Conditions: Type 2 Diabetes Diabetes Mellitus, Type 2
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 152
Healthy volunteers: no

Brief summary:
The main purpose of this study is to investigate the effects of switching from glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy to tirzepatide glucose-dependent insulinotropic polypeptide (GIP) GLP-1 RA agonist in participants with type 2 diabetes (T2D).

Detailed description:

Arms:
arm 1: Participants received 5 mg tirzepatide subcutaneously administered once weekly for 12 weeks.

Interventions: intervention 1: Tirzepatide
Intervention descriptions: intervention 1: Administered SC

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol I8F-MC-GPIL 
 
An Open-Label, Single-Arm, Phase 4 Study to Assess Glycemic Control When Adults with Type 2 
Diabetes Switch from a GLP-1 RA to Tirzepatide (SURPASS-SWITCH-2) 
 
 
NCT05706506 
 
 
Approval Date: 26-Aug-2022 
 
 
 
 
 
 


CONFIDENTIAL 
I8F-MC-GPIL 
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 tirzepatide (LY3298176), 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: An Open-Label, Single-Arm, Phase 4 Study to Assess Glycemic Control When 
Adults with Type 2 Diabetes Switch from a GLP-1 RA to Tirzepatide (SURPASS-SWITCH-2) 
Protocol Number: I8F-MC-GPIL 
Amendment Number: This is the initial protocol. 
Compound: LY3298176 
Brief Title: A study to investigate glycemic control in adults with type 2 diabetes switching to 
tirzepatide from a GLP-1 RA 
Study Phase: 4 
Acronym: SURPASS-SWITCH-2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 128801 
EudraCT: 2022-002708-18 
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below. 
Document ID: VV-CLIN-067244 
 
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2 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
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CONFIDENTIAL 
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3 
Table of Contents 
1. 
Protocol Summary ..........................................................................................................6 
1.1. 
Synopsis ............................................................................................................................6 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ..........................................................................................12 
2. 
Introduction ...................................................................................................................22 
2.1. 
Study Rationale ...............................................................................................................22 
2.2. 
Background .....................................................................................................................22 
2.3. 
Benefit/Risk Assessment ................................................................................................23 
2.3.1. 
Risk Assessment .............................................................................................................23 
2.3.2. 
Benefit Assessment .........................................................................................................23 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................23 
3. 
Objectives, Endpoints, and Estimands .......................................................................25 
4. 
Study Design ..................................................................................................................27 
4.1. 
Overall Design ................................................................................................................27 
4.1.1. 
Design Outline ................................................................................................................27 
4.2. 
Scientific Rationale for Study Design ............................................................................28 
4.3. 
Justification for Dose ......................................................................................................28 
4.4. 
End of Study Definition ..................................................................................................29 
5. 
Study Population ...........................................................................................................30 
5.1. 
Inclusion Criteria ............................................................................................................30 
5.2. 
Exclusion Criteria ...........................................................................................................31 
5.3. 
Lifestyle Considerations .................................................................................................33 
5.4. 
Screen Failures ................................................................................................................33 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................33 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................34 
6.1. 
Study Intervention(s) Administered................................................................................34 
6.1.1. 
Medical Devices..............................................................................................................35 
6.1.2. 
Rescue Therapy ...............................................................................................................35 
6.1.3. 
Background Therapy .......................................................................................................35 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................36 
6.4. 
Study Intervention Compliance ......................................................................................36 
6.5. 
Dose Modification ..........................................................................................................36 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms .......................................36 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................37 
6.7. 
Treatment of Overdose ...................................................................................................37 
6.7.1. 
Tirzepatide Overdose ......................................................................................................37 
6.8. 
Prior and Concomitant Therapy ......................................................................................37 
6.8.1. 
Allowed Concomitant Therapy .......................................................................................37 
6.8.2. 
Changing Concomitant Therapy .....................................................................................38 
6.8.3. 
Concomitant Therapy Data Collection ...........................................................................38 
6.8.4. 
Prohibited Concomitant Medications .............................................................................38 
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4 
6.8.5. 
Allowed Antihyperglycemic Treatments other than Tirzepatide ....................................38 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................39 
7.1. 
Discontinuation of Study Intervention ............................................................................39 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................40 
7.1.2. 
Temporary Discontinuation of Study Intervention .........................................................41 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................42 
7.3. 
Lost to Follow-Up ...........................................................................................................42 
8. 
Study Assessments and Procedures.............................................................................43 
8.1. 
Efficacy Assessments .....................................................................................................43 
8.1.1. 
Self-Monitoring of Blood Glucose (SMBG) ..................................................................43 
8.1.2. 
Continuous Glucose Monitoring .....................................................................................44 
8.2. 
Safety Assessments .........................................................................................................45 
8.2.1. 
Physical Examinations ....................................................................................................45 
8.2.2. 
Vital Signs .......................................................................................................................46 
8.2.3. 
Electrocardiograms .........................................................................................................46 
8.2.4. 
Dilated Fundoscopic Examination ..................................................................................46 
8.2.5. 
Clinical Safety Laboratory Tests ....................................................................................46 
8.2.6. 
Pregnancy Testing ...........................................................................................................47 
8.2.7. 
Hepatic Monitoring .........................................................................................................47 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................50 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................51 
8.3.2. 
Pregnancy ........................................................................................................................53 
8.3.3. 
Safety Topics of Special Interest ....................................................................................54 
8.4. 
Pharmacokinetics ............................................................................................................57 
8.5. 
Pharmacodynamics .........................................................................................................57 
8.6. 
Genetics ..........................................................................................................................57 
8.7. 
Biomarkers ......................................................................................................................58 
8.8. 
Immunogenicity Assessments.........................................................................................58 
8.9. 
Health Economics ...........................................................................................................58 
9. 
Statistical Considerations .............................................................................................59 
9.1. 
Statistical Hypotheses .....................................................................................................59 
9.2. 
Analyses Sets ..................................................................................................................59 
9.3. 
Statistical Analyses .........................................................................................................59 
9.3.1. 
General Considerations ...................................................................................................59 
9.3.2. 
Primary Endpoint Analysis .............................................................................................60 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................60 
9.3.4. 
Exploratory Endpoints Analysis .....................................................................................60 
9.3.5. 
Safety Analyses ...............................................................................................................60 
9.3.6. 
Subgroup Analyses .........................................................................................................61 
9.4. 
Interim Analysis ..............................................................................................................62 
9.5. 
Sample Size Determination ............................................................................................62 
10. 
Supporting Documentation and Operational Considerations ..................................63 
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5 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................63 
10.1.1. Regulatory and Ethical Considerations ...........................................................................63 
10.1.2. Financial Disclosure........................................................................................................64 
10.1.3. Informed Consent Process ..............................................................................................64 
10.1.4. Data Protection................................................................................................................64 
10.1.5. Committees Structure......................................................................................................65 
10.1.6. Dissemination of Clinical Study Data.............................................................................65 
10.1.7. Data Quality Assurance ..................................................................................................65 
10.1.8. Source Documents ..........................................................................................................67 
10.1.9. Study and Site Start and Closure ....................................................................................67 
10.1.10. Publication Policy ...........................................................................................................68 
10.1.11. Investigator Information .................................................................................................68 
10.1.12. Sample Retention ............................................................................................................68 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................69 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................71 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting ...........................................................................................................73 
10.3.1. Definition of AE .............................................................................................................73 
10.3.2. Definition of SAE ...........................................................................................................74 
10.3.3. Definition of Product Complaints ...................................................................................75 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................76 
10.3.5. Reporting of SAEs ..........................................................................................................77 
10.3.6. Regulatory Reporting Requirements ...............................................................................78 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................79 
10.4.1. Definitions.......................................................................................................................79 
10.4.2. Contraception Guidance..................................................................................................80 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................84 
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 ............................................................................86 
10.7. 
Appendix 7: Standardized Protocols for the Measurement of 
Height, Weight, Waist Circumference, BMI, and Vital Signs .......................................87 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................89 
10.9. 
Appendix 9: Abbreviations and Definitions ...................................................................93 
11. 
References ......................................................................................................................98 
 
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CONFIDENTIAL 
I8F-MC-GPIL 
6 
1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: An Open-Label, Single-Arm, Phase 4 Study to Assess Glycemic Control When 
Adults with Type 2 Diabetes Switch from a GLP-1 RA to Tirzepatide (SURPASS-SWITCH-2) 
Brief Title: A study to investigate glycemic control in adults with type 2 diabetes switching to 
tirzepatide from a GLP-1 RA 
Regulatory Agency Identifier Number(s): 
IND: 128801 
EudraCT: 2022-002708-18 
Rationale: 
No study has investigated the effects of switching from glucagon-like peptide-1 receptor agonist 
(GLP-1 RA) therapy to tirzepatide in people with type 2 diabetes (T2D). This study will inform 
providers on what to expect when switching from a GLP-1 RA to tirzepatide 5 mg but does not 
evaluate long-term efficacy, optimal dosing, or comparative improvement to other regimens. 
Prior exposure to a GLP-1 RA is associated with less frequent gastrointestinal (GI) intolerance 
when switching between GLP-1 RAs. Therefore, this study will describe an alternative way to 
switch from a GLP-1 RA to tirzepatide by using a starting dose of 5 mg and will evaluate 
changes in glycemic control, body weight, and GI tolerability occurring in the first 12 weeks for 
the targeted study population. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
To demonstrate that participants with T2D switching 
from a stable dose of GLP-1 RA to tirzepatide 5 mg 
QW have an improvement in HbA1c at Week 12 
compared to baseline  
 Change from baseline in HbA1c 
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7 
Secondary 
To evaluate the changes in CGM-assessed TAR from 
baseline at Week 4 and at Week 12 
Change from baseline in 
 Percentage of time per day that CGM-derived 
values are >180 mg/dl (10 mmol/L) 
 Duration of time in minutes per day that CGM-
derived values are >180 mg/dl (10 mmol/L) 
To evaluate the change in FSG from baseline at Week 
12 
 Change from baseline in FSG 
To evaluate the changes from baseline in weight at 
Week 12 
 Change from baseline in weight 
Abbreviations: CGM = continuous glucose monitoring; FSG = fasting serum glucose; GLP-1 RA = glucagon-like 
peptide-1 receptor agonist; HbA1c = hemoglobin A1c; QW = once-weekly; T2D = type-2 diabetes; TAR = time 
above range (>180 mg/dl or >10 mmol/L). 
The primary estimand in this study is the efficacy estimand. 
The efficacy estimand focuses on the treatment effect if participants continued to receive the 
study treatment without prohibited medication. This estimand will be used in publications to 
inform prescribers or physicians. 
Overall Design 
SURPASS-SWITCH-2 is an open-label, single-arm, multicenter, multinational, Phase 4 study to 
assess the changes in glycemic control when switching from a stable dose of a GLP-1 RA 
directly to tirzepatide 5 mg in participants with T2D. 
This study includes a screening period and a 12-week treatment period. 
Brief Summary: 
Period I: Screening 
Preparation for the switch from GLP-1 RA medication to tirzepatide 
&1.27?.<=20*=8;@255-.=.;627.=1.9*;=2,29*7=L<,>;;.7=#-1 RA medication administration 
schedule to ensure the correct timing for initiating tirzepatide 5 mg at Visit 2. 
Investigators should ensure that at least 12 days occur between Visit 1 and Visit 2 to allow for an 
adequate CGM data collection. 
Participants taking daily liraglutide at screening should continue taking liraglutide up to the day 
prior to Visit 2. 
Participants taking either weekly dulaglutide or semaglutide should take their last dose of GLP-1 
RA medication at least 3 days prior to Visit 2 but no more than 10 days prior to Visit 2. 
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CONFIDENTIAL 
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8 
Training for the study-supplied SMBG monitor and testing frequency recommendations will 
occur. Training for the CGM sensor and insertion device, including suggestions for successful 
device maintenance, will also occur in conjunction with the insertion of the CGM sensor for the 
baseline measurement session. 
Period II: Treatment period 
Visit 2 Treatment Initiation 
Participants arrive to the clinic in the fasting state. 
This is the general flow for Visit 2 
 Participant returns screening CGM sensor for compliance review and data upload 
 Study personnel confirm enrollment criteria 
 Study personnel complete all required visit procedures, including the collection of vital 
signs, all baseline procedures, and sample collection, and 
 Treatment initiation for eligible participants. 
Study intervention training 
Study personnel will provide appropriate training for use of the tirzepatide SDP. The training can 
be provided using a demonstration device, if available. This training will be repeated at 
subsequent visits, as needed. 
In addition, study personnel will provide product-<9.,2/2,J27<=;>,=287</8;><.K27/8;6*=287=8
the participants upon request, if available. 
First tirzepatide dose 
Study personnel will observe as the participant injects the first dose of tirzepatide. The remaining 
injections will occur at pa;=2,29*7=L<186. The date and time of the first dose of tirzepatide 
should be recorded on the CRF. Additionally, all medication doses administered at home should 
+.,*9=>;.-27,5>-270-*=.*7-=26.27=1.9*;=2,29*7=L<-2*;B*7-<>+<.:>.7=5B;.,8;-.-27 the 
CRF. 
Visit 5 (Week 12) Treatment Period or ED Visit 
&1.27?.<=20*=8;@255-.=.;627.*9*;=2,29*7=L<=;*7<2=287/;86<=>-B=;.*=6.7==8*78=1.;-2*+.=es 
treatment, including re-initiation of baseline GLP-1 RA. 
Study Population: 
In general, an individual may take part in the study if they 
 Are 18 years old or of an acceptable age to provide informed consent according to local 
regulations, whichever is older. 
 Have been diagnosed with T2D based on the World Health Organization classification or 
other locally applicable diagnostic standards. 
 *?.*7+,GG 6685	685=8F
F mmol/mol) as determined by the 
central laboratory at Visit 1 and in the opinion of investigator may benefit from 
tirzepatide based on individual patient needs. 
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9 
 Have been on a stable treatment dose of 1 of the listed GLP-$</8;G687=1<9;28;=8
Visit 1: 
o 
liraglutide 1.2 or 1.8 mg QD 
o 
dulaglutide 0.75, 1.5, 3, or 4.5 mg QW, or 
o 
injectable semaglutide 0.5, 1, or 2 mg QW 
 No treatment with oral antihyperglycemic medication (OAM) or on stable doses (for at 
least 3 months before Visit 1) of up to 3 OAM. The OAM may include metformin (at 
least 1000 mg/day), SGLT-2=12*C852-27.-287.<8;N-glucosidase inhibitors. 
 *?. G kg/m2 at Visit 1. 
 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 compliance with 
CGM sensor and insertion device. 
In general, an individual may not take part in the study if they 
 Have type 1 diabetes. 
 Have a history of chronic or acute pancreatitis any time prior to Visit 1. 
 Have a clinical history of 
o 
proliferative diabetic retinopathy 
o 
diabetic maculopathy, or 
o 
nonproliferative diabetic retinopathy that requires acute treatment. 
 Are at high risk for cardiovascular disease in =1.27?.<=20*=8;L<89272878;1*?.a history 
of any of these cardiovascular conditions within 60 days prior to Visit 1: 
o myocardial infarction 
o percutaneous coronary revascularization procedure 
o carotid stenting or surgical revascularization 
o nontraumatic amputation 
o peripheral vascular procedure (e.g., stenting or surgical revascularization) 
o cerebrovascular accident (stroke), or 
o hospitalization for congestive heart failure 
 Have New York Heart Association Functional Classification Class IV congestive heart 
failure. 
 Have a history of ketoacidosis or hyperosmolar state or coma. 
 Have a history of severe hypoglycemia or hypoglycemia unawareness within the 
6 months prior to Visit 1. 
Number of Participants: 
The study will enroll approximately 150 participants. 
Intervention Groups and Duration: 
Participants will be administered with tirzepatide 5 mg once-weekly by subcutaneous injection 
using a single-dose pen. 
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CONFIDENTIAL 
I8F-MC-GPIL 
10 
Ethical Considerations of Benefit/Risk: 
The safety information from the tirzepatide Phase 3 clinical studies is similar to the known safety 
information as the GLP-1 RA therapies. 
Participants may benefit by receiving personal health information, routine safety assessments, 
lifestyle management counseling, and frequent engagement with health care providers during the 
study, which provide opportunities for coaching and support. 
Considering the information available from previous completed clinical studies in people, and 
the measures taken to make sure the participants in this study are safe, the potential risks from 
taking tirzepatide are justified by the potential benefits for adults with T2D. 
Data Monitoring Committee: No 
 
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11 
1.2. 
Schema 
 
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12 
1.3. 
Schedule of Activities (SoA) 
Screening 
Visit 1 may be conducted over more than 1 day to ensure necessary conditions are met. 
Fasting visits 
Participants should fast at least 8 hours without eating, drinking (except water), or performing any significant physical activity before 
the visit. 
If a participant attends a fasting visit in the non-fasting state, the sample should still be collected, and reschedule the fasting laboratory 
sample collection. This will not be considered a protocol deviation. 
Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Informed consent 
X 
 
 
 
 
The informed consent form must be signed 
before any protocol-specific tests or 
procedures are performed. 
See Section 10.1.3 for additional details. 
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13 
Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Inclusion and exclusion criteria, review and 
confirm 
X 
X 
 
 
 
 
Confirm inclusion and exclusion criteria 
prior to administration of first dose of study 
intervention. 
Demographics 
X 
 
 
 
 
Includes ethnicity (where allowed), year of 
birth, sex, and race. 
Preexisting conditions and medical history, 
including relevant surgical history 
X 
 
 
 
 
 
Collect all conditions ongoing and relevant 
past surgical and medical history. 
Prior treatments for indication 
X 
 
 
 
 
Add details of T2D medication, which 
includes medications used for T2D since 
diagnosis. 
Substance use (alcohol, caffeine, tobacco use) 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
See Section 6.8. 
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14 
Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
AEs are any events that occur after signing 
the informed consent. Collect additional 
data for safety topics of special interest. See 
Section 8.3.3. 
Physical Evaluation 
Height 
X 
 
 
 
 
 
See Section 10.7, Appendix 7 
Weight 
X 
X 
X 
X 
X 
X 
See Section 10.7, Appendix 7 
Waist circumference 
X 
X 
X 
X 
X 
X 
See Section 10.7, Appendix 7 
Vital signs 
X 
X 
X 
X 
X 
X 
Include pulse rate and blood pressure. 
Measure after participant has been sitting 
for at least 5 min and before obtaining an 
ECG tracing and collection of blood 
samples for laboratory testing. See Section 
8.2.2. 
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15 
Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Physical examination 
X 
 
 
 
 
 
Excludes pelvic, rectal, and breast 
examinations unless clinically indicated. 
See Section 8.2.1. 
Symptom-directed physical assessment 
 
X 
Symptom-directed physical assessment will 
be conducted at the discretion of the PI or 
qualified personnel per local regulations, as 
indicated based on participant status and 
standard of care. 
12-lead ECG (local) 
X 
 
 
 
 
 
Collect ECG before blood sample collection 
for laboratory testing if these procedures 
occur at the same visit. Participants should 
be supine for approximately 5 to 10 min 
before ECG collections and remain supine 
but awake during the ECG collection. ECG 
6*B+.;.9.*=.-*==1.27?.<=20*=8;L<
discretion at any visit. See Section 8.2.3. 
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16 
Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Dilated fundoscopic examination (local) 
X 
 
 
 
 
 
An ophthalmologist or optometrist (if 
allowed by country) will perform the 
examination. Documentation of a previous 
examination F
-*B<9;28;=8<,;..72702<
acceptable to confirm eligibility. Document 
the previous examination results in CRF. 
See Section 8.2.4. 
Participant Education and Supplies 
Diabetes counseling, training, and education 
 
X 
 
 
 
 
Include counseling on diet and exercise, 
symptoms and management of 
hypoglycemia and hyperglycemia, etc. See 
Sections 5.3 and 8.3.3. After Visit 2, 
conduct as needed. 
BG meter, SMBG training 
X 
 
 
 
 
 
Train participant per provided instructions. 
Provide additional training as needed. 
Dispense BG meter/supplies 
X 
X 
X 
X 
 
 
Dispense additional supplies, as needed. 
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17 
Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Return BG meter/supplies 
 
 
 
 
X 
X 
CGM sensor and insertion kit (14-day) 
application, training, and education 
X 
 
 
 
 
 
Apply and provide instructions to 
participants for at-home insertion for future 
visits. Additional training may occur as 
needed. 
Dispense CGM sensor and insertion kit (14-
day) 
X 
X 
 
X 
 
 
Dispense CGM sensor and insertion kit and 
instruct participant on dates to collect 14-
day data prior to next scheduled visit. 
Dispense additional supplies if needed. 
CGM insertion reminder to participant 
 
 
X 
 
X 
 
Contact the participants as a reminder to 
place the CGM device 14 days prior to their 
scheduled visit. 
CGM sensor (14-day) return and data 
download  
 
X 
X 
 
X 
 
Site staff to collect at scheduled visit and 
perform compliance assessment. If 
noncompliance is noted at Visit 3, a repeat 
CGM session starting at Visit 3 can be 
performed without a protocol deviation. See 
Section 8.1.2. 
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Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Study intervention injection training with 
demo device 
 
X 
 
 
 
 
Train participant with demo device prior to 
initial injection. 
Review hypoglycemic events collected in the 
diary 
 
X 
X 
X 
X 
X 
Participant Diary 
Participant diary dispensed 
X 
X 
X 
X 
 
 
Diary includes blood glucose values, 
collection of intervention administration, 
information on dosing date/time, and 
hypoglycemia. See Section 8.1. 
Diary compliance check 
 
X 
X 
X 
X 
X 
Diary return 
 
X 
X 
X 
X 
X 
Laboratory Tests and Sample Collections 
Hematology 
X 
 
 
 
 
 
Hemoglobin A1C (HbA1c) 
X 
X 
X 
X 
X 
X 
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Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Clinical chemistry 
X 
X 
 
 
X 
X 
Includes glucose testing. 
Lipid panel 
 
X 
 
 
X 
X 
Urinalysis 
X 
 
 
 
 
 
Serum pregnancy 
X 
 
 
 
 
 
Only for WOCBP and females with a 
history of tubal ligation. See Section 10.4.2. 
Urine pregnancy (local) 
 
X 
 
 
X 
X 
Collect for WOCBP only. The result must 
be available prior to first dose of 
intervention. Perform additional pregnancy 
tests if there is clinical suspicion of 
pregnancy, or as required by local law or 
regulation. 
Follicle stimulating hormone (FSH) 
X 
 
 
 
 
 
Optional; perform as needed to confirm 
postmenopausal status. See Section 10.4. 
Calcitonin 
X 
 
 
 
 
 
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Study I8F-MC-GPIL 
Period I - 
Screening
Period II - Treatment Period 
Comments 
Visit Number 
1 
2 
3 
4 
5 
ED 
ED = early discontinuation 
Week Relative to Study Intervention Start 
-3 
0 
4 
8 
12 
I 
Visit Interval Tolerance (Days) 
+3/-7 
0 
±3 
±3 
±3 
 
Flexibility is built into the screening visit to 
ensure adequate CGM session and 
appropriate timing for stopping the baseline 
GLP-1 RA and initiating tirzepatide at Visit 
2; see Section 4.1.1. 
Fasting Visit 
 
X 
 
 
X 
X 
Estimated glomerular filtration rate (eGFR) 
X 
 
 
 
 
 
Calculate using CKD-EPI method. 
Urinary albumin/creatinine ration (UACR) 
X 
 
 
 
 
 
Dosing 
Register visit with IWRS 
X 
X 
X 
X 
X 
X 
Dispense study intervention using IWRS 
 
X 
X 
X 
 
 
Observe participant administer study 
intervention 
 
X 
 
 
 
 
Dispense ancillary supplies to participant 
 
X 
X 
X 
 
 
Participant returns unused study intervention 
and ancillary supplies 
 
 
X 
X 
X 
X 
Where applicable as per local regulations. 
Assess study intervention compliance 
 
 
X 
X 
X 
X 
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Abbreviations: BG = blood glucose; CKD-EPI = chronic kidney disease - epidemiology collaboration; CGM = continuous glucose monitoring; CRF = case 
report form; ECG = electrocardiogram; GLP-1 RA = glucagon-like peptide-1 receptor agonist; IWRS = interactive web-response system; PI = Principal 
Investigator; SoA = Schedule of Activities; SMBG = self-monitoring of blood glucose; T2D = Type 2 diabetes; WOCBP = women of childbearing potential. 
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2. 
Introduction 
Incretin receptor agonists are an established and important treatment for T2D 
Incretin receptor agonists effectively manage glycemic control in patients with T2D and can 
provide additional weight reduction for those patients who can benefit from an adjunct to 
comprehensive lifestyle interventions (Buse et al. 2020; Garber et al. 2020; ADA 2022). They 
vary in terms of pharmacokinetics, dosing regimen, and clinical effects (Neumiller 2011). 
Switching between GLP-1 RAs occurs to improve HbA1c control, promote additional weight 
reduction, or mitigate side effects (Almandoz et al. 2020; Jain et al. 2021a). Additionally, patient 
preference for different medication attributes or pharmacy coverage may also drive switching 
between agents. 
Tirzepatide 
Tirzepatide is a recently approved single molecule that acts as glucose-dependent insulinotropic 
polypeptide (GIP) and GLP-1 receptor agonist, which has demonstrated an ability to reduce 
HbA1c and body weight in adults with T2D across all 3 therapeutic doses: 5, 10, and 15 mg (Del 
Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 2021; Dahl et al. 2022). 
It is more efficacious in reducing HbA1c and promoting weight reduction than dulaglutide and 
semaglutide in people not on previous GLP-1 RA therapy (Frías et al. 2018; Frías et al. 2021). 
2.1. 
Study Rationale 
No study has investigated the effects of switching from GLP-1 RA therapy to tirzepatide in 
people with T2D. This study will inform providers on what to expect when switching from a 
GLP-1 RA to tirzepatide 5 mg but does not evaluate long-term efficacy, optimal dosing, or 
comparative improvement to other regimens. 
Prior exposure to a GLP-1 RA is associated with less frequent GI intolerance when switching 
between GLP-1 RAs (Hepprich et al. 2021; Jain et al. 2021b). Therefore, this study will describe 
an alternative way to switch from a GLP-1 RA to tirzepatide by using a starting dose of 5 mg and 
will evaluate changes in glycemic control, body weight, and GI tolerability occurring in the first 
12 weeks for the targeted study population. 
2.2. 
Background 
Phase 3 clinical studies 
Clinical reductions in HbA1c and body weight 
In a series of 5 global Phase 3 SURPASS studies, tirzepatide demonstrated clinically meaningful 
reductions in HbA1c and body weight, which were greater than placebo and active comparators 
(Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 2021; Dahl et al. 
2022). These treatment effects were sustained up to 104 weeks (Del Prato et al. 2021). 
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Improvements in metabolic endpoints 
Tirzepatide also demonstrated greater improvements than comparators in other metabolic 
endpoints, such as fasting serum glucose, 2-hour post meal glucose, CGM-assessed time in 
euglycemic range, waist circumference, volume of abdominal visceral and SC adipose tissue, 
and fasting lipid profile (Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock 
et al. 2021; Battelino et al. 2022; Dahl et al. 2022; Gastaldelli et al. 2022). 
Common adverse events 
Overall, the safety and tolerability profiles are similar to GLP-1 RAs. GI AEs, such as nausea, 
diarrhea, decreased appetite, and vomiting, were the most common AEs seen in the tirzepatide-
treated participants. 
Hypoglycemia events 
In line with the ability of tirzepatide to lower blood glucose in a glucose-dependent manner, the 
overall incidence of clinically significant or severe hypoglycemia attributable to tirzepatide was 
low. The risk of clinically significant hypoglycemia or severe hypoglycemia was higher when 
tirzepatide was used in combination with insulin glargine or sulfonylurea, as has been observed 
with GLP-1 RAs (Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 
2021; Dahl et al. 2022). 
2.3. 
Benefit/Risk Assessment 
Overall, the known benefits associated with tirzepatide in people with T2D outweigh known 
risks associated with the therapy. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of tirzepatide may be found in the IB and package insert (MounjaroE 
USPI [WWW]). 
2.3.1. 
Risk Assessment 
Management of risks 
Sections 5.1, 5.2, 8.2, and 8.3 address known potential risks associated with tirzepatide. 
2.3.2. 
Benefit Assessment 
The potential benefits from participation in this study include improved glycemic control, weight 
loss, and continued expert medical care for the study duration. 
Participants may benefit by receiving personal health information, routine safety assessments, 
lifestyle management counseling, and frequent engagement with health care providers during the 
study, which provide opportunities for coaching and support. Following study completion, the 
participantLs data from CGM, describing how their glucose responds to day-to-day activities, will 
be available for future medical decision-making. 
2.3.3. 
Overall Benefit Risk Conclusion 
The safety and efficacy profile seen to date for tirzepatide supports the overall benefit risk for 
participants in this study. Considering the measures taken to minimize risk to participants in this 
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study, the potential risks identified in association with tirzepatide are justified by the anticipated 
benefits that may be afforded to participants living with T2D. 
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3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
To demonstrate that participants with T2D switching 
from a stable dose of GLP-1 RA to tirzepatide 5 mg 
QW have an improvement in HbA1c at Week 12 
compared to baseline  
 Change from baseline in HbA1c 
Secondary 
To evaluate the changes in CGM-assessed TAR from 
baseline at Week 4 and at Week 12 
Change from baseline in 
 Percentage of time per day that CGM-derived 
values are >180 mg/dl (10 mmol/L) 
 Duration of time in minutes per day that CGM-
derived values are >180 mg/dl (10 mmol/L) 
To evaluate the change in FSG from baseline at Week 
12 
 Change from baseline in FSG 
To evaluate the changes from baseline in weight at 
Week 12 
 Change from baseline in weight 
Exploratory 
To evaluate changes in CGM-derived measures from 
baseline over the course of 12 weeks 
 Change from baseline in 
o 
standard CGM metrics (TIR, TBR, GV) 
o 
time in TITR 
o 
composite of all in-ranges 
o 
mean 24-hr daily blood glucose 
o 
estimated post-prandial glucose excursion 
o 
estimated fasting glucose 
Abbreviations: CGM = continuous glucose monitoring; FSG = fasting serum glucose; GLP-1 RA = glucagon-like 
peptide-1 receptor agonist; GV = glycemic variability; HbA1c = hemoglobin A1c; QW = once-weekly; 
T2D = type-2 diabetes; TAR = time above range (>180 mg/dl or >10 mmol/L); TBR = time below range 
(F
 60	-58;F mmol/L); TIR = time-in-range (71 to 180 mg/dL or 3.9 to 10 mmol/L); TITR = time in tight 
target range (71 to 140 mg/dL or 3.9 to 7.8 mmol/L);  
Primary estimands 
The primary estimand in this study is the efficacy estimand. 
The efficacy estimand focuses on the treatment effect if participants continued to receive the 
study treatment without prohibited medication. This estimand will be used in publications to 
inform prescribers or physicians. 
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26 
The primary clinical question of interest is 
What is the change in HbA1c from baseline to Week 12 in participants with T2D, 
regardless of changes in background OAM, and assuming that participants continue to 
take treatment without use of prohibited medication? 
This estimand is described by the following attributes: 
 Population: participants with T2D on a GLP-1 RA who may benefit from additional 
therapy regardless of background OAM. Further details can be found in Section 5. 
 Endpoint: changes from baseline to Week 12 in HbA1c. 
 Treatment condition: treatment with tirzepatide regardless of changes to the background 
OAM. Further details on study treatment can be found in Section 6. 
 Intercurre7=.?.7=<8/27=.;.<=J&;.*=6.7=-2<,87=27>*=287/8;*7B;.*<87K*7-J72=2*=287
of prohibited medicationK@255+.*--;.<<.-><270=1./8558@270<=;*=.02.< 
o As if participants stay on the treatment (hypothetical strategy) 
o As if participants did not receive prohibited medication (hypothetical strategy). 
 Population-level summary: difference in mean changes within treatment condition. 
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27 
4. 
Study Design 
4.1. 
Overall Design 
SURPASS-SWITCH-2 is an open-label, single-arm, multicenter, multinational, Phase 4 study to 
assess the changes in glycemic control when switching from a stable dose of a GLP-1 RA 
directly to tirzepatide 5 mg in participants with T2D. 
This study includes a screening period and a 12-week treatment period. 
See the SoA (Section 1.3) for additional details about the study periods and visit-specific 
assessments, including assessments needed at an ED visit. 
4.1.1. 
Design Outline 
Period I: Screening 
Preparation for the switch from GLP-1 RA medication to tirzepatide 
The investigator will determine the pa;=2,29*7=Ls current GLP-1 RA medication administration 
schedule to ensure the correct timing for initiating tirzepatide 5 mg at Visit 2. 
Investigators should ensure that at least 12 days occur between Visit 1 and Visit 2 to allow for an 
adequate CGM data collection. 
Participants taking daily liraglutide at screening should continue taking liraglutide up to the day 
prior to Visit 2. 
Participants taking either weekly dulaglutide or semaglutide should take their last dose of GLP-1 
RA medication at least 3 days prior to Visit 2 but no more than 10 days prior to Visit 2. 
Training for the study-supplied SMBG monitor and testing frequency recommendations will 
occur. Training for the CGM sensor and insertion device, including suggestions for successful 
device maintenance, will also occur in conjunction with the insertion of the CGM sensor for the 
baseline measurement session. 
Period II: Treatment Period 
Visit 2 Treatment Initiation 
Participants arrive to the clinic in the fasting state. See Section 6.1 for intervention details. 
This is the general flow for Visit 2: 
 Participant returns screening CGM sensor for compliance review and data upload 
 Study personnel confirm enrollment criteria 
 Study personnel complete all required visit procedures, including the collection of vital 
signs, all baseline procedures, and sample collection, and 
 Treatment initiation for eligible participants 
Study intervention training 
Study personnel will provide appropriate training for the use of the tirzepatide SDP. The training 
can be provided using a demonstration device, if available. This training will be repeated at 
subsequent visits, as needed. 
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In addition, study personnel will provide product-<9.,2/2,J27<=;>,=287</8;><.K27/8;6*=287=8
the participants upon request, if available. 
First tirzepatide dose 
Study personnel will observe as the participant injects the first dose of tirzepatide. The remaining 
injections will occur at participantLs home. The date and time of the first dose of tirzepatide 
should be recorded on the CRF. Additionally, all medication doses administered at home should 
be captured, including date and time, in the participantLs diary and subsequently recorded in the 
CRF. 
Visit 5 (Week 12) Treatment Period or ED Visit 
&1.27?.<=20*=8;@255-.=.;627.*9*;=2,29*7=L<=;*7<2=287/;86<=>-B=;.*=6.7==8*78=1.;-2*+.=es 
treatment, including re-initiation of baseline GLP-1 RA. 
4.2. 
Scientific Rationale for Study Design 
This study is designed to describe the changes in glycemic control and GI tolerability of people 
with T2D who are on stable doses of GLP-1 RAs as they transition to tirzepatide 5 mg. 
Primary endpoint 
The primary endpoint of the study is to assess the change in HbA1c from baseline to Week 12 in 
participants transitioning from a stable GLP-1 RA to tirzepatide 5 mg. HbA1c is the well-
established measure of glycemic status. CGM-derived measures will secondarily provide the 
daily patterns of glycemic control during the first 12 weeks of therapy. 
Duration of treatment period 
The duration of the treatment period is 12 weeks. This is based on the time required for the 
HbA1c value to reflect the change to tirzepatide 5 mg as well as the time during which most GI 
intolerance occurs after initiating tirzepatide therapy. 
The 12-week study period provides several timepoints to assess changes in intermediate 
glycemic control via CGM sensor and then overall assessment of glycemic control with change 
in HbA1c at 12 weeks. 
Open-label design 
A single-arm study supports an open-label design. 
Demographics collection 
In this study, collection of demographic information includes race and ethnicity as allowed per 
local regulations. 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 current US product label specifies that tirzepatide should be started at 2.5 mg (initiation 
dose) and escalated to 5 mg after 4 weeks. This dosing was based on GLP-1 RA naive 
participants to optimize tolerability and clinical efficacy. For participants with T2D who are 
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already on GLP-1 RA therapy, providers may consider starting at tirzepatide 5 mg dose instead 
of the 2.5 mg initiation dose for additional benefit. 
Tirzepatide at 5 mg, administered subcutaneously QW, was efficacious in reducing A1c and 
body weight in the Phase 3 program and will be evaluated in this study. Continued dose 
escalation is not required to assess the initial changes in glycemic control. 
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 trial globally. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study, including the last visit or the last scheduled procedure shown in the SoA. 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Are 18 years old or of an acceptable age to provide informed consent according to local 
regulations, whichever is older. 
Type of participant and disease characteristics 
2. Have been diagnosed with T2D based on the World Health Organization classification or 
other locally applicable diagnostic standards. 
3. Have an HbA1c G6.5% (G48 mmol/mol) to F0% (F75 mmol/mol) as determined by the 
central laboratory at Visit 1 and in the opinion of investigator may benefit from 
tirzepatide based on individual patient needs. 
4. Have been on a stable treatment dose of 1 of the listed GLP-1 RAs for G3 months prior to 
Visit 1: 
o liraglutide 1.2 or 1.8 mg QD 
o dulaglutide 0.75, 1.5, 3, or 4.5 mg QW, or 
o injectable semaglutide 0.5, 1, or 2 mg QW. 
5. No treatment with OAM or on stable doses (for at least 3 months before Visit 1) of up to 
3 OAM. The OAM may include metformin (at least 1000 mg/day), SGLT-2i, 
thiazolidinediones, or N-glucosidase inhibitors. 
Weight 
6. *?. G kg/m2 at Visit 1. 
Sex and contraceptive/barrier requirements 
7. Contraceptive use by participants should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. For the 
contraception requirements of this protocol, see Section 10.4, Appendix 4. 
Informed consent 
8. Are capable of giving signed informed consent as described in Section 10.1.3, 
Appendix 1, which includes compliance with the requirements and restrictions listed in 
the ICF and in this protocol. 
Other inclusion criteria 
9. 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 compliance with 
CGM sensor and insertion device (defined in Section 4.1.1). 
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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply at screening: 
Medical conditions 
10. Have T1D. 
11. Have a history of chronic or acute pancreatitis any time prior to Visit 1. 
12. Have a clinical history of 
o proliferative diabetic retinopathy 
o diabetic maculopathy, or 
o nonproliferative diabetic retinopathy that requires acute treatment. 
13. Are at high risk for CVD in =1.27?.<=20*=8;L<89272878;1*?.a history of any of these 
CV conditions within 60 days prior to Visit 1: 
o myocardial infarction 
o percutaneous coronary revascularization procedure 
o carotid stenting or surgical revascularization 
o nontraumatic amputation 
o peripheral vascular procedure (e.g., stenting or surgical revascularization) 
o cerebrovascular accident (stroke), or 
o hospitalization for congestive heart failure. 
14. Have NYHA Functional Classification Class IV congestive heart failure. 
15. Have a history of ketoacidosis or hyperosmolar state or coma. 
16. Have a history of severe hypoglycemia or hypoglycemia unawareness within the 
6 months prior to Visit 1. 
17. Have a known clinically significant gastric emptying abnormality, for example, severe 
diabetic gastroparesis or gastric outlet obstruction. 
18. Have undergone or plan to have during the course of the study gastric bypass (bariatric) 
surgery or restrictive bariatric surgery (for example, Lap-Band®), or chronically take 
drugs that directly affect GI motility. 
19. Have acute or chronic hepatitis, signs and symptoms of any liver disease other than 
NAFLD, or ALT level >3.0 times the ULN for the reference range, as determined by the 
central laboratory at study entry. Participants with NAFLD are eligible to participate if 
=1.2;&5.?.52<F
=26.<=1.'!/8;=1.;./erence range. 
20. Have an estimated glomerular filtration rate <30 mL/min/1.73 m2, or lower than the 
country-specific threshold for discontinuing metformin therapy (if used) or SGLT-2i (if 
used) per local label, calculated by Chronic Kidney Disease-Epidemiology equation by 
the central laboratory at Visit 1. 
21. Have evidence of a significant, uncontrolled endocrine abnormality, for example, 
thyrotoxicosis or adrenal crises, in the opinion of the investigator. 
22. Have family or personal history of MTC or MEN2. 
23. Have a s.;>6,*5,2=87275.?.58/G ng/L, as determined by central laboratory at Visit 1. 
24. Have known or suspected hypersensitivity to study product(s) or related products. 
25. Have evidence of a significant, active autoimmune abnormality, for example, lupus or 
rheumatoid arthritis, that, in the opinion of the investigator, is likely to require concurrent 
treatment with systemic glucocorticoids in the next 4 months. 
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26. Have had a transplanted organ or awaiting an organ transplant. Exception: corneal 
transplants (keratoplasty). 
27. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy for less than 5 years. 
Exceptions: 
o basal or squamous cell skin cancer 
o in situ carcinomas of the cervix, and 
o in situ or Grade 1 (for example, Gleason 6 or lower) prostate cancer. 
28. Have a history of any other condition, such as known drug, alcohol abuse, or psychiatric 
disorder that, in the opinion of the investigator, may preclude the participant from 
following and completing the protocol. 
29. Have any chronic hematological condition that may interfere with HbA1c measurement, 
such as hemolytic anemias and sickle cell disease. 
30. 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. 
Prior/concomitant therapy 
31. Have been treated with other glucose-lowering agents, not listed in Inclusion Criterion 5, 
in the 3 months prior to Visit 1. 
Exception: use of insulin for gestational diabetes or short-term use (F14 days) for acute 
conditions, such as acute illness, hospitalization, or elective surgery within the 3 months 
prior to Visit 1. 
32. Have within 90 days prior to Visit 1 received treatment with medications intended to 
promote weight loss. This includes prescribed, over-the-counter, or alternative remedies. 
See Section 6.8.4 for list of prohibited medications. 
33. Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy or have 
received such therapy within 1 month of Visit 1 or between Visits 1 and 2. 
Exceptions: topical, intraocular, intranasal, or inhaled preparations. 
Prior/concurrent clinical study experience 
34. Are currently enrolled in any other clinical study involving an investigational product 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 study involving an investigational 
product. If the previous investigational product has a long half-life, 5 half-lives, or 
30 days, whichever is longer, should have passed prior to Visit 1. 
36. Have previously completed or withdrawn from this study or any other study investigating 
tirzepatide. 
Other exclusion criteria 
37. Are Lilly employees or are employees of any third-party involved in study who require 
exclusion of their employees. 
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33 
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. Female participants who are pregnant or breastfeeding or intending to become pregnant. 
5.3. 
Lifestyle Considerations 
Diabetes management counseling 
Per the SoA (Section 1.3), qualified medical staff will provide diabetes management counseling, 
which will include instructions on diet and exercise and education about the signs, symptoms, 
and management of hypoglycemia or hyperglycemia, should it occur. 
Participant exercise and diet 
Participants should continue their usual exercise habits and generally follow a healthy meal plan 
(with consistent meal size and time of day) throughout the course of the study. 
Participants should not initiate an organized diet or exercise (weight reduction) program during 
the study other than the lifestyle and dietary measures for diabetes treatment. 
Dietary counseling may be reviewed throughout the study, as needed. 
Blood product donation 
Study participants should be instructed not to donate blood or blood products during the study. 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study but is 
not subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant 
This section is not applicable to this study. All entry criteria must be met within the specified 
visit intervals in the SoA (Section 1.3). 
See Section 10.8 for changes in study conduct during exceptional circumstance. 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to or used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
The planned treatment is tirzepatide 5 mg (Section 6.5). 
This table lists the interventions used in this clinical study. 
Intervention Name 
Tirzepatide (LY3298176) 
Dosage Level(s) 
5 mg 
Route of Administration 
Subcutaneous using an SDP 
Authorized as Defined by EU Clinical Trial 
Regulation 
Not authorized in EU 
Abbreviation: SDP = single-dose pen. 
Administration and timing of dose administration 
Tirzepatide is administered QW by SC injection. There are no restrictions on the time of day 
each weekly dose of study intervention is given, but it is advisable to administer the SC 
injections on the same day and same time each week, with or without meals. 
Anatomical location of injections 
Acceptable locations for injection include the abdomen, thigh, or upper arm if another person 
gives the injection. 
Participants should rotate injection sites from one injection to the next, even when injecting 
within the same region. 
Packaging and labeling 
Tirzepatide will be supplied by the sponsor in SDPs in accordance with current Good 
Manufacturing Practice. SDPs will be packaged in cartons to be dispensed and will be labeled as 
appropriate for country requirements. 
Tirzepatide will be dispensed at the study visits summarized in SoA (Section 1.3). 
Returned tirzepatide should not be re-dispensed to the participants. 
Missed doses 
If a dose is missed, the participant should take their dose as soon as possible, within 4 days 
(96 hours) after the missed dose. If more than 4 days have passed, that dose should be skipped, 
and the next dose should be taken at the appropriate time. 
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6.1.1. 
Medical Devices 
Tirzepatide will be provided as a drug/device combination product in a prefilled SDP for the 
administration of study intervention. A new SDP will be used for each injection. 
Medical devices for tirzepatide used in this study are manufactured by the sponsor or 
manufactured for the sponsor by a third-party. 
Instructions for medical device use for tirzepatide are provided in the Instructions for Use. 
All Product Complaints, including malfunction, use error, and inadequate labeling, shall be 
documented and reported by the investigator throughout the clinical investigation (see Section 
8.3) and appropriately managed by the sponsor. 
6.1.2. 
Rescue Therapy 
The incidence of severe hyperglycemia in the Phase 3 SURPASS clinical program was low for 
participants randomly assigned to tirzepatide 5 mg. This study will include participants with a 
baseline A1c F9.0%, which further decreases the possibility of severe hyperglycemia occurring 
in the study population within a 12-week treatment period. 
No rescue therapy will be initiated, but at the investigatorsL discretion, insulin can be used on a 
short-term basis (F14 days) for acute conditions, such as acute illness, hospitalization, or elective 
surgery. This treatment will not be considered rescue therapy, and participant will continue in the 
study as long as the tirzepatide treatment continues. Insulin use must be reported in the CRF as 
concomitant medication, not as rescue therapy. 
6.1.3. 
Background Therapy 
Participant eligibility requires them to be on a stable dose of a GLP-1 RA as listed in the 
inclusion requirements (See section 5.1). The GLP-1 RA will be stopped, and tirzepatide 5 mg 
will be started at Visit 2. 
If participants are using background OAM therapy, they will continue that therapy without dose 
modification. If the participant develops hypoglycemia or is at risk, the background OAM 
therapy can be reduced. Any dosing changes should be reported in the CRF. 
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. 
Study intervention will be dispensed at the study visits summarized in SoA. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization 
This is a descriptive study with baseline-to-endpoint comparisons; no randomization will occur. 
Blinding 
This is an open-label study. 
6.4. 
Study Intervention Compliance 
Participant compliance with study intervention will be assessed at visits summarized in the SoA. 
The investigator site personnel will review the amount of unused study intervention returned in 
addition to injection information provided by the participant. Study intervention compliance will 
be recorded for each visit interval when study intervention is dispensed. 
If a participant is considered poorly compliant with their study procedures, for example, missed 
visits or specific diagnostic tests, they will be retrained as needed by designated study personnel. 
6.5. 
Dose Modification 
This study is designed to assess the transition from a GLP-1 RA to tirzepatide 5 mg, and hence 
no dose escalation will be employed during the trial. The goal is to initiate tirzepatide at 5 mg on 
Visit 2 (Week 0) and maintain until Visit 5 (Week 12). 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms 
The dose scheme is designed to assess the glycemic transition from a GLP-1 RA directly to 5 mg 
and assess the development of intolerable GI symptoms. Every effort should be made by the 
investigator to maintain the 5 mg dose throughout the trial. 
This table describes steps the investigator should follow to mitigate GI symptoms and manage 
participants with intolerable GI AEs. 
STEP 1 
Advise participants to eat smaller meals, for example, splitting 3 daily meals into 4 or more smaller 
meals, and to stop eating when they feel full. 
STEP 2 
Continue STEP 1 + 
Prescribe symptomatic medication, for example, anti-emetic or anti-diarrheal medication, per local 
country availability and individual participant needs. Use of symptomatic medication should be 
captured as concomitant medication in the CRF. 
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STEP 3 
Continue STEP 1 + STEP 2 + 
Temporarily interrupt tirzepatide; omit 1 dose. After the interruption, the investigator should restart 
tirzepatide 5 mg, with the participant taking medication to alleviate their GI symptoms. The data 
related to temporary interruption of study treatment should be documented in source documents. 
 
STEP 3 may be repeated once, i.e., 2 non-consecutives doses of tirzepatide 5 mg can be omitted 
during the 12-week study, each with an attempt to restart the subsequent dose. 
STEP 4 
If intolerable GI symptoms or events persist despite the above measures, the investigator may 
discontinue study drug intervention. 
Abbreviations: CRF = case report form; GI = gastrointestinal. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
The sponsor will not provide participants with any ongoing supplies or study intervention after 
they have completed the study treatment period or permanently discontinued the study 
intervention. 
6.7. 
Treatment of Overdose 
6.7.1. 
Tirzepatide Overdose 
Tirzepatide overdose was defined as administration of more than a total of 15 mg in less than a 
72-hour period. An overdose will be reported as an AE per Section 10.3. 
In the event of an overdose, the investigator or treating physician should 
P contact the medical monitor immediately 
P evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted 
P closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate until, for example, study intervention no longer has a 
clinical effect, and 
 initiate ap9;89;2*=.<>998;=2?.=;.*=6.7=*,,8;-270=8=1.9*;=2,29*7=L<,5272,*5<207<*7-
symptoms. 
6.8. 
Prior and Concomitant Therapy 
6.8.1. 
Allowed Concomitant Therapy 
Participants are allowed to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study intervention. 
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6.8.2. 
Changing Concomitant Therapy 
Reduction and/or discontinuation of concomitant antihyperglycemic treatments other than study 
intervention are described in Section 6.1.3. 
Changes in other concomitant medications will be allowed at the discretion of the investigator as 
clinically indicated in accordance with local standard of care and professional society guidelines. 
Authorized study personnel should consult the medical monitor if there are any questions about 
concomitant therapies during the study. 
6.8.3. 
Concomitant Therapy Data Collection 
Any concomitant medication or vaccine including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements that the participant is receiving at the time of enrollment or 
receives during the study; authorized study personnel should collect 
 name of medication, vaccine, or therapy 
 reason for use 
 dates of administration, including start and end dates, and 
 dosage information, including dose and frequency for concomitant therapy of 
special interest. 
Contact the medical monitor if there are any questions regarding concomitant or prior therapy. 
6.8.4. 
Prohibited Concomitant Medications 
See Section 5 for prohibited antihyperglycemic medications. 
Medications intended to promote weight loss are prohibited in this study. This includes 
prescribed, over-the-counter, or alternative remedies. Examples include, but are not limited to 
 Liraglutide 3.0 mg 
 Topiramate 
 Semaglutide 2.4 mg 
 Orlistat 
 Sibutramine 
 Phenylpropanolamine 
 Mazindol 
 Phentermine 
 Lorcaserin 
 Phentermine or topiramate combination, or 
 Naltrexone or bupropion 
 Pramlintide 
 Zonisamide 
 
6.8.5. 
Allowed Antihyperglycemic Treatments other than Tirzepatide 
No new additional antihyperglycemic treatment is permitted in this study other than tirzepatide. 
As noted in Section 6.1.2, initiation of insulin is ONLY allowed for F14 days for certain clinical 
situations, for example, elective surgery, during hospitalization, or hyperosmolar states. Insulin 
use must be reported in the CRF as concomitant medication, not as rescue therapy. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.9, 
Appendix 1. 
7.1. 
Discontinuation of Study Intervention 
When necessary, a participant may be permanently discontinued from tirzepatide. If so, the 
participant will remain in the study and follow procedures for remaining study visits, as shown in 
the SoA (Section 1.3). 
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study (see Section 8.3.2) 
 the participant is diagnosed with T1D or LADA 
 the participant requests to discontinue intervention 
 the participant develops confirmed pancreatitis; if not confirmed, study intervention may 
be restarted 
 the participant is diagnosed with MTC, C-cell hyperplasia, or multiple endocrine 
neoplasia syndrome 
 the participant is diagnosed with an active malignancy or if a previously treated 
malignancy becomes known after enrollment 
 the participant experiences a significant study intervention-related hypersensitivity 
reaction after administration of study intervention 
 any other AE, SAE, or clinically significant laboratory value for which the investigator 
believes that permanent study intervention discontinuation is the appropriate measure to 
be taken, or 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons. 
Participants who stop tirzepatide permanently will receive another locally approved 
antihyperglycemic medication, if needed per clinical judgment of investigator, and will continue 
participating in the study according to the protocol to collect all planned measurements per SoA 
(Section 1.3), Adverse Events (Section 8.3), and Safety Assessments (Section 8.2) of this 
protocol. 
The choice of antihyperglycemic medication, including restarting the prestudy GLP-1 RA, will 
be at the discretion of the investigator. The investigators should follow current published 
standards of care from the American Diabetes Association and/or a consensus report by the 
American Diabetes Association and the European Association for Study of Diabetes (ADA 2022, 
Buse et al. 2020). 
The new antihyperglycemic medication will be recorded on the CRF for antihyperglycemic 
medications. 
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7.1.1. 
Liver Chemistry Stopping Criteria 
Interrupting study drug based on liver test elevations in participants with normal or 
near-normal baseline liver tests 
In study participants with normal or near normal baseline liver tests (ALT, AST, 
ALP <1.5x ULN), the study drug should be interrupted and close hepatic monitoring initiate 
(see Section 8.2.7) 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  
8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption 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  
8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT%&#GA'!=1.<=>-B
drug should be interrupted if 1 or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >4x baseline 
 
ALT or AST >3x baseline for more than 2 weeks 
 
ALT or AST >2x baseline and either TBL >2x ULN or INR >1.5  
8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN. 
ALT or AST >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
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ALP >2.5x baseline, when the source of increased ALP is the liver 
 
ALP >2x baseline and TBL > 2x ULN  
8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN. 
ALP >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited, non-drug 
etiology is identified. Otherwise, the study drug should be discontinued. 
7.1.2. 
Temporary Discontinuation of Study Intervention 
The investigator may temporarily interrupt tirzepatide due to 
 an AE 
 clinically significant laboratory value 
 hospital visits or medical procedures 
 travel or shortage of study treatment supply, or 
 any other event necessitating temporary discontinuation of tirzepatide. 
If tirzepatide is temporarily interrupted for reasons other than tolerability, participants should be 
encouraged to restart tirzepatide as soon as it is safe to do so. 
Every effort should be made by the investigator to maintain participants on tirzepatide and to 
restart after any temporary interruption, as soon as it is safe to do so. 
If the tirzepatide interruption is due to intolerable persistent GI AE, such as nausea, vomiting, or 
diarrhea, the participant should be treated as suggested in Section 6.5.1. 
Recording temporary discontinuation of tirzepatide 
The dates of study intervention interruption and restart must be documented in source documents 
and entered on the CRF. 
Participant noncompliance should not be recorded as interruption of study intervention on the 
CRF. 
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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 9*;=2,29*7=L<8@7;.:>.<= for any reason or without providing any 
reason 
 if the participant is diagnosed with T1D or LADA 
 if the participant is diagnosed with a malignancy after enrollment 
o Exceptions: 
 basal or squamous cell skin cancer 
 in situ carcinomas of the cervix, and 
 in situ or Grade 1 (for example, Gleason 6 or lower) prostate cancer. 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 if a female participant becomes pregnant; see Section 8.3.2 
 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. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an ED visit, as shown in the SoA (Section 1.3). 
If the participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, the participant may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
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 (Section 1.3), 
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 
Primary efficacy assessment 
The primary efficacy measurement in this study is change in HbA1c from baseline to Week 12 
(Section 1.3). 
Other efficacy assessments 
Other efficacy assessments include change in weight, and fasting serum glucose from baseline to 
Week 12. CGM-derived assessments will be assessed over the course of this 12-week study, 
including specific endpoints at 4 and 12 weeks. 
8.1.1. 
Self-Monitoring of Blood Glucose (SMBG) 
Participants must use only the study-provided monitors, provided per local guidelines, during the 
study. 
Glucometer for participant use during the study 
Participants will receive a glucometer and related testing supplies for use during the study. 
Glucometer training 
Site personnel will train the participant on correct use of the glucometer for self-monitoring 
blood glucose and reporting of hypoglycemia data. 
When to measure FBG during the study 
Site personnel will train the participant to measure FBG daily when possible, and a minimum of 
2 times per week using the study-provided glucometer. 
The FBG should be measured upon waking in the morning, prior to food or caloric beverage 
intake. 
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Glucometer data transfer 
The study-provided glucometer will wirelessly transmit blood glucose measurements to the 
9*;=2,29*7=L<diary. Site personnel will be able to view SMBG data that have been transmitted to 
the diary through a web-based portal as well as any reported events of hypoglycemia. 
SMBG for hypoglycemia or hyperglycemia 
Participants should perform SMBG with the study-provided BG meter whenever hypoglycemia 
is experienced or suspected, with or without symptoms. SMBG should also be measured when 
there is perceived or increased risk related to changes in dietary intake, or physical activity. 
Participants may perform SMBG more frequently to check for instances of hyperglycemia, or as 
directed by the investigator. Investigators may also instruct participants to collect SMBG, at time 
points other than at fasting, to evaluate glycemic control or based on the investigator clinical 
judgment. 
8.1.2. 
Continuous Glucose Monitoring 
The study-provided CGM sensor will be used in blinded mode during the study. The blinded 
CGM sensor will not display the sensor glucose readings to the participant or investigator, and 
high and low glucose alerts will not be available to the participant. 
Participants are not allowed to use a personal, non-study CGM device during the study or 
connect the CGM sensor to a personal smartphone, smartphone application, or other system. 
Continuous glucose monitoring procedure 
At Visit 1, trained medical site staff will train participants and have them insert the CGM sensor 
using the supplied insertion device. Site staff must check expiration date on components prior to 
insertion. Participants will wear the CGM sensor for a 14-day session. At Visit 2, prior to any 
study drug injection, the system will be collected and data transmitted. Participants will place a 
new CGM sensor at home 2 weeks prior to study Visits 3 (Week 4) and 5 (Week 12). The CGM 
sensors will be collected and data downloaded at Visits 3 and 5. 
Site personnel will dispense CGM supplies and initiate blinded CGM sessions at the times 
specified according to the SoA. Participants will be trained on the CGM sensor and insertion 
device before use and will be required to replace the sensor at designated intervals per the 
investigator instruction. 
The participant will be instructed to monitor fasting blood glucose and blood glucose during 
hypoglycemia by finger stick SMBG per study protocol. 
Continuous blood glucose monitoring system compliance assessment 
At the end of each CGM session, participants will return the CGM sensor(s) to the site. Site 
personnel will upload the CGM data to a vendor-hosted online portal to view data capture 
compliance using the available reports and visualization tools. The compliance threshold of 70% 
(at least 10 days of the 14-day session) for each session is defined as the percentage of actual 
data versus expected data collected during a session. Site personnel will re-educate participants 
on CGM operation and requirements when session compliance is <80%. 
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To minimize data loss, the CGM service vendor will review site uploads and notify site users 
and/or site monitor when sessions do not meet the compliance thresholds.  
As noted in the SoA, if a participant does not have a compliant CGM session at Visit 3, the CGM 
sensor should be inserted during the study visit with re-education of the participant to ensure 
proper collection of this session and the subsequent CGM session prior to 12 weeks. This 
replacement session is not a protocol deviation, but the updated start date/time and respective 
study week should be documented in the CRF. The replacement CGM session data must be 
collected, uploaded, and assessed for compliance no later than the next study visit. A 
replacement CGM session is not available at Visit 5 as no additional study drug will be 
administered. 
Continuous blood glucose monitoring device safety evaluations 
It is the responsibility of the investigator to report safety concerns as outlined in the Study GPIL 
protocol. A 24-hour toll-free number will be provided to the site personnel in case the personnel 
or participants have questions or complaints regarding the CGM sensor or insertion device. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of 
 skin 
 CV 
 Respiratory system 
 GI tract 
 neurological systems 
 thyroid, and 
 feet, including evaluation for diabetic neuropathy. 
The examination excludes pelvic, rectal, and breast examinations, unless clinically 
indicated. 
Physical examinations during in-clinic visits will be performed by a physician or other qualified 
healthcare professional. 
Height, weight, and waist circumference will be measured and recorded, per Appendix 7, 
Section 10.7. Investigators should pay special attention to clinical signs related to 
previous serious illnesses. 
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Symptom-directed physical assessment after screening 
These examinations are performed based on participant status and standard of care by a 
physician or other qualified healthcare professional. 
8.2.2. 
Vital Signs 
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3) and following the study-specific recommendations mentioned in Appendix 
7, Section 10.7. 
Vital signs including pulse rate (beats per minute) and blood pressure (mm Hg) will be measured 
after participant has been sitting for at least 5 minutes and before obtaining an ECG tracing and 
before collection of blood samples for laboratory testing, at visits where required. 
8.2.3. 
Electrocardiograms 
A 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that preferably automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals. 
The ECGs must 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, for 
immediate participant management, if needed. The investigator or designee must document their 
review of the ECG. If a clinically re5.?*7=*+78;6*52=B2<8+<.;?.-87=1.9*;=2,29*7=L<
then the investigator should assess the participant for symptoms, such as palpitations, near 
syncope, syncope, or chest pain. 
The original ECG must be retained at the investigative site. The investigator or qualified 
-.<207..L<27=.;9;.=*=287@2559;.?*25/8;266.-2*=.9*;=2,29*7=6*7*0.6.7=9>;98<.< 
8.2.4. 
Dilated Fundoscopic Examination 
A dilated retinal fundoscopic examination will be performed by a qualified eye care professional 
(ophthalmologist or optometrist) for all participants between Visit 1 and Visit 2 to exclude 
participants with proliferative diabetic retinopathy, diabetic macular edema, or non-proliferative 
diabetic retinopathy that requires acute treatment. The results from this examination will be 
recorded on a specific retinopathy CRF as a baseline measure of retinopathy. An adequate 
examination performed F90 days prior to screening can replace the study examination; results 
should be similarly recorded. 
A follow-up dilated fundoscopic examination should be performed by a qualified eye care 
professional (ophthalmologist or optometrist) when clinically indicated by any AE suspected of 
worsening retinopathy, and the findings should be recorded on the retinopathy eCRF. 
8.2.5. 
Clinical Safety Laboratory Tests 
See Section 10.2, Appendix 2 for the list of Clinical Laboratory Tests to be performed and the 
SoA (Section 1.3) for the timing and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. 
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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. 
5272,*55B<2072/2,*7=*+78;6*55*+8;*=8;B/27-270<*;.=18<.@12,1*;.78=*<<8,2*=.-@2=1=1.
>7-.;5B270-2<.*<.>75.<<3>-0.-+B=1.27?.<=20*=8;=8+.68;.<.?.;.=1*7.A9.,=.-/8;=1.
9*;=2,29*7=<,87-2=287 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
 If such values do not return to normal or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Section 10.2, Appendix 2, 
must be conducted in accordance with the SoA (Section 1.3), standard collection 
requirements, and laboratory manual. 
If laboratory values from non-protocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator, for example, SAE or AE or dose 
modification, then report the information as an AE. 
8.2.6. 
Pregnancy Testing 
Pregnancy testing will occur as outlined in the SoA (Section 1.3). 
Serum pregnancy test must be performed only for WOCBP and females with a history of tubal 
ligation. 
A local urine pregnancy test must be performed for WOCBP only, prior to administering study 
intervention and the result must be available prior to first dose or injection of study intervention 
(s). 
Additional pregnancy tests, beyond those required per the SoA, should be performed at any time 
during the study if a menstrual period is missed, there is clinical suspicion of pregnancy, or as 
required by local law or regulation. If the participant is pregnant, she must be permanently 
discontinued from study intervention and the study (Sections 7 and 8.3.2). 
8.2.7. 
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 if a repeat 
laboratory test is needed. 
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If a participant with baseline results of...  
develops the following elevations 
ALT or AST <1.5x ULN 
&8;%&GA'! 
ALP <1.5x ULN 
#GA'! 
TBL <1.5x ULN 
&GA'!.A,.9=/8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
&8;%&GA'! 
&8;%&GA+*<.527. 
#GA'! 
#GA+*<.527. 
&GA'! 
&GA+*<.527..A,.9=/8;9*;=2,29*7=<@2=125+.;=L<
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
	
	


 
/=1.*+78;6*552?.;=.<=;.<>5=9.;<2<=<8;@8;<.7<,5272,*5*7-5*+8;*=8;B6872=8;270*7-
.?*5>*=287/8;98<<2+5.,*><.<8/*+78;6*552?.;=.<=<<18>5-+.272=2*=.-+B=1.27?.<=20*=8;27
,87<>5=*=287@2=1=1.6.-2,*56872=8;=*62726>6=12<.?*5>*=287<18>5-27,5>-.91B<2,*5
.A*627*=287*7-*=18;8>016.-2,*512<=8;B27,5>-270 
 <B69=86< 
 ;.,.7=2557.<<.</8;.A*695.1.*;=/*25>;.<B<=.62,27/.,=2871B98=.7<2878;<.2C>;.< 
 ;.,.7==;*?.5 
 12<=8;B8/,87,862=*7=6.-2,*=287<27,5>-2708?.;=1.,8>7=.;1.;+*5*7--2.=*;B
<>995.6.7=<*7- 
 12<=8;B8/*5,8185-;274270*7-8=1.;<>+<=*7,.*+><. 
Frequency of monitoring 
72=2*55B6872=8;2708/<B69=86<*7-1.9*=2,+28,1.62,*5=.<=<<18>5-+.-87.*=*/;.:>.7,B8/
=8=26.<@..45B+*<.-87=1.9*;=2,29*7=L<,5272,*5,87-2=287*7-1.9*=2,+28,1.62,*5=.<=< 
%>+<.:>.7=5B=1./;.:>.7,B8/6872=8;2706*B+.58@.;.-=887,..?.;B=8@..4<2/=1.
9*;=2,29*7=L<,5272,*5,87-2=287*7-5*+;.<>5=<<=*+252C. 
 872=8;2708/&%&#*7-&<18>5-,87=27>.>7=255.?.5<78;6*52C.8;;.=>;7=8
*99;8A26*=.+*<.527.5.?.5< 
Special care should be taken to minimize the volume of blood taken during hepatic monitoring. 
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 
		

 
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 
&8;%&GA'!@2=11.9*=2,<207<8;<B69=86<a, or 
&8;%&GA'! 
ALP <1.5x ULN 
#GA'! 
TBL <1.5x ULN 
&GA'!.A,.9=/8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
&8;%&GA'! 
&8;%&GA+*<.527.@2=11.9*=2,<207<8;<B69=86<a, or 
&8;%&GA+*<.527. 
#GA'! 
#GA+*<.527. 
&GA'! 
&GA+*<.527..A,.9=/8;9*;=2,29*7=<@2=125+.;=L<<B7-;86. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a 
Hepatic signs or symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, 
rash, and/or eosinophilia >5%. 
		

	
 
=*62726>6=12<.?*5>*=287<18>5-27,5>-. 
 91B<2,*5.A*627*=287*7-*=18;8>016.-2,*512<=8;B*<8>=527.-*+8?. 
 =.<=</8; 
o #&!$ 
o ?2;*51.9*=2=2<8;*7- 
o *>=8266>7.1.9*=2=2<*7- 
 *7*+-8627*526*0270<=>-B/8;.A*695.>5=;*<8>7-8;,869>=.-=8680;*91B<,*7 
*<.-87=1.9*;=2,29*7=L<12<=8;B*7-272=2*5;.<>5=</>;=1.;=.<=270<18>5-+.,87<2-.;.-27
,87<>5=*=287@2=1=1.6.-2,*56872=8;27,5>-270=.<=</8; 
 1.9*=2=2<?2;>< 
 ,B=86.0*58?2;>< 
 9<=.27*;;?2;>< 
 *,.=*627891.75.?.5< 
 *,.=*627891.79;8=.27*-->,=< 
 >;27.=8A2,8580B<,;..7 
 )25<87L<-2<.*<. 
 +588-*5,81855.?.5< 
 >;27*;B.=1B505>,>;872-.*7- 
 +588-918<91*=2-B5.=1*785 
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50 
*<.-87=1.,2;,>6<=*7,.<*7-=1.27?.<=20*=8;L<*<<.<<6.7=8/=1.9*;=2,29*7=L<,5272,*5
,87-2=287=1.27?.<=20*=8;<18>5-,87<2-.;;./.;;270=1.9*;=2,29*7=/8;*1.9*=85802<=8;
0*<=;8.7=.;85802<=,87<>5=*=2876*07.=2,;.<87*7,.,185*70289*7,;.*=80;*91B.7-8<,892,
;.=;80;*-.,185*70289*7,;.*=80;*91B,*;-2*,.,18,*;-280;*68;*52?.;+289<B 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
Collect additional hepatic safety data collection in the hepatic safety CRFs if a participant 
develops 
 a hepatic event considered to be an SAE 
 discontinues study intervention due to a hepatic event, or 
 has changes in laboratory results described in this table. 
If a participant with 
baseline results of...  
	
 
 
ALT <1.5x ULN 
&=8GA'!878;68;.
consecutive blood tests 
Collect additional hepatic safety data in 
the hepatic safety CRF. 
&GA'! 
&GA+*<.527.878;68;.
consecutive blood tests 
TBL <1.5x ULN 
&GA'!.A,.9=/8;9*;=2,29*7=<
@2=125+.;=L<<B7-;86. 
&GA'! 
&GA+*<.527. 
ALP <1.5x ULN 
#GA'!878;68;.,87<.,>=2?.
blood tests 
#GAULN 
#=8GA+*<.527.878;68;.
consecutive blood tests 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CRF = case report form; TBL = total bilirubin level; ULN = upper limit of normal. 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
See Section 10.5 for hepatic laboratory tests. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Section 10.3, Appendix 3: 
 AEs 
 SAEs, and 
 PCs. 
These events will be reported by the participant, or, when appropriate, by a caregiver, surrogate, 
8;=1.9*;=2,29*7=L<5.0*55B*>=18;2C.-;.9;.<.7=*=2?. 
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 or contacts. All SAEs and safety topics of special interest, as defined in 
Section 8.3.3, will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 7.3). 
For PCs, the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Section 10.3, Appendix 3. 
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 ICF 
Participation in 
study has ended 
As soon as 
possible upon 
site 
awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE updates H 
prior to start of study 
intervention and deemed 
reasonably possibly related 
to study procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 h 
of awareness 
SAE CRF 
SAE paper 
form 
SAE and SAE updates H 
after start of study 
intervention 
Start of 
intervention 
Participation in 
study has ended 
Within 24 h 
of awareness 
SAE CRF 
SAE paper 
form 
SAEa H */=.;9*;=2,29*7=L<
study participation has ended 
and the investigator 
becomes aware 
After 
9*;=2,29*7=L<
study 
participation 
has ended 
N/A 
Promptly 
SAE paper 
form 
N/A 
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Event 
Collection 
Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-Up 
Method 
of 
Reporting 
Pregnancy 
Pregnancy in female 
participants and female 
partners of male participants 
After the 
start of 
study 
intervention 
Participation in 
study has ended 
Within 24 h 
(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 h 
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 
I 
I 
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 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; PC = product complaint; 
SAE = serious adverse event. 
a Serious adverse events should not be reported unless the investigator deems them to be possibly related to study treatment or 
study participation. 
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8.3.2. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
&1.27?.<=20*=8;@255*==.69==8,855.,=9;.07*7,B27/8;6*=28787*7B6*5.9*;=2,29*7=L</.6*5.
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 
*99;89;2*=./8;6*7-<>+62==.-=8=1.<987<8;@2=12718>;<8/5.*;72708/*9*;=2,29*7=L<
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 
G
 weeks gestational age, is always considered to be an SAE and will be reported as such. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in protocol Section 8.3.1. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. If the participant is discontinued from the study, follow the standard 
discontinuation process and continue directly to the follow-up phase. The follow-up on the 
pregnancy outcome should continue independent of intervention or study discontinuation. 
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8.3.3. 
Safety Topics of Special Interest 
8.3.3.1. 
Gastrointestinal Adverse Event 
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea. Information about 
severe GI AEs as well as anti-emetic/anti-diarrheal use will be collected in the CRF/AE form. 
For detailed information concerning the management of GI AEs, refer to Section 6.5.1. 
8.3.3.2. 
Dehydration 
Severe gastrointestinal events may lead to dehydration and volume depletion, which can cause a 
deterioration in renal function, including acute renal failure. Participants should be advised of the 
potential risk of dehydration, particularly in relation to gastrointestinal adverse reactions or other 
AEs and take precautions to avoid fluid depletion. 
8.3.3.3. 
Renal Safety 
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal disease. 
8.3.3.4. 
Exocrine Pancreas Safety 
Diagnosis of acute pancreatitis 
Acute pancreatitis is an AE of special interest in all studies with tirzepatide, including this study. 
The diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks et al. 2006; 
Koizumi 2006): 
 abdominal pain, characteristic of acute pancreatitis, that is, epigastric pain radiating to the 
back, often associated with nausea and vomiting 
 <.;>6*6B5*<.=8=*59*7,;.*=2,8;+8=1*7-	8;529*<.Gx ULN, or 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
If acute pancreatitis is suspected, the investigator should 
 obtain appropriate laboratory tests, including pancreatic amylase and lipase, via a local 
laboratory  
 perform imaging studies, such as abdominal CT scan with or without contrast, MRI, or 
gallbladder ultrasound. 
Discontinuation and rescue intervention for acute pancreatitis 
If laboratory values and/or abdominal imaging support the diagnosis of acute pancreatitis, the 
participant must discontinue therapy with investigational product(s) but will continue in the 
study on another glucose-lowering regimen; details on rescue intervention will be provided. The 
most appropriate diabetes therapeutic regimen will be decided by the investigator, based on the 
9*;=2,29*7=L<,5272,*5<=*=><;.?2.@8/=1.9*;=2,29*7=L<,87,862=*7=6.-2,*=287<<18>5-+.
conducted to assess any potential causal relationship with pancreatitis. 
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Reporting adverse events and serious adverse events of acute pancreatitis 
Each event of pancreatitis must be reported as an AE or SAE. 
The investigator must report the event as an SAE if the typical signs and/or symptoms of 
pancreatitis are present and are confirmed by 
 laboratory values (lipase or amylase [total and/or pancreatic]), and 
 imaging studies. 
If a potential event does not meet all of these criteria, the investigator will decide the seriousness 
of the event, either AE or SAE. 
&1.27?.<=20*=8;@255*5<8;.?2.@=1.9*;=2,29*7=L<,87,862=*7=6.-2,*=287<=8*<<.<<*7B
potential causal relationship with pancreatitis and will report the relatedness of study 
intervention(s) to the event. 
8.3.3.5. 
Thyroid C-Cell Hyperplasia and C-Cell Neoplasms 
Individuals with personal or family history of MTC and/or MEN2 will be excluded from the 
study. 
8.3.3.6. 
Hypoglycemia 
Participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia, how to treat hypoglycemia, and how to collect appropriate information for each 
episode of hypoglycemia in the study according to the SoA (Section 1.3). Site personnel will 
enter this information into the eCRF at each visit. 
&8*?82-->952,*=.;.98;=270*55,87<.,>=2?.?*5>.<F
 mg/dL (3.9 mmol/L) occurring 
within 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al. 
2010; Danne et al. 2013). 
CGM data will not be used to evaluate hypoglycemia. 
Hypoglycemia classification and definitions 
Level 1 
Glucose <70 mg/dL (<3.9 6685	*7-G 60	-G
 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 with glucose <54 mg/dL (<3.0 mmol/L). This glucose threshold is clinically 
relevant regardless of the presence or absence of symptoms of hypoglycemia. 
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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, which occurs 
at night and presumably during sleep. 
Reporting of severe hypoglycemic events 
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE CRF and report it to Lilly as an SAE. 
The investigator should also determine if repeated or prolonged episodes of hypoglycemia 
occurred prior to the severe event. 
8.3.3.7. 
Severe, Persistent Hyperglycemia 
Severe, persistent hyperglycemia will be assessed during the study to determine the risk of 
extreme imbalance in glycemic control. 
Severe, persistent hyperglycemia is defined as an FBG (via SMBG) >270 mg/dL (>15 mmol/L) 
during the first 4 weeks or >240 mg/dL (>13.3 mmol/L) from Weeks 5-12 occurring for at least 
2 consecutive weeks. No rescue therapy should be used, see section 6.1.2. 
8.3.3.8. 
Hypersensitivity Reactions 
Many drugs, particularly oral agents and biologic agents, carry the risk of systemic 
hypersensitivity reactions. If such a reaction occurs, additional data should be provided to the 
sponsor in the designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
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In the case of a suspected hypersensitivity event, additional blood samples should be collected as 
described in Appendix 2, Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory. 
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
27=.;?.7=287*7-=1.<987<8;L<-.<207*=ed 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. 
8.3.3.9. 
Injection-Site Reactions 
Symptoms and signs of a local ISR may include erythema, induration, pain, pruritus, and edema. 
If an ISR is reported by a participant or study personnel, the ISR CRF will be used to capture 
additional information about this reaction, for example, injection-site pain, degree and area of 
erythema, induration, pruritis, and edema. 
At the time of AE occurrence in the tirzepatide group, samples will be collected for measurement 
of tirzepatide anti-drug antibodies and tirzepatide concentration. 
8.3.3.10. Diabetic Retinopathy Complications 
Dilated retinal fundoscopic examination for all participants will be performed by a qualified eye 
care professional (ophthalmologist or optometrist) between Visit 1 and Visit 2 or at a previous 
examination F90 days of screening meeting study requirements. The results from this 
examination will be recorded on a specific retinopathy CRF as a baseline measure of retinopathy. 
Additional dilated fundoscopic examinations should be performed when clinically indicated by 
any AE suspected of worsening retinopathy, and the findings must be recorded on the 
retinopathy CRF. 
8.3.3.11. Hepatobiliary Disorders 
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed. In 
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in Section 
8.2.7. 
8.4. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.5. 
Pharmacodynamics 
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section. 
8.6. 
Genetics 
Genetics are not evaluated in this study. 
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8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity will not be proactively assessed in this study. 
In the case of hypersensitivity or ISR, samples will be collected if needed as described in 
Section 10.2.1. 
8.9. 
Health Economics 
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations 
The statistical analysis plan will be developed and approved prior to first participant first visit, 
and it will include a more technical and detailed description of the statistical analyses described 
in this section. 
9.1. 
Statistical Hypotheses 
The null hypothesis corresponding to the primary objective of this study is as follows: 
 P 
H1,0: Mean change from baseline in HbA1c is greater than or equal to zero at Week 12 in 
tirzepatide 5 mg arm. 
Operationally the hypotheses will be evaluated by 2-sided tests. 
9.2. 
Analyses Sets 
This table defines the analysis population and datasets for the purposes of analysis based on the 
estimands defined in Section 3. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
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 change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan or clinical study report. Additional exploratory analyses of the data 
will be conducted as deemed appropriate. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05/1-sided alpha 
level of 0.025, unless otherwise stated, and all confidence intervals will be given at a 2-sided 
95% level. 
Baseline is defined as the last non-missing measurement recorded on or before the treatment 
initiation visit, prior to first dose of treatment, unless otherwise specified. 
Analyses will use the EAS population set to evaluate the efficacy estimand. 
Population/Analysis Set 
Description 
Screened population 
All participants who signed informed consent 
Modified intent-to-treat population (mITT) 
All participants who are exposed to at least 1 dose of study 
intervention.  
Efficacy Analysis Set (EAS): This analysis set will 
be used to estimate the efficacy estimand for the 
primary objective 
Data obtained during the treatment period from the mITT 
population excluding participants who were inadvertently 
enrolled, excluding data after permanent discontinuation of 
treatment or initiation of prohibited medication 
Safety Analysis Set (SS): This analysis will be used 
to assess the safety of study treatment 
Data obtained during the Treatment Period from the mITT 
population, regardless of adherence to treatment or 
initiation of prohibited medication 
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Summary statistics for continuous measures may include sample size, mean, standard deviation, 
median, minimum, and maximum. The analysis model to make comparisons within treatment 
relative to continuous measurements assessed over time will be an MMRM with terms for: 
 visit 
 country 
 b*<.527.+,F

, and 
 baseline measurement as a covariate. 
For analyses of HbA1c, continuous baseline HbA1c will be included in the model instead of 
baseline HbA1c category. An unstructured covariance structure will model the relationship of 
within-participant errors. 
Summary statistics for categorical measures, including categorized continuous measures, will 
include sample size, frequency, and percentages. Logistic regression may be used to examine the 
treatment effect from baseline at 12 weeks in binary efficacy outcomes. The negative binomial 
regression model will be used to measure the within treatment effect of discrete count measures 
if deemed appropriate. 
Adjustments to the planned analyses are described in the final clinical study report or in the SAP. 
9.3.2. 
Primary Endpoint Analysis 
The primary endpoint for this study is change from baseline in HbA1c at Week 12. This endpoint 
will be used to evaluate the primary objective of the study (Section 3). 
The null hypothesis corresponding to the primary objective is specified in Section 9.1. 
The primary objective based on the efficacy estimand defined in Section 3 will be evaluated 
using the EAS dataset (Section 9.2). The primary analysis model for HbA1c measurements over 
time will be an MMRM. The response variable of MMRM will be change in HbA1c values from 
baseline obtained at each scheduled postbaseline visit. The independent variables of the MMRM 
model are visit, and country as fixed effects and baseline HbA1c as covariates. Missing data will 
be addressed by the MMRM model. No explicit imputation methods for missing data will be 
employed. The P values obtained for the least square means for change from baseline will be 
used to determine the statistical significance to achieve the primary objective. 
9.3.3. 
Secondary Endpoints Analysis 
Endpoints for secondary objectives are described in Section 3 and will be evaluated based on the 
efficacy estimand. Additional details will be provided in the SAP. 
9.3.4. 
Exploratory Endpoints Analysis 
Endpoints for exploratory objectives are described in Section 3 and will be evaluated based on 
the efficacy estimand. Additional details will be provided in the SAP. 
9.3.5. 
Safety Analyses 
Safety assessments will be done using the Safety Analysis Set (see Section 9.1) irrespective of 
adherence to study intervention or initiation of prohibited medication, unless indicated otherwise. 
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Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities and reported with preferred terms and system organ class. Selected notable AEs of 
interest may be reported using high-level terms or Standardized Medical Dictionary for 
Regulatory Activities Queries. 
Summary statistics will be provided for incidence of TEAEs, SAEs, and study discontinuation 
due to AEs, study intervention discontinuation due to AEs, or deaths from the time of first dose 
through end of study. Counts and proportions of participants experiencing AEs will be reported. 
9.3.5.1. 
Hypoglycemic Events 
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia will be 
summarized. Rate of hypoglycemic episodes will be analyzed using a generalized linear mixed-
effects model assuming negative binomial distribution for hypoglycemic episodes if data 
warrant. 
9.3.5.2. 
Gastrointestinal Events 
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided. 
9.3.5.3. 
Central Laboratory Measures and Vital Signs 
Values and changes from baseline to postbaseline values of appropriate central laboratory 
measures and vital signs will be summarized at each scheduled visit. 
The analysis model to make comparisons within treatment relative to continuous change from 
baseline values assessed over time will be an MMRM, with terms: visit, country, and baseline 
measurement as covariates. 
An unstructured covariance structure will model relationship of within-participant errors. 
The percentages of participants with treatment-emergent abnormal, high, or low laboratory 
measures at any time will be summarized. 
A treatment-emergent abnormal value is defined as a change from normal value at baseline to an 
abnormal value at any time during the follow-up. 
A treatment-emergent high result is defined as a change from a value less than or equal to the 
high limit at baseline to a value greater than the high limit at any time during the Treatment and 
Follow-Up periods. 
A treatment-emergent low result is defined as a change from a value greater than or equal to the 
low limit at baseline to a value less than the low limit at any time during the Treatment and 
Follow-Up periods. 
High and low limits will be provided in SAP. 
9.3.6. 
Subgroup Analyses 
Subgroup analyses of the primary and secondary endpoint will be made to assess consistency of 
the improvement from baseline across the following subgroups 
 Age group: < 65 B.*;<?<G65 years 
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 Sex: female vs male 
 Race: white vs black vs other 
 Ethnicity: Hispanic vs not Hispanic 
 Baseline GLP-1 RA: liraglutide vs semaglutide vs dulaglutide 
 Baseline GLP-1 RA equivalent doses (adapted from Almandoz et al. 2020):  
o dulaglutide 0.75 mg and liraglutide 1.2 mg vs  
o dulaglutide 1.5 mg, semaglutide 0.5 mg, and liraglutide 1.8 mg vs  
o dulaglutide 3 mg and semaglutide 1 mg vs  
o dulaglutide 4.5 mg and semaglutide 2 mg, and 
 *<.527.+,F

. 
9.4. 
Interim Analysis 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended. 
9.5. 
Sample Size Determination 
A sample size of 150 participants will provide at least 90% power to show an improvement in 
HbA1c from baseline at Week 12. This sample size is using the following assumptions: 
 a 1-sample t-test with 2-sided significance level of 0.05 
 within treatment difference from baseline at Week 12 is 0.3%, and 
 intra-subject variability of 1.1%. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
O consensus ethical principles derived from international guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
O applicable ICH Good Clinical Practice Guidelines 
o International Organization for Standardization (ISO) 14155, and 
O applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents, for example, advertisements, must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
O Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
O Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
O Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations, and 
o Reporting to the sponsor or designee 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 
&1.27?.<=20*=8;8;=1.27?.<=20*=8;L<;.9;.<.7=*=2?.@255.A95*27=1.7*=>;.8f the study, 
including the risks and benefits, to the potential participant and answer all questions regarding 
the study. 
Potential 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. 
Participants who are rescreened are required to sign a new ICF. 
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. 
&1.9*;=2,29*7=6><=+.27/8;6.-=1*==1.9*;=2,29*7=L<9.;<87*5<=>-B-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 Assessment Committee 
Not applicable. 
10.1.5.2. External Clinical Endpoint Committee 
Not applicable. 
10.1.6. 
Dissemination of Clinical Study Data 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, study 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 study, after 
anonymization, with the exception of pharm*,8427.=2,8;0.7.=2,-*=*R 
Data are available to request 6 months after the indication studied has been approved in the US 
*7-'*7-*/=.;9;26*;B9>+52,*=287*,,.9=*7,.@12,1.?.;2<5*=.;R!8.A92;*=287-*=.8/-*=*
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data-sharing agreement. 
Data and documents, including the study protocol, 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. 
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The investigator must review and confirm that data entries are accurate and complete throughout 
the duration of the study, by physically or electronically signing the CRF, as instructed by the 
sponsor. All completed CRFs must be signed prior to archival. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
Quality tolerance limits 
Quality tolerance limits will be predefined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These predefined parameters will be 
monitored during the study and important excursions from the quality tolerance limits 
and remedial actions taken will be summarized in the clinical study report. 
Data monitoring and management 
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. 
The sponsor or designee will perform monitoring to confirm that data transcribed into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the Clinical Trial 
Agreement unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor. 
In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by sponsor or its representatives, and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
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Electronic data capture system 
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, other data (study drug administration and hypoglycemia information) will be 
collected by the participant, via a paper source document, and will be transcribed by the 
authorized study personnel into the EDC system and will serve as the source documentation. 
Data storage and access 
Data collected via the sponsor-provided data capture system(s) 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 system(s). Prior to decommissioning, the investigator will 
receive or access an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
=1.,.7=;*5?.7-8;L<-*=*+*<.<B<=.6*7-reports or electronic transfers 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 
=1.27=.0;2=B8/=1.-*=*,855.,=.-%8>;,.-8,>6.7=<*;./25.-*==1.27?.<=20*=8;L<<2=. 
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. 
The first act of recruitment is the /2;<=<2=.L</2;<=9*;=2,29*7=?2<2=(2<2=and will be the study 
start date. 
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Study or site termination 
&1.<987<8;8;<987<8;L<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: 
o discontinuation of further study intervention development 
 For site termination: 
o failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsorLs procedures, or GCP guidelines 
o inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, and 
o total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy 
7*,,8;-*7,.@2=1=1.<987<8;L<9>+52,*=2879852,B, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information 
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical study. 
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 
8/R=2;C.9*=2-.R8;*/=.;R=2;C.9*=2-. become(s) commercially available. 
Sample Type  
Custodian  
Retention Period after Last Patient Visita  
Tirzepatide concentrationb 
Sponsor or designee 
1 year 
Tirzepatide anti-drug antibodiesb 
Sponsor or designee 
15 years 
a Retention periods may differ locally. 
b Sample collection only for hypersensitivity and injection-site reactions. 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in the table below will be performed by the Lilly-designated laboratory or by 
the local laboratory as specified. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded. 
In circumstances where the sponsor approves local laboratory testing in lieu of central laboratory 
testing (in the table below), the local laboratory must be qualified in accordance with applicable 
local regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
 
 
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Clinical Laboratory Tests  
Comments 
Hematology 
Assayed by Lilly-designated laboratory. 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs - red blood cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs - white blood cells)  
  
Differential 
  
  Neutrophils, 
  
  Lymphocytes 
  
  Monocytes 
  
  Eosinophils 
  
  Basophils 
  
Platelets 
  
Cell morphology (RBCs and WBCs) if indicated 
  
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  
  
Creatine kinase (CK) 
  
Uric acid 
  
Total protein 
  
Albumin 
  
Calcium 
  
Phosphorus 
  
Glucose 
 
Lipid Panel 
Assayed by Lilly-designated laboratory.  
Total cholesterol 
 
Triglycerides 
 
High-density lipoprotein (HDL-C) 
 
Low-density lipoprotein (LDL-C) 
Generated by Lilly-designated laboratory. 
If triglycerides are >400, direct LDL will be measured. 
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Very low-density lipoprotein (VLDL-C) 
Generated by Lilly-designated laboratory. 
Hormones (female) 
  
Serum pregnancy  
Assayed by Lilly-designated laboratory.  
Urine pregnancy 
Assayed and evaluated locally.  
Follicle-stimulating hormone (FSH)  
Assayed by Lilly-designated laboratory.  
Urine Chemistry 
Assayed by Lilly-designated laboratory. 
Albumin 
  
Creatinine 
  
Calculations 
Generated by Lilly-designated laboratory.  
eGFR (CKD-EPI) calculated using creatinine 
Urinary albumin/creatinine ratio (UACR) 
  
Additional Testing  
Assayed by Lilly-designated laboratory.  
 
HbA1c 
  
Calcitonin 
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event 
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory test results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection, 
ideally prior to the next dose after the event, to assess post-event return-to-baseline values. 
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Timing 
Laboratory Testa 
Collect from 30 min to 4 h after the start of the 
event. 
P 
Note: The optimal collection time is from 1 
to 2 h after the start of event. 
Total tryptase 
Complements (C3, C3a, and C5a) 
Cytokine panel (IL-SQS
8;*7B,B=8427.9*7.5
that includes these 3 cytokines)  
Collect only if not already collected on the same 
day as the event. 
P 
Note: If collecting, collect up to 12 h after 
the start of the event. 
Tirzepatide anti-drug antibodies 
Tirzepatide concentration 
Abbreviation: IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory, if a validated assay is 
available. 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. 
What 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. 
 Section 8.3.1 provides information on the timing and mechanism for collecting events. 
 Section 8.3.3 provides more information on the collection and reporting of AEs and 
SAEs for the clinical endpoints. 
10.3.1. 
Definition of AE 
AE definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This definition 
includes events related to the investigational medical device or comparator and events 
related to the procedures involved except for events in users or other persons, which only 
include events related to investigational devices. 
Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator, that is, not related to 
progression of underlying disease. 
 Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
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 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT meeting the AE definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
27?.<=20*=8;=8+.68;.<.?.;.=1*7.A9.,=.-/8;=1.9*;=2,29*7=L<,87-2=287 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
-2<.*<.	-2<8;-.;+.270<=>-2.->75.<<68;.<.?.;.=1*7.A9.,=.-/8;=1.9*;=2,29*7=L<
condition. 
 Medical or surgical procedure, for example, endoscopy and appendectomy: the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more 
of the criteria listed: 
 Results in death 
 Is life-threatening 
o 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. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
o 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 
91B<2,2*7L<8//2,.8;8>=9*=2.7=<.==27086952,*=28ns 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. 
o Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent disability/incapacity 
o &1.=.;6-2<*+252=B6.*7<*<>+<=*7=2*5-2<;>9=2878/*9.;<87L<*+252=B=8,87->,=
normal life functions. 
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o 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. 
 Is a congenital anomaly/birth defect 
o Abnormal pregnancy outcomes, for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy, are considered SAEs. 
 Other situations 
o 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. 
o 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. 
 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 to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a 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. 
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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 
=1.9*;=2,29*7=L<6.-2,*5;.,8;-<27*,,8;-*7,.with =1.27?.<=20*=8;L<78;6*5,5272,*5
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 *,,.9=*+5./8;=1.27?.<=20*=8;=8<.7-918=8,892.<8/=1.9*;=2,29*7=L<6.-2,*5
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 or 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 1 of the following categories: 
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. An 
AE that is assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. 
An event is defined as JseriousK when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
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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. 
 Jreasonable possibilityK8/*;.5*=287<129,87?.B<=1*==1.;.*;.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 in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any postmortem 
findings including histopathology. 
10.3.5. 
Reporting of SAEs 
SAE reporting via an electronic data collection tool 
 The primary mechanism for reporting an SAE will be the electronic data collection tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see next 
section) 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. 
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 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on an SAE paper form (see next section) or 
to the sponsor or designee by telephone. 
 Contacts for SAE reporting can be found in site training materials. 
SAE reporting via paper form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in site training materials. 
10.3.6. 
Regulatory Reporting Requirements 
SAE regulatory reporting 
Prompt notification by the investigator to the sponsor of 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, IRB/IEC, and 
investigators. 
 An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (for example, summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
(WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Women not of 
childbearing 
potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 have a congenital anomaly such as Müllerian agenesis 
 are infertile due to surgical sterilization, or 
 are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral 
salpingo-oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal 
state 
The postmenopausal state is defined as a woman: 
 at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or 
 aged at least 40 years and up to 55 years with an intact uterus, not 
on hormone therapya, who has had cessation of menses for at least 
12 consecutive months without an alternative medical cause, AND 
with a follicle-stimulating hormone >40 mIU/mL; or 
 55 years or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea, or 
 aged at least 55 years with a diagnosis of menopause prior to 
starting hormone replacement therapy. 
a Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
SERMs, or chemotherapy that could induce transient amenorrhea. 
Abbreviation: SERMs = selective estrogen receptor modulators. 
 
 
 
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10.4.2. 
Contraception Guidance 
10.4.2.1. Females  
Women of childbearing potential (WOCBP) and women not of childbearing potential 
(WNOCBP) may participate in this study. See Section 10.4.1 for definitions and additional 
requirements related to contraception. 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
 
 
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 the study, 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 agree to do the following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative 
urine result within 24 hours prior to first dose of study intervention. See 
the protocol Schedule of Activities for subsequent pregnancy testing 
requirements. 
Contraception 
Agree to use 2 forms of effective contraception, where at least 1 form 
must be highly effective. 
These forms of contraception must be used during the study and for at 
least 30 days after the last dose of the study intervention. 
 
 
 
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Examples of different forms of contraception: 
Methods 
Examples 
Highly effective 
contraception (less than 
1% failure rate) 
 female sterilization 
 combination oral contraceptive pill 
 progestin-only contraceptive pill (mini-pill) 
 implanted contraceptives 
 injectable contraceptives 
 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, or 
o diaphragm with spermicide, or 
o female condom with spermicide. 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 
 spermicide alone 
 periodic abstinence 
 fertility awareness (calendar method, temperature method, 
cervical mucus, or symptothermal) 
 withdrawal 
 postcoital douche, or 
 lactational amenorrhea 
 
 
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10.4.2.2. Men 
The table below describes contraception guidance for all men. 
Topic 
Guidance 
For all men  
should refrain from sperm donation for the 
duration of the study and for 5 half-lives of 
study intervention, plus 90 days, corresponding 
to 4 months after the last injection 
Contraception for men with partners of 
childbearing potential  
 either remain abstinent, if this is their 
preferred and usual lifestyle 
or 
 must use condoms during intercourse 
for the duration of the study, and 
 for 5 half-lives of study intervention, 
plus 90 days, corresponding to 4 months 
after the last injection 
Contraception for men in exclusively same-
sex relationships, as their preferred and usual 
lifestyle 
Are not required to use contraception 
Examples of highly effective, effective, and unacceptable methods of contraception can be found 
below. 
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and mini-
pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or 
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide 
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o 
condom with spermicide 
o 
diaphragm with spermicide, or 
o 
female condom with spermicide 
 
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, diaphragm 
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with spermicide, female condom with spermicide) to 
be considered effective. 
Ineffective forms of contraception 
 
spermicide alone 
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of above 2, 
cervical mucus, symptothermal) 
 
withdrawal 
 
post coital douche, and 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic evaluation testing 
See protocol Section 8.2.7 or guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing 
   Hemoglobin 
    HAV total antibody 
   Hematocrit 
    HAV IgM antibody 
   Erythrocytes (RBCs - red blood cells) 
Hepatitis B virus (HBV) testing 
   Leukocytes (WBCs - white blood cells) 
    Hepatitis B surface antigen (HBsAg) 
   Differential: 
    Hepatitis B surface antibody (anti-HBs) 
       Neutrophils, segmented 
    Hepatitis B core total antibody (anti-HBc) 
       Lymphocytes 
    Hepatitis B core IgM antibody 
       Monocytes 
    HBV DNAb 
       Basophils 
Hepatitis C virus (HCV) testing 
       Eosinophils 
    HCV antibody 
   Platelets 
    HCV RNAb 
   Cell morphology (RBC and WBC) 
Hepatitis D virus (HDV) testing 
Hepatic Clinical Chemistry Panel 
    HDV antibody 
   Total bilirubin 
Hepatitis E virus (HEV) testing 
   Direct bilirubin 
    HEV IgG antibody 
   Alkaline phosphatase (ALP) 
    HEV IgM antibody 
   Alanine aminotransferase (ALT) 
    HEV RNAb 
   Aspartate aminotransferase (AST) 
Anti-nuclear antibody (ANA) 
   Gamma-glutamyl transferase (GGT) 
Anti-smooth muscle antibody (ASMA)a 
   Creatine kinase (CK) 
Anti-actin antibodyc 
Hepatic Coagulation Panel 
Immunoglobulin IgA (quantitative) 
   Prothrombin time, INR (PT-INR) 
Immunoglobulin IgG (quantitative) 
Urine Chemistry 
Immunoglobulin IgM (quantitative) 
   Drug screen 
Epstein-Barr virus (EBV) testing 
Haptoglobin 
    EBV antibody 
 
Tests assayed ONLY by investigator-designated local laboratory  
Acetaminophen 
Cytomegalovirus (CMV) testing 
Acetaminophen protein adducts 
    CMV antibody 
Alkaline phosphatase isoenzymes 
    CMV DNAb 
Ceruloplasmin 
Herpes simplex virus (HSV) testing 
Copper 
    HSV (Type 1 and 2) antibody 
Ethyl alcohol (EtOH) 
    HSV (Type 1 and 2) DNAb 
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Phosphatidylethanol (PEth) 
Liver kidney microsomal type 1 (LKM-1) antibody 
Urine Chemistry 
Microbiology  
    Ethyl glucuronide (EtG) 
Culture: 
Epstein-Barr virus (EBV) testing 
    Blood 
    EBV DNAb 
    Urine 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
 
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10.6. Appendix 6: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device Deficiencies: 
Definition and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
Refer to Section 10.3, Appendix 3 for definitions and procedures for recording, evaluating, 
follow-up, and reporting of all events. 
 
 
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10.7. Appendix 7: Standardized Protocols for the Measurement of Height, 
Weight, Waist Circumference, BMI, and Vital Signs 
The following information has been adapted from standardized physical measurement protocols 
/8;=1.)8;5-.*5=1";0*72C*=287L< STEP wise approach to Surveillance Manual. 
Measuring height 
Step 1.  Ask the participant to remove their footwear and any headgear; light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured. 
Step 2.  Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall. 
Step 3.  Ask the participant to look straight ahead without tilting their head up. 
Step 4.  Ask the participant to breathe in and stand tall. If using a stadiometer or fixed measuring 
device, move the -.?2,.L<6.*<>;.6.7=*;60.7=5B-8@787=8=1.=898/=1.9*;=2,29*7=L<1.*-
$.,8;-=1.9*;=2,29*7=L<1.201=27,.7=26.=.;,6=8-.,26*595*,. 
Measuring weight 
 Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilogram. 
 All weights for a given participant should be measured using the same scale, whenever 
possible. 
 Participants should be lightly clothed but not wearing shoes while their weight is measured. 
 
Step 1.  Ask the participant to remove their footwear, outerwear (coat, jacket, etc.), and any 
headgear; light headgear worn for religious reasons can remain, but this should be worn by the 
participant at every clinic visit when weight is measured. 
Step 2.  Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface). 
Step 3. Ask the participant to step onto the scale with 1 foot on each side of the scale. 
Step 4. Ask the participant to stand still with arms by sides and then record weight in kilogram 
(kg) to the nearest one-tenth kg. 
Measuring waist circumference 
 Use non-stretchy tape 
 Waist circumference should be measured at midpoint, between lower margin of last palpable 
rib and top of iliac crest (approximately 1 inch [2.54 cm] above the navel) 
 Participants should be lightly clothed, and 
 Measure to the nearest 0.5 cm. 
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Step 1. Ask the participant to stand with their feet close together, and arms at their side with their 
body weight evenly distributed. 
Step 2. Ask participant to relax. 
Step 3. Measurements should be recorded at the end of a normal expiration. 
Calculation of BMI 
Height and weight measurements will be used to calculate BMI. 
 
BMI = weight (kg) / [height (m)]2. 
Calculation of BMI with amputation or limb loss 
In participants with limb amputation or limb loss, use the formula given in the following link: 
Amputee Coalition H https://www.amputee-coalition.org/limb-loss-resource-center/resources-
filtered/resources-by-topic/healthy-living/about-bmi/. 
Vital sign measurements (blood pressure and heart rate) 
 
Vital sign measurements, measured by pulse, should be taken before obtaining an ECG 
tracing and before collection of blood samples for laboratory testing. 
 An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be 
used to ensure the accuracy of BP measurements. 
 
Blood pressure should be taken with an automated blood pressure instrument. 
 
If blood pressure and pulse measurements are taken separately, pulse should be taken 
prior to blood pressure. 
Step 1. The participant should sit quietly for approximately 5 minutes before vital signs 
measurements are taken. 
Step 2. For each parameter, 3 measurements will be taken using the same arm, preferably the 
nondominant arm. 
Step 3. The recordings should be taken at least 1 minute apart. Each measurement of sitting 
pulse and blood pressure needs to be recorded in the CRF. 
Note: In the event pulse measurement cannot be taken via an automated blood pressure 
instrument, the preferred location for measurement of pulse is the radial artery. 
 
 
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10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
7*7.A,.9=287*5,2;,>6<=*7,.*/=.;;.,.2?270=1.<987<8;L<@;2==.7*99;8?*5<2=.<6*B
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 J$.68=.(2<2=<K 
 a change in the method of study intervention administration 
 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. The study site should capture the visit location and method with 
a specific explanation for any data missing because of missed in-person site visits in 
source document and CRF. Examples of assessments to be completed in this manner 
include AEs and PCs, concomitant medications, review study participant diary, including 
study intervention compliance, review diet, and exercise goals. 
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 and permitted by local 
regulations. Procedures performed at such visits may include, but are not limited to, 
weight measurement, blood sampling, vital signs, conducting physical assessments, and 
collecting health information. 
Every effort should be made for the participant to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of the participant and investigational site 
staff. 
Additional consent from the participant will be obtained for participants if needed per 
local regulations. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for calcitonin. The local laboratory must be qualified in 
accordance with applicable local regulations. 
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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 
 *<4270=1.9*;=2,29*7=L<-.<207..=808=8=1.<2=.*7-;.,.2?.<=>-Bsupplies on a 
9*;=2,29*7=L<+.1*5/*7- 
 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 
?.;2/2,*=2878/9*;=2,29*7=L<;.,.29=8/<=>-B<>9952.< 
 When delivering supplies to a location other than the study site (for example, 
parti,29*7=L<186.=1.27?.<=20*=8;<987<8;8;+8=1, 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. 
If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, this additional requirement must be met: 
 Only authorized study personnel may supply, prepare, or administer study 
intervention. 
Screening period guidance 
Visit 1 to Visit 2 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening are valid for a maximum of 30 days. The following rules will be applied for active 
participants whose participation in the study must be paused due to exceptional circumstances: 
 If screening is paused for less than 30 days from screening to Visit 2: the participant 
will proceed to the next study visit per the usual SoA, provided that Visit 2 must be 
conducted within 14 days from first screening. 
o &1.<2=.<18>5-,87->,==1.7.A=?2<2=2/=1.9*;=2,29*7=L<.5202+252=B,;2=.;2**;.
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
9*;=2,29*7=L<,87<.7=*7--8,>6.7==12<,87/2;6*=28727=1.<8>;,.
documentation. 
 If screening is paused for more than 30 days from screening: The participant must be 
discontinued because of screening interruption due to an exceptional 
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92 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. This rescreen is in addition to the 
one allowed by the main protocol. The screening procedures per the usual SoA should 
be followed, starting at the screening visit to ensure participant eligibility by Visit 2. 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the inves=20*=8;L<-2<,;.=2879*;=2,29*7=<
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. 
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. 
The primary endpoint visit and end of treatment visit, Visit 5 (Week 12), should be completed 
per original schedule whenever possible and safe to do so. The visit window should be within ±3 
days relative to the target visit date. 
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/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 
27?.<=20*=8;L< source documentation and should be transferred to the site in a secure and timely 
manner. 
 
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93 
10.9. 
Appendix 9: Abbreviations and Definitions 
Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
American Diabetes Association 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
Anti-GAD 
anti-glutamic acid decarboxylase 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CGM 
continuous glucose monitoring 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease - epidemiology collaboration 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety or effectiveness, or performance of 
a drug or drug delivery system 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements 
CONSORT 
Consolidated Standards of Reporting Trials 
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 
CT 
computed tomography 
CV 
cardiovascular 
CVD 
cardiovascular disease 
Device 
deficiencies 
equivalent to product complaint 
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EAS 
efficacy analysis set 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ED 
early discontinuation 
eGFR 
estimated glomerular filtration rate 
enroll 
the act of assigning a participant to a treatment. Participants who are enrolled in the study are 
those who have been assigned to a treatment 
enter 
participants entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives 
FBG 
fasting blood glucose 
FSG 
fasting serum glucose 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide  
GLP-1 
05>,*087S524.9.9=2-.S 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
HbA1c 
hemoglobin A1c 
IB 
7?.<=20*=8;L<;8,1>;. 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
7?.<=20*=287*5 .-2,27*5#;8->,=<..*5<8Jinvestigational productK 
A medicinal product which is being tested or used as a reference, including as a placebo, in a 
clinical trial. 
informed 
consent 
a process by which a participant voluntarily confirms their willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to the 
9*;=2,29*7=L<-.,2<287=89*;=2,29*=.7/8;6.-,87<.7=2<-8,>6.7=.-+B6.*7<8/*@;2==.7
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 
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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 
*>=18;2C.-/8;6%..*5<8J #K 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ISR 
injection-site reaction 
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 
IW-SP 
Impact of Weight on Self Perception 
LADA 
latent autoimmune diabetes in adults 
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 */*25>;.=8>9185-8;68;.8/=1.J;201=<K8/
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:  
D-8<.862<<287*<<8,2*=.-@2=1*78;*9;8->,=,8695*27= 
D-2<9.7<2708;><.8/.A92;.-6.-2,*=287 
D><.8/6.-2,*=2879*<==1.;.,866.7-.-27-use date 
D-2<9.7<2708;><.8/*7269;89.;5B<=8;.-6.-2,*=287 
D><.8/ an adulterated dosage form or administration technique inconsistent with the 
6.-2,*=287L<5*+.5270, for example, Summary of Product Characteristics, IB, local label, 
protocol, or 
D<1*;.-><.8/,*;=;2-0.<9;.-filled 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 
MEN2 
multiple endocrine neoplasia syndrome type 2 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid carcinoma 
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96 
MTD 
maximum tolerated dose 
NAFLD 
nonalcoholic fatty liver disease 
OAM 
oral antihyperglycemic medication 
participant 
e:>2?*5.7==8%=.;6J<>+3.,=K*727-2?2->*5 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 
QTc 
corrected QT interval 
QD 
once-daily 
QW 
once-weekly 
RA 
receptor agonist 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
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  
SDP 
single-dose pen 
SGLT-2i 
sodium-glucose cotransporter-2 inhibitor 
SMBG 
self-monitoring of blood glucose 
SoA 
schedule of activities 
T1D 
Type-1 diabetes 
T2D 
Type-2 diabetes 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
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WNOCBP 
women not of childbearing potential 
 
 
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CONFIDENTIAL 
I8F-MC-GPIL 
98 
11. 
References 
[ADA] American Diabetes Association. Introduction: Standards of Medical Care in DiabetesI
2022. Diabetes Care. 2022;45(Suppl 1): S1-S2. https://doi.org/10.2337/dc22-Sint 
Almandoz JP, Lingvay I, Morales J, Campos C. Switching between glucagon-like peptide-1 
receptor agonists: rationale and practical guidance. Clin Diabetes. 2020;38(4): 390-402. 
https://doi.org/10.2337/cd19-0100 
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400. https://doi.org/10.1111/j.1572-0241.2006.00856.x 
Battelino T, Bergenstal R, Rodriguez A. et al. Effect of tirzepatide versus insulin degludec on 
glycaemic control captured with continuous glucose monitoring in patients with type 2 
diabetes (SURPASS-3 CGM). In Diabetologia (Vol. 64, No. Suppl 1, pp. 244-244); 2022. 
New York, NY, United States: Springer 
Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of hyperglycemia in type 2 
diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the 
European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487-493. 
https://doi.org/10.2337/dci19-0066. Erratum in: Diabetes Care. 2020;43(7):1670. 
https://doi.org/10.2337/dc20-er07 
Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to 
titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 
randomized clinical trial. JAMA. 2022;327(6):534-545. 
https://doi.org/10.1001/jama.2022.0078 
Danne T, Philotheou A, Goldman D, et al. A randomized trial comparing the rate of 
hypoglycemia H assessed using continuous glucose monitoring H in 125 preschool children 
with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study). 
Pediatr Diabetes. 2013;14(8):593-601. https://doi.org/10.1111/pedi.12051 
Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and 
increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, 
multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. https://doi.org/10.1016/S0140-
6736(21)02188-7 
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients 
with type 2 diabetes. N Engl J Med. 2021;385(6):503-515. 
https://doi.org/10.1056/NEJMoa2107519 
Frías JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-
1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and 
active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193. 
https://doi.org/10.1016/S0140-6736(18)32260-8 
Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American 
association of clinical endocrinologists and American college of endocrinology on the 
comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr 
Pract. 2020;26(1):107-139. https://doi.org/10.4158/CS-2019-0472 
$SSURYHGRQ$XJ*07


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99 
Gastaldelli A, Cusi K, Lando LF, et al. Effect of tirzepatide versus insulin degludec on liver fat 
content and abdominal adipose tissue in patients with type 2 diabetes (SURPASS-3 MRI). In 
Diabetologia (Vol. 64, No. Suppl 1, pp. 219-220); 2022. New York, NY, United States: 
Springer 
Hepprich M, Zillig D, Florian-Reynoso MA, et al. Switch-to-semaglutide study (STS-Study): a 
retrospective cohort study. Diabetes Ther. 2021;12(3):943-954. 
https://doi.org/10.1007/s13300-021-01016-y 
Jain AB, Ali A, Gorgojo Martínez JJ, et al. Switching between GLP-1 receptor agonists in 
clinical practice: Expert consensus and practical guidance. Int J Clin Pract. 
2021a;75(2):e13731. https://doi.org/10.1111/ijcp.13731 
Jain AB, Kanters S, Khurana R, et al. Real-world effectiveness analysis of switching from 
liraglutide or dulaglutide to semaglutide in patients with type 2 diabetes mellitus: the 
retrospective REALISE-DM study. Diabetes Ther. 2021b;12(2):527-536. 
https://doi.org/10.1007/s13300-020-00984-x 
Koizumi M, Takada T, Kawarada Y, et al. JPN guidelines for the management of acute 
pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32. https://doi.org/10.1007/s00534-005-1048-2 
Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec 
as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes 
(SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 
2021;398(10300):583-598. https://doi.org/10.1016/S0140-6736(21)01443-4 
Mounjaro [package insert]. Indianapolis, IN, USA: Eli Lilly and Company; 2022. 
Neumiller JJ. Clinical pharmacology of incretin therapies for type 2 diabetes mellitus: 
implications for treatment. Clin Ther. 2011;33(5):528-576. 
https://doi.org/10.1016/j.clinthera.2011.04.024 
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 
receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, 
randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. https://doi.org/10.1016/S0140-
6736(21)01324-6. Erratum in: Lancet. 2021;398(10296):212. https://doi.org/10.1016/S0140-
6736(21)01556-7 
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582. https://doi.org/10.1177/193229681000400311 
$SSURYHGRQ$XJ*07


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PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan Version 2 -I8F-MC-GPIL 
 
An Open-Label, Single-Arm, Phase 4 Study to Assess Glycemic Control When Adults with Type 
2 Diabetes Switch from a GLP-1 RA to Tirzepatide (SURPASS-SWITCH-2) 
 
  
NCT05706506 
 
Approval Date: 19-Sep-2023 
 
 


CONFIDENTIAL 
I8F-MC-GPIL Statistical Analysis Plan FINAL V2.0 
LY3298176 
PAGE 1 
Title Page 
Protocol Title: An Open-Label, Single-Arm, Phase 4 Study to Assess Glycemic Control When 
Adults with Type 2 Diabetes Switch from a GLP-1 RA to Tirzepatide (SURPASS-SWITCH-2) 
Protocol Number: I8F-MC-GPIL 
Compound Number: LY3298176 
Short Title: A study to investigate glycemic control in adults with type 2 diabetes switching to 
tirzepatide from a GLP-1 RA 
Acronym: SURPASS-SWITCH-2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND 
128801 
EudraCT 
2022-002708-18 
 
 
Confidential Information  
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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.  
 
 
 
 
 
 
 
 
 
Document ID: 
Template Version: 1.0 
 


CONFIDENTIAL 
I8F-MC-GPIL Statistical Analysis Plan FINAL V2.0 
LY3298176 
PAGE 2 
 
 
Eli Lilly and Company 
 
I8F-MC-GPIL 
 
An Open-Label, Single-Arm, Phase 4 Study to Assess Glycemic Control When 
Adults with Type 2 Diabetes Switch from a GLP-1 RA to Tirzepatide 
(SURPASS-SWITCH-2) 
 
September 19, 2023 
 
Statistical Analysis Plan Version 2.0 
 
Prepared by: 
PPD, part of Thermo Fisher Scientific 
7551 Metro Center Drive 
Austin, TX 78744, USA 
 
 
 
Issued by: 
 
 
 
 
 
 
 
 
Upon review of this document the undersigned approves the statistical analysis plan. The 
analysis methods and data presentation are acceptable, and the table, listing, and figure 
production can begin. 
 
 
Approved by: 
 
 
 
 
PPD
PPD


CONFIDENTIAL 
I8F-MC-GPIL Statistical Analysis Plan FINAL V2.0 
LY3298176 
PAGE 3 
Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................3 
Version history ...............................................................................................................................4 
1. 
Introduction .....................................................................................................................5 
1.1. 
Objectives, Endpoints, and Estimands ..............................................................................6 
1.2. 
Study Design ...................................................................................................................11 
2. 
Statistical Hypotheses ...................................................................................................12 
2.1. 
Multiplicity Adjustment ..................................................................................................12 
3. 
Analysis Sets ..................................................................................................................13 
4. 
Statistical Analyses .......................................................................................................14 
4.1. 
General Considerations ...................................................................................................14 
4.2. 
Participant Dispositions ..................................................................................................16 
4.3. 
Primary Endpoint Analysis .............................................................................................17 
4.3.1. 
Definition of endpoint .....................................................................................................17 
4.3.2. 
Main analytical approach ................................................................................................17 
4.4. 
Secondary Endpoint Analysis .........................................................................................18 
4.4.1. 
Definition of endpoints ...................................................................................................18 
4.4.2. 
Main analytical approach ................................................................................................18 
4.5. 
Exploratory Endpoints Analysis .....................................................................................20 
4.5.1. 
Summary for the Analysis of Exploratory Measures ......................................................23 
4.6. 
Safety Analyses...............................................................................................................24 
4.6.1. 
Extent of Exposure ..........................................................................................................24 
4.6.2. 
Adverse Events ...............................................................................................................25 
4.6.3. 
Product Complaints .........................................................................................................28 
4.6.4. 
Additional Safety Assessments .......................................................................................28 
4.7. 
Other Analyses ................................................................................................................35 
4.7.1. 
Subgroup analyses ..........................................................................................................35 
4.8. 
Interim Analyses .............................................................................................................35 
4.8.1. 
Data Monitoring Committee (DMC) or Other Review Board ........................................35 
4.9. 
Changes to Protocol-Planned Analyses ..........................................................................35 
5. 
Sample Size Determination ..........................................................................................36 
6. 
Supporting Documentation ..........................................................................................37 
6.1. 
Appendix 1: Demographic and Baseline Characteristics ...............................................37 
6.1.1. 
Prior and Concomitant Medications/Therapy .................................................................37 
6.1.2. 
Medical History ..............................................................................................................38 
6.2. 
Appendix 2: Treatment Compliance ...............................................................................39 
6.3. 
Appendix 3: Search Criteria for Standardized MedDRA Queries ..................................39 
7. 
References ......................................................................................................................41 
 


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I8F-MC-GPIL Statistical Analysis Plan FINAL V2.0 
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PAGE 4 
Version History 
This Statistical Analysis Plan (SAP) for study I8F-MC-GPIL is based on the protocol dated 
16AUG2022. 
The second version of SAP (SAP V2.0) for study I8F-MC-GPIL incorporates the updates jointly 
decided by Eli Lilly & Co. and PPD. Please see Revision History for details. 
 
SAP Version History Summary 
SAP Version Approval Date 
Change 
Rationale 
1.0 
13 Feb 2023 
Not Applicable 
Original version 
2.0 
19 Sep 2023 
Post-Dry Run 1 update 
 
 
Revision History 
The key changes of SAP V2.0 for study I8F-MC-GPIL are summarized below: 
• Section 3 (p. 13). Add the definition of inadvertent enroller. 
• Section 4.1 (p. 15). Clarify the CGM data from a non-compliant session will be excluded 
from CGM-related analysis. 
• Section 4.5 (p. 22). Remove the formula of mean 24-hour daily blood glucose. 
• Section 4.6.2 (p. 25). Explain how the AE of interest is defined. 
• Section 6.1.1 (p. 37). Add additional criteria to distinguish prior and con med. 
• Section 6.1.1 (p. 38). Defines OAM. 
• Section 6.3 (p. 39). List all SMQs requested in the TLF outputs. 
 
 
 


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I8F-MC-GPIL Statistical Analysis Plan FINAL V2.0 
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PAGE 5 
1. 
Introduction 
This study aims to investigate the effects of switching from glucagon-like peptide-1 receptor 
agonist (GLP-1 RA) therapy to tirzepatide in people with type 2 diabetes (T2D). Tirzepatide is a 
recently approved single molecule that acts as glucose-dependent insulinotropic polypeptide (GIP) 
and GLP-1 RA, which has demonstrated an ability to reduce HbA1c and body weight in adults 
with T2D across all 3 therapeutic doses: 5, 10, and 15 mg (Del Prato et al. 2021; Frías et al. 2021; 
Ludvik et al. 2021; Rosenstock et al. 2021; Dahl et al. 2022). 
The study will assess the efficacy and safety characteristics of the study intervention by using a 
starting dose of 5 mg tirzepatide and will evaluate changes in glycemic control, body weight, and 
gastrointestinal (GI) tolerability occurring in the first 12 weeks for the targeted study population. 
There are no changes to the analyses described in the protocol. Table, figure, and listing 
specifications are contained in a separate document. 
 


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1.1. 
Objectives, Endpoints, and Estimands 
 
Objectives 
Endpoints 
Primary 
 
• To demonstrate that participants with 
T2D switching from a stable dose of 
GLP-1 RA to tirzepatide 5 mg QW 
have an improvement in HbA1c at 
Week 12 compared to baseline 
• Change from baseline in HbA1c 
Secondary 
 
• To evaluate the changes in CGM-
assessed TAR from baseline at Week 
4 and at Week 12 
• Change from baseline in 
▪ Percentage of time per day that 
CGM-derived values are >180 
mg/dl (10 mmol/L) 
▪ Duration of time in minutes 
per day that CGM-derived 
values are >180 mg/dl (10 
mmol/L) 
• To evaluate the change in FSG from 
baseline at Week 12 
• Change from baseline in FSG  
• To evaluate the changes from baseline 
in weight at Week 12 
• Change from baseline in weight 
Exploratory 
 


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• To evaluate changes in CGM-derived 
measures from baseline over the 
course of 12 weeks 
 
• Change from baseline in  
▪ standard CGM metrics (TIR, 
TBR, GV)  
▪ time in TITR  
▪ composite of all in-ranges  
▪ mean 24-hr daily blood 
glucose  
▪ estimated post-prandial 
glucose excursion  
▪ estimated fasting glucose  
Abbreviations:  
CGM = continuous glucose monitoring; FSG = fasting serum glucose; GLP-1 RA = glucagon-like peptide-1 
receptor agonist; GV = glycemic variability; HbA1c = hemoglobin A1c; QW = once-weekly; T2D = type-2 
diabetes; TAR = time above range (>180 mg/dl or >10 mmol/L); TBR = time below range (≤70 mg/dl or ≤3.9 
mmol/L); TIR = time-in-range (71 to 180 mg/dL or 3.9 to 10 mmol/L); TITR = time in tight target range (71 to 
140 mg/dL or 3.9 to 7.8 mmol/L); 


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Primary estimand 
The primary estimand in this study is the efficacy estimand. 
The efficacy estimand focuses on the treatment effect if participants continued to receive the study treatment without prohibited 
medication. This estimand will be used in publications to inform prescribers or physicians. 
The primary clinical question of interest is 
What is the change in HbA1c from baseline to Week 12 in participants with T2D, regardless of changes in background oral 
antihyperglycemic medication (OAM), and assuming that participants continue to take treatment without use of prohibited 
medication? 
This estimand is described by the following attributes: 
• Population: participants with T2D on a GLP-1 RA who may benefit from additional therapy. Further details can be found in 
Protocol Section 5. 
• Endpoint: changes from baseline to Week 12 in HbA1c. 
• Treatment condition: treatment with tirzepatide regardless of changes to the background OAM. Further details on study 
treatment can be found in Protocol Section 6. 
• Intercurrent events of interest: “Treatment discontinuation for any reason” and “Initiation of prohibited medication” will be 
addressed using the following strategies: 
o As if participants stay on the treatment (hypothetical strategy) 
o As if participants did not receive prohibited medication (hypothetical strategy). 
• Population-level summary: Mean HbA1c change from baseline 
• Rationale for estimand: Estimating the effect of study intervention without confounding from prohibited mediations or 
treatment discontinuation 


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Secondary Endpoints based on Primary Estimand 
1) The first clinical question of interest is for the secondary objective regarding continuous glucose monitoring levels: 
What is the change in CGM-assessed time above range (TAR) from baseline in participants with T2D, regardless of changes in 
background OAM, and assuming that participants continue to take treatment without use of prohibited medication? 
There are two endpoints defined for the above question based on the primary estimand: 
a) The first endpoint is 
o the change from baseline to Week 12 in percentage of time per day that CGM-derived values are >180 mg/dl 
(10 mmol/L) 
b) The second endpoint is 
o the change from baseline to Week 12 in duration of time in minutes per day that CGM-derived values are >180 
mg/dl (10 mmol/L) 
Of note, the primary estimand is described by the following attributes: 
• Population: participants with T2D on a GLP-1 RA who may benefit from additional therapy. Further details can be found 
in Protocol Section 5. 
• Treatment condition: treatment with tirzepatide regardless of changes to the background OAM. Further details on study 
treatment can be found in Protocol Section 6. 
• Intercurrent events of interest: “Treatment discontinuation for any reason” and “Initiation of prohibited medication” will be 
addressed using the following strategies: 
o As if participants stay on the treatment (hypothetical strategy) 
o As if participants did not receive prohibited medication (hypothetical strategy). 
• Population-level summary: Mean HbA1c change from baseline 


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Rationale for estimand: Estimating the effect of study intervention without confounding from prohibited mediations or 
treatment discontinuation. 
2) The second clinical question of interest is for the secondary objective regarding fasting serum glucose levels: 
What is the change in fasting serum glucose (FSG) from baseline to Week 12 in participants with T2D, regardless of changes 
in background OAM, and assuming that participants continue to take treatment without use of prohibited medication? 
The endpoint corresponding to this question is the change from baseline to Week 12 in FSG. 
3) The third clinical question of interest is for the secondary objective regarding weight: 
What is the change in weight from baseline to Week 12 in participants with T2D, regardless of changes in background OAM, 
and assuming that participants continue to take treatment without use of prohibited medication? 
The endpoint corresponding to this question is the change from baseline to Week 12 in weight. 
 


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1.2. 
Study Design 
SURPASS-SWITCH-2 is a study to assess the changes in glycemic control when switching from 
a stable dose of a GLP-1 RA directly to tirzepatide 5 mg in participants with T2D. It has the 
following main design attributes: 
• Phase 4 study 
• Multicenter, single arm 
• Open label 
• The study consists of 2 periods: 
o Screening period: 3 weeks, starting from Visit 1 to Visit 2. 
o Treatment period: 12 weeks, starting from Visit 2 to Visit 5, where Visit 2 (on Week 
0) and Visit 5 (on Week 12) are fasting visits. 
• No dose escalation will be employed during the trial. The goal is to initiate tirzepatide at 
5 mg on Visit 2 (on Week 0) and maintain until Visit 5 (on Week 12). 
• The study will enroll approximately 150 participants. 
 
 
 
 


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2. 
Statistical Hypotheses 
For the primary estimand with primary endpoint, mean change in HbA1c percentage from 
baseline to Week 12, the following hypothesis is planned to be tested for tirzepatide 5 mg. Let 
the mean treatment difference be defined as μ = mean of ([HbA1c percentage at Week 12] – 
[baseline HbA1c percentage]), the statistical hypotheses are formulated as follows: 
H0: μ ≥ 0.0  vs.  Ha: μ < 0.0 
Operationally the hypothesis will be evaluated by 2-sided test, at a 2-sided alpha level of 0.05. 
2.1. 
Multiplicity Adjustment 
Multiplicity adjustment will not be implemented in this study. 
 
 


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3. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Population/Analysis Set 
Description 
Screened population 
• All participants who signed informed consent 
Modified intent-to-treat 
population (mITT) 
• All participants who are exposed to at least 1 dose of study 
intervention 
Efficacy Analysis Set 
(EAS) 
• This analysis set will be used to estimate the efficacy 
estimand for the primary objective, and for all other 
(secondary, exploratory) endpoints. 
• 
Data obtained during the treatment period from the mITT 
population, excluding (1) participants who were 
inadvertently enrolled* and (2) data after permanent 
discontinuation of treatment or initiation of prohibited 
medication. 
Safety Analysis Set (SS) 
• This analysis will be used to assess the safety of study 
treatment  
• Data obtained during the Treatment Period from the mITT 
population, regardless of adherence to treatment or initiation 
of prohibited medication. 
* An inadvertent enroller refers to a subject who does not meet inclusion/exclusion criteria but 
receives study intervention. 
 
 


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4. 
Statistical Analyses 
4.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
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 change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
statistical analysis plan or clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate. 
Nominal significance levels: 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless 
otherwise stated, and all confidence intervals will be given at a 2-sided 95% level. 
Timing of Primary Analysis: 
Primary analysis will be performed at database release after Last Participant Last Visit 
(LPLV). 
Definition of baseline: 
Baseline is defined as the last non-missing measurement recorded on or before the 
date/time of first dose. If the measurement time is not specified, it is assumed that any 
measurement taken on the date of first dose occurred prior to dosing. 
Populations for analysis: 
• Analyses will use the EAS to evaluate the primary efficacy estimand for all (secondary 
and exploratory) endpoints. 
• Safety analysis will be performed on the SS. 
Pooling of data: 
Study data will be pooled across centers. 
Analysis Windows: 
Visit windows will be defined for by-visit summary and analysis purposes. Summary data 
such as adverse events and concomitant medications which are not reported by visit will 
not use visit windows. Visit labels will be assigned to each post-baseline record based on 
the windows or intervals for study day relative to the date of first dose. A record with the 
study day closest to the target visit day (week × 7 days + 1) will be chosen when multiple 
records fall in the same visit window. In case of a tie, the record with the earlier date will 
be chosen. If Day 1 is missing, the closest visit on or before the date of first dose will be 
used as baseline. All visits will be included in the summary tables for worst post-baseline 
values. 
All efficacy and safety analyses will be based on the visit windows in Table 1. 
 
 


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Table 1. 
Visit Windows 
Study Day Relative to First Dose 
Visit 
Target Day 
Study day ≤ 1 
Baseline 
1 
  2 ≤ study day ≤ 43 
Week 4 (Visit 3) 
29 
44 ≤ study day ≤ 81 
Week 8 (Visit 4) 
57 
82 ≤ study day ≤ 88 
Week 12 (Visit 5)  
85 
General details of obtaining CGM-derived endpoints: 
Participants will wear the study-provided CGM sensor to complete three 14-day sessions. 
The 14-day session should be conducted over the period indicated below: 
1) Right after Visit 1, ideally Weeks -3 and -2. 
2) Before Visit 3, ideally Weeks 3 and 4. 
3) Before Visit 5, ideally Weeks 11 and 12. 
Compliance is defined as the percentage of expected data that are actually collected (i.e., 
number of actually collected measurements / number of expected measurements × 100%). 
For each of the session, the compliance must reach at least 70%, which equals to at least 
10 out of 14 days. If a participant fails to reach the 70% compliance threshold on the session 
before Visit 3, the participant can attempt another session right after Visit 3 (ideally Weeks 
5 and 6). CGM data collected from a non-compliant session will not be included in efficacy 
analysis. 
CGM measurements over the 14-day session will be downloaded from the sensor on Visits 
2, 3 (or 4 if non-compliance occurs), and 5, and are used to compute CGM-derived 
endpoints. 
General statistical methods: 
Summary statistics for continuous measures will include n, mean, standard deviation, 
median, minimum, and maximum. Categorical data (including categorized continuous 
measures) will be described using the sample size, participant count and percentage in each 
category. For the summary statistics of all numerical variables unless otherwise specified, 
minimum and maximum will be displayed to the same level of precision as reported. Mean 
and median will be displayed to one level of precision greater than the data collected. 
Standard deviation / standard error will be displayed to two levels of precision greater than 
the data collected. P-values will be rounded to three decimal places. If a P-value is less 
than 0.001 it will be reported as ‘<0.001.’ If a P-value is greater than 0.999 it will be 
reported as ‘>0.999.’  
Data will be displayed in all listings sorted by participant ID. Participants will be identified 
in the listings by the participant identification number concatenated with the investigator 
number. 
When count data are presented, the percentage will be suppressed when the count is zero 
in order to draw attention to the non-zero counts. A row denoted “Missing” will be included 
in count tabulations where specified on the shells to account for dropouts and missing 


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values. The denominator for all percentages will be the number of subjects in that treatment 
within the analysis set of interest, unless otherwise specified. 
The analysis model to make comparisons within treatment relative to continuous 
measurements assessed over time will be an MMRM with terms for: 
• Visits, as fixed effects 
• Baseline HbA1c (≤8.0%, >8.0%), as a covariate 
• Baseline measurement, as a covariate 
For analyses of HbA1c, continuous baseline HbA1c will be included in the model instead 
of baseline HbA1c category. An unstructured covariance structure will model the 
relationship of within-participant errors.  
Logistic regression may be used to examine the within-treatment effect from baseline at 12 
weeks in binary efficacy outcomes. The negative binomial regression model will be used 
to measure the within-treatment effect of discrete count measures if deemed appropriate. 
Summary of intercurrent events: 
The number of participants who experience an intercurrent event will be summarized in a 
table by event type (treatment discontinuation for any reason, or initiation of prohibited 
medication) and visit. For each visit, the number of intercurrent events which happened 
before or during the measurements taken on that visit will be calculated, excluding the 
events which happened during or before the measurements taken at the previous visits. 
Furthermore, the number of participants without any intercurrent events will be presented 
by visit too. At each visit the number and percentage of participants without intercurrent 
events will be shown. 
All analyses will be conducted using SAS Version 9.4 or higher. 
4.2. 
Participant Dispositions 
Participant disposition will be summarized in a table for the Screened population. A disposition of 
participants includes the number and percentage of participants for the following categories: 
participants who were screened, participants who were screen failures, participants who completed 
treatment, participants who permanently discontinued treatment, participants who completed the 
study, participants who discontinued from the study. All percentages will be based on the mITT 
population. 
The reasons for permanent discontinuation of treatment and study participation will also be 
summarized in this table. The reason for permanent discontinuation of study participation will be 
also summarized by study period (Screening Period, Treatment Period) The reason for either 
discontinuation of study treatment or study participation may include any of the following: 
• 
Adverse Event 
• 
Death 
• 
Protocol Deviation 
• 
Pregnancy 
• 
Non-Compliance With Study Drug 


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• 
Withdrawal by Subject 
• 
Physician Decision 
• 
Study Terminated by Sponsor 
• 
Site Terminated by Sponsor 
• 
Study Terminated by IRB / ERB 
• 
Lost to follow up 
• 
Other 
4.3. 
Primary Endpoint Analysis 
4.3.1. 
Definition of endpoint 
The primary endpoint for this study is change from baseline in HbA1c at Week 12. This endpoint 
will be used to evaluate the primary objective of the study.  
4.3.2. 
Main analytical approach 
The primary objective based on the efficacy estimand defined in Section 1.1 will be evaluated 
using the EAS dataset (Section 3). The primary analysis model for HbA1c measurements over 
time will be a mixed model for repeated measures (MMRM). 
The observed changes in HbA1c level from baseline (Visit 2 on Week 0) to each of the scheduled 
post-baseline visits (Visit 3 on Week 4, Visit 4 on Week 8, and Visit 5 on Week 12) of each 
participant are the dependent variable. The baseline HbA1c value is incorporated as a covariate, 
and the visits are treated as fixed effects. 
Mean change from baseline at Week 12 will be estimated by least square means (LS means), with 
accompanying P-value and 95% CI. 
Operationally, the hypothesis defined in Section 2 will be tested at a two-sided 0.05 level by 
performing the test on the least square mean of changes from baseline at Week 12. 
An unstructured covariance pattern will be used to estimate the variance-covariance of the within-
participant repeated measures. Parameters will be estimated by REML with the Newton-Raphson 
algorithm and using the Kenward-Roger method for calculating the denominator degrees of 
freedom. 
In case the model fails to converge, the following covariance structures will be tested in the 
following order:  
1. Heterogenous Toeplitz  
2. Heterogeneous First Order Autoregressive 
3. Heterogeneous Compound Symmetry 
4. Toeplitz 
5. First Order Autoregressive, and 
6. Compound Symmetry  
The first covariance structure that converges will be used. 
Missing data will not be imputed because the maximum likelihood estimate is unbiased for this 
model in case of a Missing at Random (MAR) mechanism. The P-value obtained for the least 


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square means for change from baseline will be used to determine the statistical significance to 
achieve the primary objective. 
HbA1c values and change from baseline in HbA1c will also be summarized by visit using 
descriptive statistics. 
4.4. 
Secondary Endpoint Analysis 
Endpoints for secondary objectives will be evaluated based on the primary efficacy estimand. 
Missing data will be addressed by the MMRM model.  
4.4.1. 
Definition of endpoints 
The following secondary endpoints are defined: 
• Change from baseline in %TAR: 
o Change from baseline to Week 12 in percentage of time per day that CGM-derived 
values are >180 mg/dl (10 mmol/L) 
▪ Percentage of time above range for a given day will be calculated as 100 times the 
number of CGM readings where a participant’s blood glucose falls above the 
specified range during a day (00:00 to 23:59, inclusive), divided by the total 
number of CGM readings in the time interval (00:00 to 23:59, inclusive). This 
will be averaged over the days from Day 1 to Day 14 to obtain the %TAR for a 
participant. 
• Change from baseline in TAR: 
o Changed from baseline to Week 12 in duration of time in minutes per day that CGM-
derived values are >180 mg/dl (10 mmol/L) 
▪ Duration of time in minutes will be calculated as the percentage of time above 
range (%TAR) multiplied by the length of the time period (1440 minutes). 
• Change from baseline to Week 12 in Fasting Serum Glucose (FSG) 
• Change from baseline to Week 12 in weight 
4.4.2. 
Main analytical approach 
The same analytical approach will be applied for all secondary endpoints as for the primary 
endpoint, which is detailed under Section 4.3.2. 
For secondary endpoints, MMRM will include baseline HbA1c (≤8.0%, >8.0%) category as a 
covariate instead of continuous baseline HbA1c. 
 
 


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Table 2. 
Summary of the analysis of Secondary Endpoints. 
Objective 
Efficacy Measure 
Analysis Conducted 
Additional information 
CGM 
parameters 
Change from baseline 
in %TAR at Week 12 
MMRM as specified 
in Section 4.3.2. 
MMRM with terms for: 
• Visits 
• Baseline HbA1c category 
(≤8.0%, >8.0%) 
• Baseline %TAR 
CGM 
parameters 
Change from baseline 
in TAR at Week 12 
MMRM as specified 
in Section 4.3.2. 
MMRM with terms for: 
• Visits 
• Baseline HbA1c category 
(≤8.0%, >8.0%) 
• Baseline TAR 
FSG 
Change from baseline 
at Week 12 in FSG  
MMRM as specified 
in Section 4.3.2. 
MMRM with terms for: 
• Visits 
• Baseline HbA1c category 
(≤8.0%, >8.0%) 
• Baseline FSG 
Weight 
Change from baseline 
at Week 12 in weight 
MMRM as specified 
in Section 4.3.2. 
MMRM with terms for: 
• Visits 
• Baseline HbA1c category 
(≤8.0%, >8.0%) 
• Baseline weight 
 
 
 


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4.5. 
Exploratory Endpoints Analysis 
The objective of the exploratory analysis is to evaluate changes in CGM-derived measures from 
baseline over the course of 12 weeks. Endpoints for exploratory objectives will be evaluates 
based on the efficacy estimand, using the EAS. 
The following exploratory endpoints will be evaluated: 
• TIR – Time in Range (71 to 189 mg/dL or 3.9 to 10 mmol/L) 
o Calculated as a percentage of time per day: 
▪ Percentage of time in range for a given day will be calculated as 100 times the 
number of CGM data readings where a participant’s blood glucose falls within the 
specified range during a day (00:00 to 23:59, inclusive), divided by the total 
number of CGM readings in the time interval (00:00 to 23:59, inclusive). This 
will be averaged over the days from Day 1 to Day 14 to obtain the TIR for a 
participant at a visit. 
• TBR – Time Below Range (≤70 mg/dl or ≤3.9 mmol/L) 
o Calculated as a percentage of time per day: 
▪ Percentage of time below range for a given day will be calculated as 100 times the 
number of CGM data readings where a participant’s blood glucose falls below the 
specified range during a day (00:00 to 23:59, inclusive), divided by the total 
number of CGM readings in the time interval (00:00 to 23:59, inclusive). This 
will be averaged over the days from Day 1 to Day 14 to obtain the TBR for a 
participant at a visit. 
• GV – Glycemic Variability 
o Calculated as glycemic standard deviation (SD): 
▪ Within-day SD (SDw) 
Each participant should have one SDw per CGM session. SDw is calculated by 
calculating the SD individually on all valid days within a session and then 
averaging across those days. Specifically, 
𝑆𝐷𝑤=
∑
𝑆𝐷𝑗
𝑚
𝑗=1
m
 
where m stands for the number of valid CGM days in the session and SDj is the 
standard deviation of blood glucose on day j, 
𝑆𝐷𝑗= √∑
(𝐵𝐺𝑖𝑗−𝐵𝐺𝑗)
2
𝑛𝑗
𝑖=1
𝑛𝑗−1
 
where BGij is the blood glucose measure at time i on day j, nj is the number of 
blood glucose measures on day j, and 
𝐵𝐺𝑗=
∑
𝐵𝐺𝑖𝑗
𝑛𝑗
𝑖=1
𝑛𝑗
 


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▪ Between-day SD of the daily average (SDb) 
Each participant should have one SDb per CGM session. SDb is calculated by 
averaging the glucose values individually on each valid day within a session and 
then calculating the SD across those days. Specifically, 
𝑆𝐷𝑏=
√∑
(𝐵𝐺𝑗−
∑
𝐵𝐺𝑗
𝑚
𝑗=1
m
)
2
𝑚
𝑗=1
𝑚−1
 
o Calculated as glucose coefficient of variation (CV): 
▪ Within-day CV (CVw) 
Each participant should have one CVw per CGM session. CVw is calculated by 
calculating the CV individually on all valid days withing a CGM session and then 
averaging those CVs across all days in the session: 
𝐶𝑉𝑤=
∑
𝐶𝑉𝑗
𝑚
𝑗=1
𝑚
 
where m stands for the number of valid CGM days in a session and 
𝐶𝑉𝑗= 𝑆𝐷𝑗
𝐵𝐺𝑗
× 100 
▪ Between-day CV (CVb) 
Each participant should have one CVb per CGM session. CVb is calculated by 
averaging the glucose values individually on each valid day within a session and 
then calculating the CV across those days: 
𝐶𝑉𝑏= [𝑆𝐷𝑏
∑
𝐵𝐺𝑗
̅̅̅̅̅
𝑚
𝑗=1
𝑚
⁄
] × 100 
• TITR – Time in Tight Target Range (71 to 140 mg/dL or 3.9 to 7.8 mmol/L) 
o Calculated as percentage of time per day in tight target range: 
▪ Percentage of time in tight target range for a given day will be calculated as 100 
times the number of CGM data readings where a participant’s blood glucose falls 
within the specified range during a day (00:00 to 23:59, inclusive), divided by the 
total number of readings in the time interval (00:00 to 23:59, inclusive). This will 
be averaged over the days from Day 1 to Day 14 to obtain TITR for a participant 
at a visit. 
• Composite of all in ranges 
o Composite endpoint of the recommended time in all three International CGM 
Consensus Guidelines ranges (<4% in TBR [≤70 mg/dL], >70% in TIR, and <25% in 
TAR [>180 mg/dL]): 


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▪ A binary endpoint will be created. If for a participant at a visit all three CGM 
measures (TAR, TIR, TBR) are within the recommended time-ranges then the 
composite endpoint will be set to “Y” for that participant, otherwise it will be set 
to “N”. 
• Mean 24-hr daily blood glucose 
Calculated by averaging all non-missing glucose readings a day (00:00 to 23:59, 
inclusive) and averaging across the 14 days to obtain mean daily glucose for a participant 
at a visit. 
• Fasting glucose and post-prandial glucose excursion 
Both the endpoints are algorithmically derived from the entire CGM dataset. An 
algorithm reviews the entire CGM dataset, evaluates excursions, and time periods then 
estimates either the fasting glucose or post-prandial glucose excursion. 
Summary statistics will be provided for actual values by visit (Baseline, Week 4, and Week 12) 
and changes from baseline values by each post-baseline visit (Week 4 and Week 12). The odds for 
a subject to reach a composite endpoint of the recommended time in all three International CGM 
Consensus Guideline ranges will be compared between baseline and Week 12 by a logistic 
regression model. The model will also include, baseline HbA1c (≤8.0%, >8.0%), and baseline 
composite endpoint as fixed effect. 
 
 


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4.5.1. 
Summary for the Analysis of Exploratory Measures 
Table 3. 
Exploratory measures not controlled for Type 1 error 
Objective 
Relative to the 
efficacy measure 
Analysis 
Conducted 
Additional information 
CGM parameters 
Mean change in 
TIR from baseline 
at week 12 
MMRM model as 
specified in 
Section 4.3.2. 
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline TIR as a covariate 
CGM parameters 
Mean change in 
TBR from baseline 
at week 12 
MMRM model as 
specified in 
Section 4.3.2. 
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline TBR as a covariate 
CGM parameters 
Mean change in 
TITR from baseline 
at week 12 
MMRM model as 
specified in 
Section 4.3.2. 
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline TITR as a 
covariate 
CGM parameters 
Mean change in GV 
from baseline at 
week 12 
MMRM model as 
specified in 
Section 4.3.2. 
Separate MMRM model for 
all measures of GV.  
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline GV measure as a 
covariate 
CGM parameters 
Change in odds for 
reaching composite 
endpoint of all in 
ranges from 
baseline to week 12 
Logistic regression 
model as specified 
in Section 4.5 
Logistic Regression with 
terms for: 
• Visit 


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• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline composite endpoint 
as a covariate 
CGM parameters 
Mean change in 
mean 24-hr daily 
blood glucose from 
baseline at week 12 
MMRM model as 
specified in 
Section 4.3.2. 
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline mean 24-hr daily 
blood glucose as a covariate 
CGM parameters 
Mean change in 
estimated post-
prandial glucose 
excursion from 
baseline at week 12 
MMRM model as 
specified in 
Section 4.3.2. 
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline estimated post-
prandial glucose excursion 
as a covariate 
CGM parameters 
Mean change in 
estimated fasting 
glucose at week 12 
MMRM model as 
specified in 
Section 4.3.2. 
MMRM with terms for: 
• Visit 
• Baseline HbA1c category 
(≤8.0%, >8.0%), and 
• Baseline estimated fasting 
glucose as a covariate 
4.6. 
Safety Analyses 
Safety assessments will be done using the Safety Analysis Set (SS) irrespective of adherence to 
study intervention or initiation of prohibited medication, unless indicated otherwise. 
4.6.1. 
Extent of Exposure 
Duration of exposure is defined as the total number of days a subject is exposed to any study 
intervention and will be presented as the total number of days from the first dose date (Day 1) to 
the last dose date (date of last dose minus the date of first dose + 1) as recorded on the 
Disposition Event: Treatment / Dosing pages on the CRF. If the last dose date on Disposition 
Event: Treatment / Dosing pages is missing, or if a participant is lost to follow-up, but the drug 
accountability log confirms that the participant has taken study drug, the visit date following the 
last completed drug accountability log will be used. 


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Missing doses will be ignored in this calculation. 
The duration of exposure to study intervention will be summarized for all participants in the SS 
and will be presented in a table by summary statistics. The duration of exposure will then be 
classified into one of the following categories: > 0 Week, >= 4 Weeks, >= 8 Weeks, and >= 12 
Weeks and will be presented as the number and percentage of participants in each duration 
category. Percentages will be computed from the number of participants in the SS. 
4.6.2. 
Adverse Events 
All adverse events will be classified by System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities. Selected notable AEs of interest 
may be reported using high-level terms or Standardized Medical Dictionary for Regulatory 
Activities Queries. As an example, ‘renal safety event’, defined in the protocol as an AE of interest, 
is defined by the high-level group term ‘Renal disorders (excl nephropathies)’. Please refer to 
Section 6.3 for the SMQs of interest. 
A treatment-emergent AE (TEAE) is defined as an AE that meets any of the following 
conditions: 
• begins on or after the first dose of study intervention 
• begins before the first dose of study drug and worsens in severity on or after the first dose 
of study drug 
• is completely missing an onset date and end date 
• is completely missing an onset date and the end date is on or after the first dose of study 
intervention. 
An overview summary of the number and percentage of participants with any TEAE, serious 
TEAE, study drug-related TEAE, study drug-related serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to study termination, and AE leading to death will be provided. 
The number of events will also be summarized. 
Local Adverse Events (i.e., injection site reactions) will be tabulated separately in addition to the 
overall TEAE tables. 
Summaries of the total number of TEAEs and the number and percentage of participants with at 
least one TEAE will be provided. The number and percentage of participants and the number of 
events will also be presented by SOC and PT. At each level of participant summarization, a 
participant is counted once if the participant reported one or more events. Percentages will be 
calculated out of the number of participants in the SS. The number of events at each level of SOC 
and PT will also be summarized.  
A summary of TEAEs will also be presented in descending order from the SOC with the highest 
total incidence (that is, summed across treatment group) to the SOC with the lowest total incidence. 
If the total incidence for any two or more SOCs is equal, the SOCs will be presented in alphabetical 
order. Within each SOC, the PTs will be presented in alphabetical order. 
A summary of AEs where the answer to “Outcome” is “Fatal” will be presented in a table. At each 
level of participant summarization, a participant is counted once if the participant reported one or 
more events. Percentages will be calculated out of the number of participants in the Safety set 
within the subgroup category.  


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A summary of TEAEs with a study intervention action taken of “Drug Withdrawn” will be 
presented in a table. At each level of participant summarization, a participant is counted once if 
the participant reported one or more events. Percentages will be calculated out of the number of 
participants in the Safety set within the subgroup category. 
A summary of TEAEs which are linked to study discontinuation via the “Disposition Event: 
Treatment Phase” CRF page will be presented in a table. At each level of participant 
summarization, a participant is counted once if the participant reported one or more events. 
Percentages will be calculated out of the number of participants in the Safety set within the 
subgroup category.  
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the CRF page. The possible severities are 
“Mild,” “Moderate,” and “Severe.”  In the TEAE severity table, if a participant reported multiple 
occurrences of the same TEAE, only the most severe will be presented. Treatment-emergent AEs 
that are missing severity will be presented in tables as “Severe” but will be presented in the data 
listing with a missing severity. Percentages will be calculated out of the number of participants in 
the Safety set. 
A summary of TEAEs by relationship (i.e., “Related” and “Not Related”) to study drug will be 
presented in a table by incidence of occurrence. The investigator will provide an assessment of the 
relationship of the event to the study drug. The possible relationships are “Not Related”, 
“Related”. Treatment –emergent AEs that are missing a relationship will be presented in the 
summary table as “Related” but will be presented in the data listing with a missing relationship. 
Percentages will be calculated out of the number of participants in the Safety set. 
The seriousness of an AE should be assessed by the Investigator independently from the severity 
of the AE. A serious AE (SAE) is defined as any untoward medical occurrence that at any dose 
results in death, is life-threatening, is a congenital anomaly/birth defect, requires in-patient 
hospitalization or prolongation, or results in significant disability/incapacity. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered SAEs when, based upon medical judgment, they may jeopardize the participant 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 
Serious treatment-emergent adverse events (SAEs) will be presented in a table. Treatment-
emergent SAEs by relationship to study drug will be presented in a table. A treatment-related 
treatment-emergent SAE is a treatment-emergent SAE with the answer “Yes” to the question “Is 
this event related to study treatment?” on the SAE CRF page. Treatment-emergent SAEs that are 
missing a relationship will be presented in the table as “Related” but will be presented in the data 
listing with a missing relationship. At each level of participant summarization, a participant is 
counted once if the participant reported one or more events. Percentages will be calculated out of 
the number of participants in the Safety set.  
The treatment-emergent SAE data will be categorized and presented by SOC and PT in a manner 
similar to that described for TEAEs. 
The number and percentage of participants who prematurely discontinue the study due to an AE 
will be summarized using MedDRA PT nested within SOC. Events will be ordered by decreasing 


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frequency within SOC. A listing of all the discontinuation from Study due to Adverse Event will 
be provided. 
The number and percentage of participants who prematurely discontinue study drug due to an AE 
will be summarized using MedDRA PT nested within SOC. Events will be ordered by decreasing 
frequency within SOC. A listing of all the discontinuation from Study Treatment due to Adverse 
Event will be provided. 
All participants who have an AE related to study treatment with an outcome of “Death Related to 
Adverse Event” will be presented in a listing. The listing will include patient identification 
including the treatment, site number, date of death, age at the time of enrollment, gender, MedDRA 
PT of associated AE, time from first dose of study drug to death, time from last dose of study drug 
to death (if patient had discontinued study drug), cause of death as reported by investigator, cause 
of death as adjudicated by Clinical Endpoint Committee (CEC). 
Patient narratives will be provided for all patients who experience any of the following “notable” 
events: 
• Deaths 
• SAEs 
• Pregnancy 
• Permanent Discontinuations of study treatment due to AEs 
All AEs will be presented in a listing. 
Handling of missing TEAE start and end dates: 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be 
imputed as follows: 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• 
UK-MMM-YYYY: If the month and year are different from the month and year 
of the first dose of study drug, assume 01-MMM-YYYY. If the month and year 
are the same as the first dose of study drug month and year, and the end date (after 
any imputation) is on or after the first dose of study drug, then assume the date of 
the first dose of study drug. If the month and year are the same as the first dose of 
study drug month, and year and the end date (after any imputation) is prior to the 
first dose of study drug, then assume the end date for the onset date.  
• 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first 
dose of study drug, assume 01-JAN-YYYY of the collected year. If the year is the 
same as the first dose of study drug year, and the end date (after any imputation) 
is on or after the first dose of study drug, then assume the date of the first dose of 
study drug. If the year is the same as the first dose of study drug, and the end date 
(after any imputation) is prior to the first dose of study drug, then assume the end 
date for the onset date.  
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• UK-MMM-YYYY: Assume the last day of the month. 


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• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
4.6.3. 
Product Complaints 
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. 
Product complaints related to study interventions used in clinical studies are collected in order to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
Investigators will instruct participants to contact the site as soon as possible if he or she has a 
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. 
A listing of all device product complaints, inclusive of device product complaints that lead to an 
AE or that could have led to an SAE had intervention not been taken will be provided. Additional 
summaries will be provided as deemed appropriate. 
4.6.4. 
Additional Safety Assessments  
4.6.4.1. 
Central Laboratory Measures and Vital Signs 
Summary tables will be presented for clinical laboratory tests with numeric values for participants 
in the Safety set. Observed results at each visit will be presented. 
Summary tables presenting observed values and changes from baseline (for those parameters 
which are measured post-baseline) will be presented for clinical laboratory tests with numeric 
values for participants in the Safety set. Changes from baseline to each scheduled post-baseline 
visit will be presented. 
A listing of abnormal findings will be created for laboratory analyte measurements. The listing 
will include patient ID, laboratory collection date, study day, analyte name, and analyte finding. 
For clinical chemistry, the following laboratory tests will be included:  
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, Creatine 
kinase (CK), Uric acid, Total protein, Albumin, Calcium, Phosphorus, Glucose.  
All chemistry data by participant will be presented in a listing. 
For hematology, the following laboratory tests will be included: 
Hemoglobin, Hematocrit, Erythrocyte count (RBCs - red blood cells), Mean cell volume, 
Mean cell hemoglobin, Mean cell hemoglobin concentration, Leukocytes (WBCs - white 
blood cells), Differential (Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, 
Platelets, Cell morphology (RBCs and WBCs) if indicated. 
All hematology data by participant will be presented in a listing. 


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For lipid panel, the following laboratory tests will be included: 
Total cholesterol, Triglycerides, High-density lipoprotein (HDL-C), Low-density 
lipoprotein (LDL-C), Very low-density lipoprotein (VLDL-C). 
All lipid panel data will be presented in a listing. 
As for urine chemistry, the following tests will be included: 
 
Albumin, Creatinine 
All urine chemistry data will be presented in a listing. 
Additional tests: 
 
Calcitonin 
 
All additional tests will be presented in a listing. 
Calculations: 
 
Urinary albumin/creatinine ratio (UACR), eGFR (CKD-EPI) calculated using creatinine. 
 
All calculations will be listed. 
Laboratory Tests for Hepatic Evaluation 
• Hepatic Hematology Panel: 
Hemoglobin, Hematocrit, Erythrocytes (RBCs - red blood cells), Leukocytes (WBCs - 
white blood cells), Differential (Neutrophils, segmented Lymphocytes, Monocytes, 
Basophils, Eosinophils, Platelets, Cell morphology (RBC and WBC). 
• Hepatic Clinical Chemistry Panel: 
Total bilirubin, Direct bilirubin, Alkaline phosphatase (ALP), Alanine aminotransferase 
(ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transferase (GGT), Creatine 
kinase (CK) 
• Hepatic Coagulation Panel: 
Prothrombin time, INR (PT-INR) 
• Urine Chemistry: 
Drug screen 
• Haptoglobin 
• Hepatitis A virus (HAV) testing: 
HAV total antibody, HAV IgM antibody 
• Hepatitis B virus (HBV) testing: 
Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (anti-HBs), Hepatitis 
B core total antibody (anti-HBc), Hepatitis B core IgM antibody, HBV DNA 
• Hepatitis C virus (HCV) testing: 
HCV antibody, HCV RNA 
• Hepatitis D virus (HDV) testing: 
HDV antibody 


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• Hepatitis E virus (HEV) testing: 
HEV IgG antibody, HEV IgM antibody, HEV RNA 
• Anti-nuclear antibody (ANA) 
• Anti-smooth muscle antibody (ASMA) 
• Anti-actin antibody 
• Epstein-Barr virus (EBV) testing: 
EBV antibody 
Laboratory assessments will be performed by a central laboratory. All summaries will be based on 
the units provided by the central laboratory, no conversion will be done.  
All relevant clinical laboratory tests will be classified as treatment emergent Low, Normal, and 
High, or Normal/Abnormal according to the normal ranges. This categorical data will be 
summarized in shift tables comparing the results at each scheduled post-baseline visit with those 
at the baseline visit. The percentages of participants with treatment-emergent abnormal, high, or 
low laboratory measures at each post-baseline visit will be summarized. 
When there are multiple values within a visit for a particular laboratory variable, the worst value 
will be taken (worst being the smallest value for criteria below a certain threshold or the largest 
value for criteria above a certain threshold). If a participant has a value below the threshold and 
above the threshold, the value furthest from the threshold will be chosen. 
A treatment-emergent abnormal value is defined as a change from normal value at baseline to an 
abnormal value at any time during the follow-up. 
Definition of treatment emergent Low/High results: 
• A treatment-emergent high result is defined as a change from a value less than or equal to 
the high limit at baseline to a value greater than the high limit at any time during the 
Treatment and Follow-up periods. 
• A treatment-emergent low result is defined as a change from a value greater than or equal 
to the low limit at baseline to a value less than the low limit at any time during the 
Treatment and Follow-up periods. 
o Laboratory normal ranges will be provided by the Central Lab. 
An MMRM using REML model will be used to analyze the changes in lipid panel parameters from 
baseline to all scheduled post-baseline visits. The model will include visits and baseline HbA1c 
category (≤8.0%, >8.0%) as fixed effects and baseline value of the dependent variable as a 
covariate. 
Vital signs: 
Summary tables presenting observed values and changes from baseline will be presented for vital 
sign data, systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate (bpm), 
weight (kg), Waist Circumference measurement (cm) and BMI for participants in the Safety set. 
For height (cm), only observed values will be summarized at baseline. 
Height and weight measurements will be used to calculate BMI, with following formula: 


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BMI = weight (kg) / [height (m)]2 
Descriptive summaries by nominal visit will be provided for baseline and postbaseline values as 
well as change from baseline values. If 2 records are taken at the same visit, they will be 
averaged prior to being used for data summaries and analyses. 
An MMRM using REML model will be used to analyze the changes in vital signs from baseline 
to all scheduled post-baseline visits. The model will include visits and baseline HbA1c category 
(≤8.0%, >8.0%) as fixed effects and baseline value of the dependent variable as a covariate. 
Counts and percentages of patients with treatment-emergent abnormal sitting systolic blood 
pressure (BP), sitting diastolic BP, and pulse will be presented. The criteria for identifying 
patients with treatment-emergent vital sign abnormalities are stated in Table 4. 
 
4.6.4.2. 
Hypoglycemic events 
The following hypoglycemic events (HEs) will be summarized respectively: 
• Level 1 hypoglycemia 
o Glucose <70 mg/dL (<3.9 mmol/L) and ≥54 mg/dL (≥3.0 mmol/L) 
o Level 1 hypoglycemia can alert a person to take action such as treatment with fast-
acting carbohydrates. Providers should continue to counsel participants to treat 
hypoglycemia at this glucose alert value. 
• Level 2 hypoglycemia 
o Glucose <54 mg/dL (<3.0 mmol/L) 
o Level 2 hypoglycemia is also referred to as documented or BG-confirmed 
hypoglycemia with glucose <54 mg/dL (<3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence or absence of symptoms of 
hypoglycemia. 
• Level 3 hypoglycemia (Severe) 
Table 4. 
Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure and 
Pulse Measurement 
Parameter 
Low 
High 
Systolic BP (mm Hg) 
(Supine or sitting – 
forearm at heart level) 
Observed value ≤ 90 and 
decrease from baseline ≥ 20 
Observed value ≥ 140 and 
increase from baseline ≥ 20 
Diastolic BP (mm Hg) 
(Supine or sitting – 
forearm at heart level) 
Observed value ≤ 50 and 
decrease from baseline ≥ 10 
Observed value ≥ 90 and 
increase from baseline ≥ 10 
Pulse (bpm) 
(Supine or sitting) 
Observed value ≤ 50 and 
decrease from baseline ≥ 15 
Observed value ≥ 100 and 
increase from baseline ≥ 15 


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▪ 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. 
Those hypoglycemic events for which the answer is “yes” to the question “Did the 
subject experience a severe hypoglycemic episode with neurological (cognitive) 
impairment requiring assistance?“ on the Hypoglycemic Events eCRF page and/or 
it is recorded as a SAE will be classified as Level 3. 
• Severe hypoglycemia 
o 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 
o 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. 
• Nocturnal hypoglycemia 
o Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, 
which occurs at night and presumably during sleep. 
o Defined as a hypoglycemia event, including severe hypoglycemia, which occurs at 
night and presumably during sleep. If for a hypoglycemia event the answer to the 
question “When did the hypoglycemic event occur?” is “Between bedtime and waking 
(while asleep)” on the Hypoglycemic Events eCRF page, then that event will be 
classified as nocturnal hypoglycemia. 
To avoid duplicate reporting, all consecutive BG values occurring within a 1-hour period may be 
considered to be a single hypoglycemic event and the one with the lowest BG value can be selected 
to be the representative. If two records with the same lowest values within a hour, the earlier 
occurrence will be selected. 
Statistical summaries and analyses will exclude hypoglycemic events occurring after initiation of 
a new antihyperglycemic therapy. For severe hypoglycemia and level 2 hypoglycemia incidence 
as well as rate per patient per year of exposure will be provided at specified time intervals. 
For each HEs defined above, the total number of the respective HEs occurring between Week -3 
and Day 1 will be used to calculate baseline frequency of total HEs respectively. Similarly, for 
each HEs defined above, the total number of respective HEs occurring in the 14 calendar days 
prior to Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12) will be used to calculate 
frequency of total HEs for each HE defined above at each visit respectively. 
Hypoglycemia events will be summarized by descriptive statistics. Summaries will include the 
number and percentage of participants experiencing at least 1 event and the total number of events 
for each visit. Where possible, the summaries will be presented by Level as well.  
The incidence of hypoglycemic event will be analyzed using logistic regression with baseline 
HbA1c category (≤8.0%, >8.0%) as fixed effects.  


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The rate of hypoglycemic episodes per patient month may be analyzed using a generalized linear 
MMRM assuming the number of hypoglycemic episodes follows a negative binomial distribution 
with the mean modeled using visits and baseline HbA1c category (≤8.0%, >8.0%) as fixed effects 
if data warrants. The logarithm of months in specified time interval will be adjusted as an offset to 
account for possible unequal treatment duration in the specified time interval between patients. 
When the number of hypoglycemic events is less than 10, the listing of hypoglycemic events will 
be provided instead. 
Data collected on the Hypoglycemic Events CRF page will be presented in listings. 
4.6.4.3. 
Severe Persistent Hyperglycemia  
Defined as Fasting Blood Glucose (via SMBG) >270 mg/dL (>15 mmol/L) during the first 4 weeks 
or >240 mg/dL (>13.3 mmol/L) from Weeks 5-12 occurring for at least 2 consecutive weeks. The 
number and percentage of participants with severe, persistent hyperglycemia will be summarized 
and data will be listed. 
4.6.4.4. 
Gastrointestinal Events 
The following gastrointestinal events will be summarized respectively: 
• Nausea 
• Vomiting 
• Diarrhea 
• Abdominal Pain/Abdominal Cramps 
• other 
These events are recorded on the “Hypersensitivity, Anaphylactic and Infusion/Injection Related 
Reaction Follow-up” eCRF page. If the answer to the question “Does subject have gastrointestinal 
signs or symptoms?” is “Yes” then the applicable event type is recorded as well (“Nausea”, 
“Vomiting”, “Diarrhea”, “Abdominal Pain/Abdominal Cramps”, “Other”). The events are defined 
based on this information. Additionally, this information is linked to the AE page where their 
severity is also captured. 
A summary of the number of gastrointestinal events by severity and event type will be presented 
in a table, and the number and percentage of participants with at least one event will be provided. 
The severity that will be presented represents the most extreme severity captured on the CRF page. 
The possible severities are “Mild,” “Moderate,” and “Severe.”  If a participant reported multiple 
occurrences of the same event, only the most severe will be presented. Events that are missing 
severity will be presented in tables as “Severe” but will be presented in the data listing with a 
missing severity. Percentages will be calculated out of the number of participants in the Safety set. 
The time courses of prevalence and incidence (newly-occurring episodes) of nausea, vomiting, 
diarrhea, and combined will be plotted and maximum severity. 
The maximum severity and duration of treatment-emergent nausea, vomiting, diarrhea, and 
combined through the end of the study will be summarized. 


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4.6.4.5. 
Hypersensitivity, Anaphylactic and Infusion/Injection Related Reaction Follow-
up 
Data collected on Hypersensitivity, Anaphylactic and Infusion/Injection Related Reaction Follow-
up CRF page will be listed. Information to be summarized includes the timing of the reaction 
relative to study drug administration, and characteristics of the injection site reaction: erythema, 
induration, pain, pruritis, and edema. Patient based and event-based summaries will be created. 
Data collected on this page for gastrointestinal events will be summarized (See Section 4.6.4.4). 
Additionally, summaries will be created for mucocutaneous, cardiovascular, central nervous 
system, respiratory and general signs or symptoms in a similar way as for gastrointestinal events. 
Percentages will be calculated out of the number of participants in the Safety set. 
4.6.4.6. 
Hepatic evaluation 
Liver Biopsy Assessment, Hepatic Monitoring Procedures, Hepatic Risk Factor Assessment and 
Liver Related Signs and Symptoms data will be presented in listings. 
• Hepatobiliary Disorders: 
The AE database will be searched using Standardized MedDRA Queries (SMQs) to 
identify events consistent with hepatobiliary disorders. Detailed searching criteria can be 
found in Section 6.3 (Appendix 3). A summary by PT within SMQ will be provided. 
• Acute Gallbladder Disease 
The AE database will be searched using predefined SMQs to identify events consistent 
with acute gallbladder diseases. Detailed searching criteria can be found in Section 6.3 
(Appendix 3). A summary by PT within SMQ will be provided. 
• Liver Enzymes: 
Analyses for laboratory analyte measurements are described in Section 4.6.4.1. This 
section describes additional analyses of liver enzymes. In addition, the following will be 
provided: 
o A shift table of maximum to maximum alanine aminotransferase (ALT) measurement 
from baseline (≤1 × ULN, > 1 × ULN) to postbaseline with the following categories - 
≤1 × ULN, >1 to <3 × ULN, ≥3 to <5 × ULN, ≥5 to <10 × ULN, ≥10 × ULN 
o A shift table of maximum to maximum aspartate transaminase (AST) measurement 
from baseline (≤1 × ULN, > 1 × ULN) to postbaseline with the following categories - 
≤1 × ULN, >1 to <3 × ULN, ≥3 to <5 × ULN, ≥5 to <10 × ULN, ≥10 × ULN. 
o Shift tables of maximum to maximum total bilirubin and direct bilirubin from 
baseline to postbaseline with the following categories - ≤1 × ULN, > 1 to <2 × ULN, 
≥2 × ULN. 
o Shift tables of serum alkaline phosphatase from baseline to postbaseline with the 
following categories - ≤1 × ULN, >1 to <2 × ULN, ≥2 × ULN. 
Of note, maximum baseline will be the maximum non-missing observation in the 
baseline period. The maximum postbaseline value will be the maximum non-missing 


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value from the postbaseline period. Planned and unplanned measurements will be 
included. 
4.6.4.7. 
Acute pancreatitis 
Acute pancreatitis is an AE of special interest in all studies with tirzepatide, including this study. 
AE listing of acute pancreatitis will be provided separately from other AEs. Determination of 
reported events will be through the pre-defined SMQ search for acute pancreatitis and MedDRA 
PT of pancreatitis chronic. Detailed searching criteria can be found in Section 6.3 (Appendix 3). 
4.7. 
Other Analyses 
4.7.1. 
Subgroup analyses 
Subgroup analyses of the primary and secondary endpoint will be made to assess consistency of 
the improvement from baseline across subgroups. 
The primary and secondary endpoints will be examined using the same MMRM model defined in 
Section 4.3.2. but additionally, a SUBGROUP term will be included as fixed effects. LS-means 
with their corresponding 95% CIs and P-values will be reported for the subgroups. 
The following subgroups are defined: 
• Age group: < 65 years vs ≥ 65 years 
• Sex: female vs male 
• Race: white vs black vs other 
• Ethnicity: Hispanic vs not Hispanic 
• Baseline GLP-1 RA: liraglutide vs semaglutide vs dulaglutide 
• Baseline GLP-1 RA equivalent doses (adapted from Almandoz et al. 2020): 
o dulaglutide 0.75 mg and liraglutide 1.2 mg vs. 
o dulaglutide 1.5 mg, semaglutide 0.5 mg, and liraglutide 1.8 mg vs. 
o dulaglutide 3 mg and semaglutide 1 mg vs. 
o dulaglutide 4.5 mg and semaglutide 2 mg 
• Baseline HbA1c (≤8.0%, >8.0%) 
If the number of participants is too small (less than [10%]) within a subgroup, then the subgroup 
categories may be redefined prior to unblinding the study. 
4.8. 
Interim Analyses  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended. 
4.8.1. 
Data Monitoring Committee (DMC) or Other Review Board 
No DMC or other review board meeting is planned. 
4.9. 
Changes to Protocol-Planned Analyses 
There are no changes to protocol planned analyses. 


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5. 
Sample Size Determination 
A sample size of 150 participants will provide at least 90% power to show an improvement in 
HbA1c from baseline at Week 12. This sample size is using the following assumptions:  
• a 1-sample t-test with 2-sided significance level of 0.05  
• within treatment difference from baseline at Week 12 is 0.3%, and  
• intra-subject variability of 1.1%.  


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6. 
Supporting Documentation 
6.1. 
Appendix 1: Demographic and Baseline Characteristics 
A summary of demographics and baseline information will be presented. The demographic 
characteristics consist of age (in years), sex, race, and ethnicity. The baseline characteristics consist 
of baseline height (cm), baseline weight (kg), and Waist Circumference measurement (cm), 
fundoscopy exam results and substance use. All demographic and baseline characteristics will be 
presented in listings. 
A participant’s age in years is calculated using the date of the informed consent and date of birth. 
Age (years), baseline height (cm), baseline weight (kg), Waist Circumference measurement (cm), 
Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), and Pulse Rate (bpm) will 
be summarized using descriptive statistics.  
The number and percentage of participants by age category (< 65 years vs ≥ 65 years), sex (Male, 
Female), race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander) and ethnicity (Hispanic or Latino, Not Hispanic or 
Latino), will also be reported.  
Baseline fundoscopy results will be presented in a table for both eyes. For each eye respectively, 
number and percentage of participants with non-proliferative diabetic retinopathy will be presented 
by severity. Number and percentage of participants with proliferative diabetic retinopathy and 
macular edema will also be presented.  
Percentages will be based on the total number of participants in the mITT set.  
Collected data about substance use, including alcohol, caffein, recreational drugs, and tobacco will 
be listed. 
6.1.1. 
Prior and Concomitant Medications/Therapy 
All medications will be coded according to the World Health Organization drug dictionary  
A prior medication/therapy is defined as those for which the end date is prior to the date of first 
study intervention administration or confirmed as ‘not ongoing’ by the participant before the start 
of study intervention. A concomitant medication/therapy is defined as any medication that has a 
stop date that is on or after the date of first dose of study intervention or confirmed as ‘ongoing’ 
by the participant at the start of study intervention. If a medication is not clearly indicated as 
ongoing nor the end date is documented, it will be treated as a concomitant medication. 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete 
medication start and stop dates will be imputed as follows: 
Missing start dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively):  
• UK-MMM-YYYY: Assume 01-MMM-YYYY. If the month and year are the same as the 
first dose of study intervention month and year, then assume the date of first dose of study 
drug. 


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• UK-UKN-YYYY: If the year is prior to the year of first dose of study intervention, assume 
01-JAN-YYYY of the collected year. If the year is the same as the first dose of study 
intervention year, then assume the date of first dose of study intervention. 
• UK-UKN- UNKN: Assume date of first dose of study intervention. 
Missing stop dates for concomitant medications data will be handled as follows (where UK, 
UKN and UNKN indicate unknown or missing day, month, and year respectively):  
• UK-MMM-YYYY: Assume the last day of the month. 
• UK-UKN-YYYY: Assume 31-DEC-YYYY. 
• UK-UKN- UNKN: Assume ongoing and leave it missing. 
The total number of concomitant medications and the number and percentages of participants with 
at least one concomitant medication will be summarized. The number and percentages of all 
concomitant medications will be summarized and listed by Anatomical Therapeutic Chemical 
(ATC) level 4 and preferred term. Prespecified concomitant medications Acetaminophen / 
Paracetamol will be summarized in the same way. 
The same summary will be presented for the prior medications/therapies as for concomitant 
medications. 
The same summary will be presented for the background oral antihyperglycemic medications 
(OAMs), defined as medications belonging to the category of ‘antihyperglycemics’, taken via oral 
route, and starting prior to the start of study intervention. 
All summaries will be performed using the Safety set. 
6.1.2. 
Medical History 
For Medical History, medical condition or event terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA).  
The number and percentage of participants with any Pre-Existing Conditions and Medical History 
will be summarized overall and for each system organ class and preferred term. Participant Pre-
Existing Conditions and Medical History data including specific details will be presented in a 
listing. 
General Associated Person Medical History data will be listed for each participant. The number 
and percentage of participants having first degree relative with medical history will be summarized 
overall and for each system organ class and preferred term. 
Associated Person Medical History data for Liver Disease will also be listed and the number 
(percentage) of participants associated with a certain medical condition or event (Alpha-1 
antitrypsin Deficiency, Autoimmune disorder, Hemochromatosis) will be summarized by 
preferred term. 
Prespecified Medical History including the date of diabetes diagnosis, Liver and Concurrent 
Disease will be listed. The number and percentage of participants with any Liver and Concurrent 
Disease will be summarized overall and for each system organ class and preferred term. 
Percentages will be calculated based on number of participants in the mITT set. 


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6.2. 
Appendix 2: Treatment Compliance 
Participants should administer Tirzepatide once weekly by SC injection.  
Treatment overdose is defined as administration of more than a total of 3 SDPs (15mg) of 
Tirzepatid within a 72-hour period. If a dose is missed, the participant should take their dose as 
soon as possible, within 4 days (96 hours) after the missed dose. If more than 4 days have passed, 
that dose should be skipped, and the next dose should be taken at the appropriate time. 
For each participant, study treatment compliance will be determined for each week by taking into 
account whether a participant takes all doses of study treatment as instructed based on the subject 
diary. If on a given week a participant overdosed treatment or a dose had to be skipped then that 
will count as non-compliance for that week. Weekly compliance along with weekly actual dose 
and skipped doses will be listed for each participant. Number and percentage of participants who 
were compliant, non-compliant (due to overdosing or due to skipping dose) will be summarized 
by week. 
Furthermore, compliance will be characterized by accountability data for each visit. The number 
of SC injections taken will be calculated by subtracting the number of SDPs returned from the 
number of SDPs dispensed at a visit. 
The study intervention compliance (%) for each visit will be calculated by dividing the total 
number of SDPs used up to the next visit by the total number of SDPs prescribed at each visit and 
then multiplying by 100. The overall study intervention compliance (%) will be calculated by 
dividing the total number of SDPs used at all visits by the total number of SDPs prescribed for all 
visits and then multiplying by 100. 
Compliance (%) = [(total number of SDPs dispensed – total number of unused SDPs returned) / 
(Number of weeks in visit interval × Number of SDPs prescribed per week)] × 100. 
Treatment compliance will be summarized descriptively. Furthermore, for overall compliance a 
categorical summary of whether participants were compliant (yes/no) will be presented. A 
participant is considered compliant if overall study intervention compliance is greater than or equal 
to 75%.  
Percentages will be calculated out of the number of participants who were dosed at that dosing 
period in the Safety set. 
6.3. 
Appendix 3: Search Criteria for Standardized MedDRA Queries 
The Standardized MedDRA Queries of interest are listed as follows: 
• Systemic hypersensitivity and anaphylactic reactions: 
- 
Anaphylactic reaction (SMQ), narrow search 
- 
Hypersensitivity (SMQ), narrow search 
- 
Angioedema (SMQ), narrow search 
- 
Severe cutaneous adverse reactions (SMQ), narrow search 
• Hepatic disorders (SMQ) 
• Gallbladder related disorders (SMQ) 
• Acute pancreatitis (SMQ) 
• Cardiac arrythmias (SMQ) 


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• Biliary disorders (SMQ) 
The search criteria for each of the SMQs are stored in PPD Biostatistics Technology 
Infrastructure (BTI) in: 
\\wilbtib\wilbtia00\Global Bios Library\Dictionaries\MedDRA\Current\MedAscii\smq_list.asc 
 


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7. 
References 
Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and 
increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, 
multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. 
https://doi.org/10.1016/S0140 6736(21)02188-7 
 
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients 
with type 2 diabetes. N Engl J Med. 2021;385(6):503-
515.https://doi.org/10.1056/NEJMoa2107519 
 
Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec 
as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes 
(SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 
2021;398(10300):583-598. https://doi.org/10.1016/S0140-6736(21)01443-4 
 
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 
receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-
blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. 
https://doi.org/10.1016/S0140-6736(21)01324-6. Erratum in: Lancet. 
2021;398(10296):212. https://doi.org/10.1016/S0140-6736(21)01556-7 
 
Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to 
titrated insulin glargine on glycemic control in patients with type 2 diabetes: The 
SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534-
545.https://doi.org/10.1001/jama.2022.0078