting for prandial insulin dosing 
[yes/no]), and baseline of the dependent variable will be used.  
The MMRM model will include treatment, strata (country, baseline HbA1c stratum [<8.0%, 
≥8.0%], CGM use prior to study entry [yes/no], and carbohydrate counting for prandial insulin 
dosing [yes/no]), visit and treatment-by-visit interaction as fixed effects, and baseline of the 
dependent variable as a covariate.  
For treatment regimen estimand, the missing data will be imputed by multiple imputation with 
the approach similar to the imputation used for the primary endpoint. 
9.3.3.2. 
Other Secondary Endpoints 
Other secondary endpoints include various measures for efficacy, safety, and patient-reported 
outcome questionnaires.  
Efficacy measures and patient-reported questionnaires will be analyzed using the EAS2 unless 
otherwise noted.  
Safety measures will be analyzed using the SS regardless of LY3209590 or insulin degludec 
discontinuation and use of rescue medications. 
Analysis details will be provided in the SAP. 
9.3.4. 
Tertiary Endpoints Analysis 
Refer to the SAP for analyses related to tertiary endpoints. 
9.3.5. 
Safety Analyses 
Safety measures include  
 treatment exposure 
 AE 
 vital signs 
 weight 
 hypoglycemia 
 laboratory measures and  
 immunogenicity. 
All safety analyses will be based on the SS. 
Events that are newly reported after the first dose of LY3209590 or insulin degludec or reported 
to worsen in severity from baseline will be considered TEAEs. The Medical Dictionary for 
Regulatory Activities lowest level term will be used in the treatment-emergent assessment. The 
maximum severity for each lowest level term during the baseline period will be used as baseline 
severity.  
Summary statistics will be provided for incidence of 
 TEAEs 
 SAEs 
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 study discontinuation due to AEs 
 intervention discontinuation due to AEs, and 
 deaths. 
For continuous safety variables, such as laboratory measures, vital signs, and weight, the 
MMRM or ANCOVA models will be used.  
For categorical safety variables, such as AEs, incidence of hypoglycemia, treatment-emergent 
abnormal laboratory measurements, either the Fisher’s exact test or logistic regression will be 
used for treatment comparison. 
Hypoglycemia analysis 
The participant-reported hypoglycemia will be analyzed using data from the e-diary by  
 Level 1 (defined by glucose value ≥ 54 to < 70 mg/dL [3.0 to 3.9 mmol/L])  
 Level 2 (defined by glucose < 54 mg/dL [3.0 mmol/L])  
 Level 3 (severe hypoglycemia), and  
 the composite of Levels 2 and 3.  
The analysis periods of 0 to 6, 0 to 12, 0 to 26, 0 to 52, 12 to 26, and 26 to 52 weeks of treatment 
will be considered. Documented hypoglycemia will be defined as 
 All documented hypoglycemia - episodes for the 24-hour period  
 Non-nocturnal hypoglycemia - episodes during 6 AM to midnight, and 
 Nocturnal hypoglycemia - episodes during midnight to 6 AM. 
The incidence and rate of hypoglycemia will be summarized by treatment and analysis period for 
different types of hypoglycemia. 
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-LY3209590-antibody (ADA) status (detected or not detected) will be 
summarized by treatment for the participants evaluable for TEADA defined as participants with 
non-missing baseline and at least 1 non-missing postbaseline measurement. 
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The number and percentage of participants who are TEADA+ will be summarized by treatment 
group.  
The frequency of cross-reactive binding to endogenous insulins may also be summarized for the 
participants with TEADA+. 
The relationship between the presence of TEADA and the safety and efficacy measures may be 
assessed. 
Definition of TEADA+ 
A participant is considered TEADA+ if either treatment-induced ADA or treatment-boosted 
ADA 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.  
9.4. 
Interim Analysis  
A program-level safety review using selected efficacy and safety data will be conducted on a 
periodic basis across all ongoing Phase 3 clinical trials evaluating LY3209590. The analysis will 
be performed using the unblinded data and be reviewed by the DMC consisting of experienced 
members external to Lilly (Section 10.1.5). 
Study team personnel will remain blinded. Detailed information for the data review and the 
unblinding are specified in the DMC Charter or a separate unblinding plan document.  
9.5. 
Sample Size Determination 
Approximately 670 participants will be randomized to LY3209590 and insulin degludec in a 1:1 
ratio. With the assumption of 15% dropout at Week 26, approximately 284 and 284 participants 
will complete 26 weeks of treatment on LY3209590 and insulin degludec, respectively.  
The primary objective of this study is to test the hypothesis that LY3209590 is noninferior to 
insulin degludec on glycemic control as measured by change from baseline to Visit 22 (Week 
26) in HbA1c in participants with T1D currently basal-bolus insulin.  
Assuming an NIM of 0.4%, no true difference between treatment groups, and an SD of 1.1%, 
568 completers (284 on LY3209590 and 284 on insulin degludec) will provide at least 99% 
statistical power to show noninferiority between LY3209590 and insulin degludec using the 
upper limit of a 2-sided 95% CI (LY3209590 – insulin degludec). This sample size also has at 
least 90% statistical power to show noninferiority between LY3209590 and insulin degludec 
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 degludec) of change in HbA1c from baseline to 26 weeks (assuming an 
SD of 1.1% and true mean difference is -0.3%) using the alpha of 0.05. 
The 568 completers will provide at least 99% statistical power to show the superiority of the 
percentage of time in glucose range between 70 and 180 mg/dL (3.9 and 10.0 mmol/L) inclusive 
measured by CGM 4 weeks prior to Week 26 between LY3209590 and insulin degludec 
(assuming an SD of 10% and true mean difference is 5%) at alpha = 0.05. 
The 568 completers will provide 80% statistical power to show the superiority of the event rate 
of clinically significant nocturnal hypoglycemia (<54 mg/dL [3.0 mmol/L] or severe) during 
treatment phase up to Week 52 (assuming event rate of 3.37 [SD = 7.13] and 4.87 [SD = 7.13] 
events per participant per year for LY3209590 and insulin degludec, respectively) using a 
negative binomial distribution at alpha = 0.05. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
○ Applicable ICH Good Clinical Practice (GCP) Guidelines 
○ International Organization for Standardization (ISO) 14155 
○ Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (for example, advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations, and 
o Reporting significant issues related to participant safety, participant rights, or data 
integrity. 
Investigator sites are compensated for participation in the study as detailed in the clinical 
trial agreement. 
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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 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant and is kept on file. 
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records, 
datasets or tissue samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
The participant must be informed that the participant’s personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent.  
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor has processes in place to ensure data protection, information security and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach. 
 
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10.1.5. 
Committees Structure 
10.1.5.1. Internal Safety Review Team 
Participant safety will be continuously monitored by the sponsor’s internal safety review team, 
which includes safety signal detection at any time during the study. 
All safety data collected will be summarized and reviewed by the sponsor’s internal safety 
review team for agreement of next steps. 
10.1.5.2. Clinical Event Committee for Adjudication of Events 
A blinded Clinical Event Committee, external to Lilly, will adjudicate 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 analysis. 
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. 
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Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
Data and documents, including the study protocol, statistical analysis plan, 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. 
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Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the Clinical Trial 
Agreement (CTA) unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
In addition, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by Sponsor or its representatives, and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs. 
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 electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture 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 data (participant-focused outcome 
instrument) will be directly recorded by the participant, into an instrument, for example, hand 
held smart phone or tablet. The electronic Clinical Outcome Assessment data will serve as the 
source documentation, and the investigator does not maintain a separate written or electronic 
record of these data. 
Data storage and access 
Data collected via the sponsor-provided data capture systems will be stored at third parties.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture systems. Prior to decommissioning, the investigator will 
receive or access an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the Sponsor data 
warehouse. 
Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
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. 
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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 Section 10.1.7. 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or Site Termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
● Discontinuation of further study intervention development 
For site termination: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
● 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. 
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10.1.11. 
Investigator Information 
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
 
 
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10.1.12. 
Sample Retention 
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3209590 or after LY3209590 become(s) commercially available. 
Sample Type 
Custodian 
Maximum Retention Period after Last Patient 
Visita 
Exploratory biomarkers 
Sponsor or designee 
15 years 
Pharmacokinetic 
Sponsor or designee 
1 year 
Immunogenicity 
Sponsor or designee 
15 years 
a  Sample retention periods may differ dependent upon local regulations.  
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in the table below will be performed by the Lilly-designated laboratory 
or 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 a Lilly-designated laboratory 
Hemoglobin 
 
Hematocrit 
 
Erythrocyte count (RBCs - red blood cells) 
 
Mean cell volume  
 
Mean cell hemoglobin 
 
Mean cell hemoglobin concentration  
 
Leukocytes (WBCs - white blood cells)  
 
Differential 
 
Percent and absolute count of: 
 
    Neutrophils, segmented 
 
    Lymphocytes 
 
    Monocytes 
 
    Eosinophils 
 
    Basophils 
 
Platelets 
 
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
Alanine aminotransferase (ALT) 
  
Aspartate aminotransferase (AST) 
  
Gamma-glutamyl transferase (GGT) 
  
Blood urea nitrogen (BUN) 
  
Creatinine  
  
Uric acid 
  
Total protein 
  
Albumin 
  
Calcium 
  
Phosphorus 
  
Glucose  
 Fasting or random (refer to SOA) 
Cholesterol  
  
Triglycerides 
  
Lipid Panel 
Assayed by Lilly-designated laboratory 
High-density lipoprotein (HDL) 
  
Low-density lipoprotein (LDL-C) 
This value will be calculated. If triglycerides >400 
mg/dL, the direct LDL will be assayed 
Very low-density lipoprotein (VLDL-C) 
  
Urinalysis 
Assayed by Lilly-designated laboratory 
Specific gravity 
  
pH 
  
Protein 
  
Glucose 
  
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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 
  
Glucose 
Fasting per SOA 
HbA1c 
  
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  
  
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event 
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory tests results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
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Timing 
Sample Type 
Laboratory Testa 
Collect from 30 min to 4 hr after the 
start of the event.  
Note: The optimal collection time 
is from 1 to 2 hours 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 hours after the start 
of the event. 
Serum 
LY3209590 anti-drug antibodies (ADA) 
Plasma 
LY3209590 concentration 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
Information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
 The definitions and procedures detailed in this appendix are in accordance with 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. See definitions in Section 10.8. 
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
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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 pre-existing 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 pre-existing 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 a SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB for LY3209590 and the Product Information 
for degludec 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 a 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 a 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 a 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 a SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Women of childbearing potential 
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.  
Women not of childbearing potential 
Females are considered women not of childbearing potential if 
 they have a congenital anomaly such as Mullerian agenesis 
 they are infertile due to surgical sterilization, or  
 they are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-oophorectomy, 
bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal 
The postmenopausal state should be defined as 
 A woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, confirmed by operative note 
OR  
 A woman at least 40 years of age and up to 55 years old with an intact uterus, not on 
hormone 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 years of age or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea  
OR 
 A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone replacement therapy. 
a Women should not be taking medications during amenorrhea, such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, SERMs, or chemotherapy that could 
induce transient amenorrhea. 
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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.  
 
 
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Methods of contraception for women of childbearing potential 
Methods 
Examples 
Highly effective contraception (less than 1% 
failure rate) 
 
combination oral contraceptive pill  
 
progestin-only contraceptive pill (mini-
pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide 
Note: The barrier method must include use of a 
spermicide (that is, condom with spermicide, 
diaphragm with spermicide, or female condom 
with spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone  
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, cervical mucus, or 
symptothermal) 
 
withdrawal 
 
post coital douche, or 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic Evaluation Testing 
See Section 8.2.5 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
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    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a 
    HBV DNAb 
Anti-actin antibodyc 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNAb 
    EBV DNAb 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNAb 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody 
    HEV RNAb 
    HSV (Type 1 and 2) DNAb 
Microbiologyd 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
    Blood 
 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Reflex or confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 
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10.6. Appendix 6: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device Deficiencies: 
Definition and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
Refer to Appendix 3 for definitions and procedures for recording, evaluating, follow-up, and 
reporting of all events.  
 
 
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10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
After approval by local Ethical Review Boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required, for example, upon implementation and suspension of changes. All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
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The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments according to the SoA, if written approval is provided by the 
sponsor.  
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor.  
Other alternative locations: Laboratory draws may be done at an alternate location in exceptional 
circumstances, if written approval is provided by the sponsor.  
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing, except for HbA1c 
and serum glucose testing. Lilly-designated laboratory testing must be retained for HbA1c and 
serum glucose.  
The local laboratory must be qualified in accordance with applicable local regulations. 
Obtain local labs for safety hematology, chemistry, hormone panel, and urinalysis, when 
applicable, per the SoA. Safety labs should be obtained as specified in the SoA. 
All labs will be reviewed by the investigators. Sign and date review of local labs per normal 
process and follow up with the participant as needed. Results will not be recorded in the eCRF. 
Lilly Medical should be informed of any labs that meet criteria for temporary or permanent study 
intervention discontinuation. 
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Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site, for example, 
participant’s home, the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality, that is, storage 
conditions maintained and intact packaging upon receipt. 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening or the lead-in visits are valid for a maximum of 24 days. The following rules will be 
applied for active, nonrandomized participants whose participation in the study must be paused 
due to exceptional circumstances: 
 If screening is paused for less than 24 days from the signing of the ICF to the 
randomization visit, the participant will proceed to the next study visit per the usual 
SoA, provided that the randomization visit is conducted within 30 days from first 
screening.  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 24 days from signing of the ICF to the 
randomization visit, the participant must be discontinued because of screening 
interruption due to an exceptional circumstance. This is documented as a screen 
failure in the CRF. The participant can reconsent and be rescreened as a new 
participant. The screening procedures per the usual SoA should be followed, starting 
at the screening visit to ensure participant eligibility by the randomization visit. 
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Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
The primary endpoint visit, Visit 22 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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10.8. 
Appendix 8: Abbreviations and Definitions 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
antidrug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal 
product, which is used as an investigational medicinal product 
authorized AxMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal 
product, which is used as an auxiliary medicinal product 
AxMP 
Auxiliary medicinal product. See also NIMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. AxMP does not include investigational medicinal product (IMP) or 
concomitant medications. Concomitant medications are medications unrelated to the 
clinical trial and not relevant for the design of the clinical trial 
BG 
blood glucose 
CGM 
continuous glucose monitoring 
CGM-derived variables may include 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  
CI 
confidence interval 
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. 
DMC 
data monitoring committee: a data monitoring committee or data monitoring board 
(DMB) is a group of independent scientists who are appointed to monitor the safety 
and scientific integrity of a human research intervention, and to make 
recommendations to the sponsor regarding the stopping of a study for efficacy, or for 
harms, or for futility. The composition of the committee is dependent upon the 
scientific skills and knowledge required for monitoring the particular study 
Device deficiencies 
equivalent to product complaint 
EAS1 
Efficacy Analysis Set 1 
EAS2 
Efficacy Analysis Set 2 
ECG 
electrocardiogram 
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 
eGFR (CKD-EPI) 
estimated glomerular filtration rate (chronic kidney disease epidemiology 
collaboration) 
FBG 
fasting blood glucose 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
HbA1c 
hemoglobin A1c 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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 
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informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created or locked 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. See also “IMP.” 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
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 
LS 
least-squares 
MDI 
multiple daily injection 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involves a failure to uphold one or 
more of the 5 “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling, for example, Summary of Product Characteristics, IB, local 
label, and protocol, or 
• shared use of cartridges, prefilled pens, or both 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MMRM 
mixed-model repeated measures 
NIM 
noninferiority margin 
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NIMP 
Non-investigational Medicinal Product. See AxMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment 
participant 
equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK/PD 
pharmacokinetics/pharmacodynamics 
PPS 
per-protocol set: the set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
QTc 
corrected QT interval 
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 
SERM 
selective estrogen receptor modulator 
SMBG 
self-monitoring of blood glucose 
T1D 
Type 1 diabetes 
T2D 
Type 2 diabetes 
TBL 
total bilirubin level 
TEADA 
treatment-emergent antidrug 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 
 
 
 
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10.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment (b): 21-June-2022  
Overall Rationale for the Amendment: 
The primary rationale for the current amendment is to address the change in the study continuous 
glucose monitoring (CGM) system. The unblinded CGM receiver will be used. These and other 
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 
Section 1.3 Schedule 
of Activities (SoA) 
Thirteen telehealth visits have been 
changed to in-office visits and Visit 
Interval Tolerance (days) have been 
changed from ±7 to ±3 in Table 1.3.2.  
To accommodate CGM 
data downloads 
 
Added new activity row to SoA stating to 
“Download and review CGM data in study 
vendor portal” 
Added to prompt sites to 
capture CGM data 
 
Deleted word “review” from the activity 
“Review and discuss CGM and 
hypoglycemia data” 
For clarity 
 
Updated “Dispense of CGM supplies” 
schedule to include each in-office visit and 
Visit 801 
To align with the revised 
in-office visit schedule 
 
Deleted “mobile device” from activity 
“Return CGM mobile device” and added 
the term “receiver” 
The term “mobile 
device” is no longer 
appropriate 
 
Updated “Dispense glucometer supplies as 
needed”  
To align with “dispense 
study intervention” 
activity schedule 
 
Updated “Dispense ancillary supplies as 
needed”  
To align with “dispense 
study intervention” 
activity schedule  
 
Updated schedules in activities “Dispense 
study intervention and in Participant 
returns unused intervention and supplies  
To reduce the longer visit 
intervals to 4 weeks for 
study intervention 
dispensing 
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Section 2.3.1 Risk 
Assessment 
Added text “to download and” 
For clarification 
Deleted text “at any time throughout the 
study” 
Text is no longer 
applicable 
Section 3 
Objectives, 
Endpoints, and 
Estimands 
Deleted text “Potential intrinsic and 
extrinsic factors” from tertiary endpoints 
for PK/PD of LY3209590 
Error correction 
Section 8.1.1.2 
Continuous glucose 
monitoring (CGM) 
system 
Edited text to describe use of the unblinded 
CGM receiver 
To address change in 
CGM strategy to use 
unblinded CGM 
receivers 
Section 8.3.6 
Hypoglycemia 
Deleted text “at any time” 
No longer applicable 
Section 10.2.1 
Laboratory Samples 
to be Obtained at the 
Time of Systemic 
Hypersensitivity 
Event 
Changed complements sample type to 
“Serum/Plasma” 
Correction-serum and 
plasma are used in this 
series of tests 
 
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, rescue medication, and stratification factors. These and 
other 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 
1.1. Synopsis 
In Other Secondary endpoints for first 
objective, deleted Week 26. 
Redundant; Week 
26 is already an 
endpoint of Key 
Secondary. 
3. Objectives, 
Endpoints, and 
Estimands 
In Other Secondary endpoints for first 
objective, deleted Week 26. 
Redundant; Week 
26 is already an 
endpoint of Key 
Secondary. 
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3. Objectives, 
Endpoints, and 
Estimands 
In Primary estimand subsection, United States 
registration, added text in primary clinical 
question to clarify “study eligible” 
participants, use of MDI, and potential rescue 
therapy.   
For clarity. 
3. Objectives, 
Endpoints, and 
Estimands 
Edited Treatment regimen estimand attributes 
table 
- Population: added cross reference to 
Section 9.2, and removed other cross 
references 
- Remaining intercurrent events: inserted text 
for initiation of rescue medication 
- Treatment condition: inserted text for use 
of rescue medications 
For clarity and to 
address regulator 
feedback. 
3. Objectives, 
Endpoints, and 
Estimands 
In Primary estimand section, Registration for 
countries outside the United States, added text 
in primary clinical question of interest to 
clarify “study eligible” participants and use of 
MDI therapy.   
For clarity. 
3. Objectives, 
Endpoints, and 
Estimands 
Edited Efficacy estimand attributes table 
- Population: added cross reference to 
Section 9.2, and removed other cross 
references 
- Remaining intercurrent events: inserted text 
for initiation of rescue medication 
For clarity and to 
address regulator 
feedback. 
3. Objectives, 
Endpoints, and 
Estimands 
In Rationale for the efficacy estimand 
subsection, added text addressing confounding 
effect of rescue medications. 
For clarity and to 
address regulator 
feedback. 
5.1. Inclusion Criteria 
In inclusion criterion 3, added “as determined 
by the central laboratory”. 
For clarity. 
5.1. Inclusion Criteria 
In inclusion criterion 4, added trademark 
information. 
For clarity. 
5.2. Exclusion Criteria 
In exclusion criterion 17, corrected “of” to 
“or” in “obvious clinical signs or symptoms of 
any other liver disease” 
Error correction. 
5.2. Exclusion Criteria 
In exclusion criterion 17, ALT and AST 
thresholds were increased from 2.5x ULN to 
3x ULN. 
Addressing 
regulator 
feedback. 
5.2. Exclusion Criteria 
In exclusion criterion 36, added wording “after 
having signed the informed consent form 
For clarity. 
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(ICF)” and “after receiving at least 1 dose of 
the study basal insulin”.  
6.1.3. Rescue Therapy 
for Management of 
Participants with 
Severe, Persistent 
Hyperglycemia during 
the Treatment Period 
Added new subsection and content for 
management of severe, persistent 
hyperglycemia. 
Addressing 
regulator 
feedback. 
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
In the Randomization and stratification 
subsection, replaced the stratification factor 
“prestudy basal insulin treatment with insulin 
glargine U-300 or other basal insulin” with a 
new stratification factor “CGM use prior to 
study entry (yes/no)”.  
Addressing 
regulator 
feedback. 
6.5.2.1. LY3209590 
Dose Initiation and 
Modification 
Corrected “30” to “29” in subheading for 
“Visits 5 to 29 (Weeks 2 to 52) weekly 
dosing”. 
Error correction. 
6.5.2.2. Insulin 
Degludec Dose 
Initiation and 
Modification 
Corrected “30” to “29” in subheading for 
“Visits 4 to 29 (Weeks 1 to 52)”. 
Error correction. 
6.8. Concomitant 
Therapy 
In Excluded concomitant medications, 
Exceptions, added “Note: Participants who 
require treatment with non-study basal insulins 
as rescue therapy for management of severe or 
persistent hyperglycemia as outlined in 
Section 6.1.3., must discontinue study basal 
insulin therapy (LY3209590 or insulin 
degludec). The participant will remain in the 
study and follow procedures for the remaining 
study visits”. 
For clarity. 
9. Statistical 
Considerations 
Made updates to endpoint word order 
throughout section and subsections. 
For clarity. 
9.2. Analyses Sets 
Updated the analysis populations/sets. 
To meet the 
anticipated 
requirement for 
excluding 
inadvertently 
enrolled 
participants in 
some countries. 
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I8H-MC-BDCY(c) 
124 
9.3. Statistical Analyses 
Made updates throughout section and 
subsections according to changes in analysis 
sets table. 
As in Section 9.2, 
and for clarity. 
9.3.1. General 
Considerations 
In the fourth paragraph, inserted text regarding 
the initiation of rescue medication. 
Addressing 
regulator 
feedback. 
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis 
In Treatment regimen estimand subsection, 
added text “or rescue medication”. 
For clarity. 
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis 
Replaced the stratification factor “prestudy 
basal insulin glargine U-300 or other basal 
insulin” with a new stratification factor “CGM 
use prior to study entry [yes/no]” in ANCOVA 
and MMRM models. 
Related to change 
in stratification 
factor in Section 
6.3 to address 
regulator 
feedback. 
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis 
In the Efficacy estimand, Missing measures 
subsection, replaced “imputed” with 
“handled”. 
For clarity. 
9.3.2. Primary 
Endpoint(s)/Estimand(s) 
Analysis 
In the Treatment regimen Estimand 
subsection, and in the Efficacy estimand 
Missing measures subsection, added text 
regarding rescue medication. 
Addressing 
regulator 
feedback. 
9.3.3.1. Multiplicity 
Adjusted Endpoints 
Replaced the stratification factor “prestudy 
basal insulin glargine U-300 or other basal 
insulin” with a new stratification factor “CGM 
use prior to study entry [yes/no]” use in 
ANCOVA and MMRM models. 
Related to change 
in stratification 
factor in Section 
6.3 to address 
regulator 
feedback. 
9.3.3.2. Other 
Secondary Endpoints 
Added text regarding rescue medication. 
Addressing 
regulator 
feedback. 
9.3.5. Safety Analyses 
Removed inadvertently hidden text format 
applied to hypoglycemia time period 
definitions. 
Error correction. 
10.8. Appendix 8: 
Abbreviations and 
Definitions 
Under CGM term, added a list of possible 
CGM-derived variables. 
Addressing 
regulator 
feedback. 
Throughout protocol 
Following glucose values in units of mg/dL, 
added corresponding values in mmol/L. 
For clarity. 
 
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11. 
References 
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compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a treat-
to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial. 
Diabet Med. 2008;25:442-449. https://doi.org/10.1111/j.1464-5491.2007.02407.x 
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://www.doi.org/10.2337/dc07-2137 
Bolli GB, Kerr D, Reena T, et al. Comparison of a multiple daily insulin injection regime (basal 
once-daily glargine plus mealtime lispro) and CSII (lispro) in Type 1 diabetes: a randomized 
open parallel multicenter study. Diabet Care. 2009;32:1170-1176. 
https://www.doi.org/10.2337/dc08-1874 
Bradley C. Diabetes Treatment Satisfaction Questionnaire: Change version for use alongside 
status version provides appropriate solution where ceiling effects occur. Diabet Care. 
1999;22(3):530-532. https://doi.org/10.2337/diacare.22.3.530 
Bradley C, editor. Handbook of psychology and diabetes: a guide to psychological measurement 
in diabetes research and practice. Harwood Academic Publishers; 1994.  
Bradley C, Lewis KS. Measures of psychological well-being and treatment satisfaction 
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Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective multiple 
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Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison procedures 
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EuroQol Research Foundation. EQ-5D-5L user guide, version 3.0. Updated September 2019. 
Accessed 04 March 2022. https://euroqol.org/publications/user-guides 
Holt R, DeVries J, Hess-Fischl A. The management of type 1 diabetes in adults. A consensus 
report by the American Diabetes Association (ADA) and the European Association for the Study 
of Diabetes (EASD). Diabetes Care. 2021;44(11):2589-2625. https://doi.org/10.2337/dci21-0043 
Maruish ME, editor. User’s Manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality 
Metric Incorporated; 2011. 
[NGSP] National Glycohemoglobin Standardization Program. IFCC Standardization of HbA1c. 
Accessed February 22, 2022. http://www.ngsp.org/ifccngsp.asp 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley; 1987.  
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