A Randomized, Phase 3, Open-label Trial Comparing the Effect of Tirzepatide Once Weekly Versus Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes on Metformin With or Without a Sulfonylurea
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

 
 
 
Protocol I8F-MC-GPHO(a) 
 
 
A Randomized, Phase 3, Open-label Trial Comparing the Effect of Tirzepatide Once Weekly 
Versus Titrated Insulin Glargine on Glycemic Control in Patients with Type 2 Diabetes on 
Metformin with or without a Sulfonylurea (SURPASS-AP-Combo) 
  
 
NCT04093752 
 
Approval Date: 23-Feb-2021 
 
 

I 8 F-M C -G P H O ( a) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 2 9 8 1 7 6
Pr ot o c ol I 8 F-M C -G P H O ( a)
A R a n d o mi z e d, P h a s e 3, O p e n -l a b el Tri al C o m p ari n g t h e 
Eff e ct of Tir z e p ati d e O n c e W e e kl y  V er s u s Titr at e d I n s uli n 
Gl ar gi n e o n Gl y c e mi c C o ntr ol i n P ati e nt s wit h T y p e 2 
Di a b et e s o n M etf or mi n wit h or wit h o ut a S ulf o n y l ur e a
(S U R P A S S -A P -C o m b o )
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s int e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e o s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
tir z e p ati d e (tir z e p ati d e), u nl e s s s u c h p er so n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .  
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. 
I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o u t t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Tir z e p ati d e ( L Y 3 2 9 8 1 7 6)
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n a p pr o v al d at e pr o vi d e d b el o w
A m e n d m e nt ( a ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y
o n a p pr o v al d at e pr o vi d e d b el o w.
A p pr o v al D at e: 2 3- F e b- 2 0 2 1 G M T

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Table of Contents
Section
Page
Protocol I8F-MC-GPHO A Randomized, Phase 3, Open-label Trial 
Comparing the Effect of Tirzepatide Once Weekly Versus Titrated 
Insulin Glargine on Glycemic Control in Patients with Type 2 
Diabetes on Metformin with or without a Sulfonylurea (SURPASS-
AP-Combo).........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................21
3.1.
Study Rationale............................................................................................................21
3.2.
Background..................................................................................................................22
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................26
5.1.
Overall Design .............................................................................................................26
5.2.
Number of Participants.................................................................................................31
5.3.
End of Study Definition ...............................................................................................31
5.4.
Scientific Rationale for Study Design...........................................................................31
5.5.
Justification for Dose ...................................................................................................32
6.
Study Population...............................................................................................................34
6.1.
Inclusion Criteria..........................................................................................................34
6.2.
Exclusion Criteria ........................................................................................................35
6.3.
Lifestyle Restrictions....................................................................................................38
6.4.
Screen Failures.............................................................................................................38
7.
Treatments........................................................................................................................39
7.1.
Treatments Administered .............................................................................................39
7.1.1.
Packaging and Labelling ......................................................................................40
7.1.2.
Medical Devices...................................................................................................40
7.2.
Method of Treatment Assignment ................................................................................40
7.2.1.
Selection and Timing of Doses.............................................................................40
7.2.1.1.
Tirzepatide .....................................................................................................40
7.2.1.2.
Insulin glargine...............................................................................................40
7.3.
Blinding .......................................................................................................................41
7.4.
Dosage Modification....................................................................................................42
7.4.1.
Study drugs..........................................................................................................42

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7.4.2.
Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications...........................................................................42
7.5.
Preparation/Handling/Storage/Accountability...............................................................42
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................44
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................45
7.7.2.
Severe, Persistent Hyperglycemia ........................................................................46
7.8.
Treatment after the End of the Study............................................................................47
7.8.1.
Treatment after Study Completion........................................................................47
7.8.2.
Special Treatment Considerations ........................................................................47
8.
Discontinuation Criteria ....................................................................................................48
8.1.
Discontinuation from Study Treatment.........................................................................48
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................48
8.1.2.
Temporary Discontinuation from Study Treatment...............................................49
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................49
8.2.
Discontinuation from the Study....................................................................................50
8.3.
Lost to Follow-Up........................................................................................................50
9.
Study Assessments and Procedures ...................................................................................52
9.1.
Efficacy Assessments...................................................................................................52
9.1.1.
Primary Efficacy Assessments and Procedures.....................................................52
9.1.2.
Secondary Efficacy Assessments and Procedures.................................................52
9.1.3.
Exploratory Efficacy Assessments and Procedures...............................................52
9.1.4.
Appropriateness of Assessments ..........................................................................53
9.2.
Adverse Events ............................................................................................................53
9.2.1.
Serious Adverse Events........................................................................................54
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................55
9.2.2.
Adverse Events of Special Interest .......................................................................55
9.2.2.1.
Hypoglycemia ................................................................................................55
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................56
9.2.2.3.
Pancreatitis.....................................................................................................57
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia................................................58
9.2.2.5.
Major Adverse Cardiovascular Events............................................................58
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................58
9.2.2.7.
Hypersensitivity Events..................................................................................59
9.2.2.7.1.
Injection Site Reactions ............................................................................59
9.2.2.7.2.
Anti-Drug Antibodies ...............................................................................59
9.2.2.8.
Diabetic Retinopathy Complications...............................................................59

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9.2.2.9.
Hepatobiliary Disorders..................................................................................59
9.2.2.10.
Severe Gastrointestinal Adverse Events..........................................................59
9.2.2.11.
Acute Renal Events ........................................................................................59
9.2.2.12.
Metabolic Acidosis, including Diabetic Ketoacidosis......................................60
9.2.2.13.
Amputation/Peripheral Revascularization .......................................................60
9.2.2.14.
Major Depressive Disorder/Suicidal Ideation..................................................60
9.2.3.
Complaint Handling.............................................................................................60
9.3.
Treatment of Overdose.................................................................................................60
9.4.
Safety...........................................................................................................................60
9.4.1.
Electrocardiograms ..............................................................................................60
9.4.2.
Vital Signs ...........................................................................................................61
9.4.3.
Laboratory Tests ..................................................................................................61
9.4.4.
Immunogenicity Assessments ..............................................................................61
9.4.5.
Safety Monitoring ................................................................................................62
9.4.5.1.
Hepatic Safety Monitoring..............................................................................62
9.5.
Pharmacokinetics .........................................................................................................62
9.6.
Pharmacodynamics ......................................................................................................62
9.7.
Pharmacogenomics ......................................................................................................62
9.8.
Biomarkers...................................................................................................................62
9.9.
Health Economics ........................................................................................................63
9.9.1.
Diabetes Treatment Satisfaction Questionnaire (DTSQ).......................................63
9.9.2.
Impact of Weight on Self-Perception Questionnaire .............................................63
9.9.3.
Ability to Perform Physical Activities of Daily Living .........................................63
9.9.4.
European Quality of Life......................................................................................63
10.
Statistical Considerations ..................................................................................................65
10.1. Sample Size Determination ..........................................................................................65
10.2. Populations for Analyses..............................................................................................66
10.3. Statistical Analyses ......................................................................................................66
10.3.1.
General Statistical Considerations ........................................................................66
10.3.2.
Treatment Group Comparability...........................................................................67
10.3.2.1.
Patient Disposition..........................................................................................67
10.3.2.2.
Patient Characteristics ....................................................................................67
10.3.2.3.
Concomitant Therapy .....................................................................................67
10.3.2.4.
Treatment Compliance....................................................................................68
10.3.3.
Efficacy Analyses ................................................................................................68
10.3.3.1.
Primary Analyses ...........................................................................................68
10.3.3.2.
Secondary Analyses........................................................................................69
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................69

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10.3.4.
Safety Analyses....................................................................................................69
10.3.4.1.
Hypoglycemic Events.....................................................................................70
10.3.4.2.
Gastrointestinal Events...................................................................................70
10.3.4.3.
Adjudicated Cardiovascular Events ................................................................70
10.3.4.4.
Central Laboratory Measures, Vital Signs, and 
Electrocardiograms.........................................................................................70
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................70
10.3.6.
Evaluation of Immunogenicity .............................................................................71
10.3.7.
Other Analyses.....................................................................................................71
10.3.7.1.
Health Economics...........................................................................................71
10.3.7.2.
Subgroup Analyses.........................................................................................71
10.3.8.
Interim Analyses..................................................................................................71
11.
References ........................................................................................................................72
12.
Appendices .......................................................................................................................74

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List of Tables
Table
Page
Table GPHO.1.
Schedule of Activities....................................................................................14
Table GPHO.2.
Objectives and Endpoints...............................................................................24
Table GPHO.3.
Treatment Regimens......................................................................................39
Table GPHO.4.
Dosing Titration Schedule for Once-Daily Insulin Glargine (TTT 
Algorithm).....................................................................................................41
Table GPHO.5.
Use of Concomitant Medications that May Interfere with Efficacy and 
Safety Assessments in Study GPHO ..............................................................44
Table GPHO.6.
Description of Analysis Sets ..........................................................................66

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List of Figures
Figure
Page
Figure GPHO.1. Illustration of study design for Clinical Protocol I8F-MC-GPHO...................27

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................75
Appendix 2.
Clinical Laboratory Tests...............................................................................77
Appendix 3.
Study Governance Considerations..................................................................79
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................84
Appendix 5.
World Health Organization Classification of Diabetes and Diagnostic 
Criteria ..........................................................................................................85
Appendix 6.
Classification of Contraceptive Methods........................................................86

I 8 F-M C -G P H O ( a) Cli ni c al Pr ot o c ol
P a g e 9
L Y 3 2 9 8 1 7 6
1. S y n o p si s
Title of St u d y:
A Ra n d o mize d, P hase 3, O pe n -lab el  Trial C o mpari n g t he Effect of Ti rze pati de O nce Wee kl y 
Vers us Ti trate d I ns uli n Glar gi ne o n Gl yce mic C o ntr ol i n Patie nts wit h T ype 2 Di a betes o n 
Metf or mi n wi t h or wit ho ut a sulf o n yl urea .
R ati o n ale: 
T y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c haracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y increase d i ns uli n resista nce a n d pr o gressi ve beta -cell fail ure a n d c o nse q ue nt l y 
i na de q uate i ns uli n secreti on.  T he di a betes t hera p y us uall y starts wit h lifestyle a n d diet c ha n ges 
f oll owe d b y 1 or m ore oral me dicat i ons. W he n or al  a nti h y per gl yce mic me dicat i ons ( O A Ms) are 
i ns ufficie nt t o reac h tar get gl yce mia, i njecta ble t hera pies are a d de d t o t he m.
For m ost pati e nts, 
a gluca g o n -li ke pe pti de- 1 ( G L P-1) rece pt or a g o nist s h o ul d be t he first c h oice, a hea d of i ns uli n. 
Basal i ns uli n al o ne is t he m ost c on ve nie nt i nit ial i ns uli n re gi me n a n d ca n be a d de d t o metf or mi n 
a n d ot her oral a ge nts ( A merica n Dia betes Ass ociati on [ A D A] 2 0 1 9) .  A de q uatel y titrate d 
gl ar gi ne t hera p y, i n c o m bi natio n wi t h or al - O A Ms, fre q ue nt l y ac hie ves t he tar get gl yce mic le vel.
Gl ar gi ne t hera p y, h o we ver, is fre q ue ntl y ass ociate d wit h wei g ht i ncrease a n d e ve nt ual 
h y p o gl yce mia.
I njecta ble i ncreti n-base d treat me nts (e. g., G L P -1 rece pt or a g o nists) are rec o me n de d as first 
i njecta ble use d i n c o m bi nat i on wi t h O A Ms t o ac hie ve a n d mai ntai n gl uc ose c o ntr ol ( A D A 2 0 1 9 ).  
W hile ass ociate d wit h l o wer ris k f or h y p o gl yce mia a n d eit her wei g ht ne utral or wei g ht l oss 
effects, c urre nt pre parati o ns are directe d at a si n gle m o lec ular tar get ( G L P -1 rece pt ors) a n d 
pr o vi de d ose -de pe n de nt gl uc ose -l oweri n g effects, w hic h ca n be li mite d b y gastr oi ntesti nal ( GI) 
t olera bilit y ( Na uc k 2 0 1 6).
Ti rze patid e is a o nce-wee kl y d ual GI P/ G L P -1 rece pt or a g o nist.  It is a 3 9 -a mi n o aci d s y nt het ic 
pe pti de wi t h a g o nist acti vity at b ot h t he GI P ( gl uc ose -de pe n de nt i n s uli n otr o pic p ol y pe pt i de) a n d 
G L P -1 rece pt ors.  Its str uct ure is base d o n t he GI P se q ue nce a n d i ncl u des a C 2 0 fatt y  di-aci d 
m o iety 
.  It is a d mi nistere d o nce-wee kl y 
( Q W) b y s u bc uta ne o us ( S C) i njecti o n.
St u d y  I 8 F-M C -G P H O ( G P H O) is a p hase 3, m ultice nter, ra n d o mize d, o pe n-label, parallel -gr o u p 
st u d y t o c o mpare t he efficac y a n d safet y of  3 mai nte na nce d oses of tirze pati de wi t h titrate d 
i ns uli n glar gi ne i n patient s wit h T 2 DM
naï ve o f i ns uli n treat me nt w h o have i na de q uate gl yce mic 
c o ntr ol o n sta ble d oses of metf or mi n wi t h or wit ho ut a s ulf on yl urea .
C CI

I8F-MC-GPHO(a) Clinical Protocol
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Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To demonstrate that once-weekly tirzepatide
10 mg and/or 15 mg is non-inferior to titrated 
insulin glargine as measured by change from 
baseline in hemoglobin A1c (HbA1c) at 40 
weeks

Mean change in HbA1c from baseline
Key Secondary (controlled for Type I error)
Efficacy

To demonstrate that once-weekly tirzepatide 5 
mg is noninferior to titrated insulin glargine 
for change from baseline in HbA1c at 40 
weeks

Mean change in HbA1c from baseline

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior in weight 
loss to titrated insulin glargine at 40 weeks

Mean change in body weight from baseline

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior to 
titrated insulin glargine for change from 
baseline in HbA1c at 40 weeks

Mean change in HbA1c from baseline

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior to 
titrated insulin glargine for the proportion of 
patients with HbA1c target value of <7.0% 
(53 mmol/mol) at 40 weeks

Proportion of patients achieving HbA1c target 
of <7.0% (53 mmol/mol)
Additonal Secondary (not controlled for type 1 
error)

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior to titrated 
insulin glargine at 40 weeks for:

Mean change in fasting serum glucose (central 
lab) from baseline

Proportion of patients achieving an HbA1c 
target values of  ≤6.5% (48 mmol/mol) and 
<5.7% (39 mmol/mol)

Mean change in daily glucose average of 7-
point self-monitored blood glucose (SMBG)
profiles from baseline

Proportion of patients who achieved weight 
loss ≥5%, ≥10%, and ≥15% from baseline

To compare tirzepatide 5 mg, 10 mg, and 15 
mg to titrated insulin glargine at 40 weeks for:

Patient-reported outcomes:
o
Diabetes Treatment Satisfaction 
Questionnaire status/ Diabetes
Treatment Satisfaction Questionnaire 
change

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Objectives
Endpoints
Safety

To compare tirzepatide 5 mg, 10 mg, and 
15 mg to titrated insulin glargine for: 

Treatment-emergent adverse events (TEAEs)

Early discontinuation of study drug due to 
adverse events (AEs)

Adjudicated pancreatic AEs

Serum calcitonin

Incidence of allergic and hypersensitivity 
reactions 

Incidence of treatment-emergent anti-drug 
antibodies to tirzepatide

Mean change in systolic and diastolic blood 
pressure and pulse rate from baseline

Occurrence of hypoglycemic events 

Incidence of initiation of rescue therapy for 
severe persistent hyperglycemia
Summary of Study Design:  
Study GPHO is a phase 3, multicenter, randomized, open-label, parallel-group study to compare 
the efficacy and safety of 3 maintenance doses of tirzepatide with titrated insulin glargine in 
patients with T2DM who have inadequate glycemic control on stable doses of metformin with or 
without a sulfonylurea (Figure GPHO.1).
Treatment Groups and Duration:  
Study GPHO will consist of 3 periods:  an approximately 3-week screening/lead-in period, 
followed by a 40 week treatment period, and a 4-week safety follow-up period.  Patients will be 
randomized in a 1:1:1:1 ratio (tirzepatide 5 mg, 10 mg and 15 mg QW, and insulin glargine QD).  
Patients will be stratified at randomization based on HbA1c (≤8.5%, >8.5% [69 mmol/mol]), 
country and use of concomitant oral antidiabetic treatments (Metformin alone, metformin plus a 
sulfonylurea).
Number of Patients:
A total of approximately 956 patients will be randomized in a 1:1:1:1 ratio to tirzepatide doses:  
5 mg QW (239 patients), 10 mg QW (239 patients), 15 mg QW (239 patients), and insulin 
glargine QD (239 patients).
Statistical Analysis:
Efficacy Analyses:
Efficacy and safety will be assessed using the modified intent-to-treat (mITT) population, which 
consists of all randomly assigned participants who are exposed to at least one dose of study drug.  
The primary efficacy assessment will be performed on data obtained before the initiation of any 
rescue therapy and before premature treatment discontinuation. The analysis model for change 
from baseline in HbA1c assessed over time will be a mixed-model for repeated measures 
(MMRM), with terms: treatment, visit, and treatment-by-visit interaction, stratification factors: 

I8F-MC-GPHO(a) Clinical Protocol
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country and concomitant oral antidiabetic treatment (Metformin alone, metformin plus a 
sulfonylurea) as fixed effects, and baseline HbA1c as a covariate.  An unstructured covariance 
structure will model relationship of within-patient errors.
Supportive analyses will be performed with the same MMRM model on per-protocol (PP) 
population and with an analysis of covariance (ANCOVA) model on mITT population. Details 
for the analysis conducted on PP population will be included in SAP. The ANCOVA analysis 
will be conducted using the Full Analysis Set (FAS), which consists of all available change from 
baseline in HbA1c data at week 40, irrespective of whether they were obtained while the 
participants had discontinued the investigational product or whether the participant had been 
given rescue medication. Additionally, data for subjects with missing values will be imputed 
based on observed data in the same treatment group from subjects who had their efficacy 
measure at the Week 40 visit assessed after early discontinuation of investigational product 
and/or initiation of rescue medication (retrieved drop outs). Analysis will be conducted with 
multiple imputations and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (Rubin 1987).
Additional details, including analysis methods for key secondary endpoints and a strategy for 
controlling overall family-wise Type 1 error rate at an alpha of 0.05 of primary and key 
secondary endpoint evaluation, will be provided in the statistical analysis plan (SAP).
Safety Analysis:
Safety assessment will be based on all available data including 4-week safety follow up period, 
irrespective of whether they were obtained while the participants had discontinued the study drug 
or whether the participant had been given rescue medication. Summary statistics will be 
provided for incidence of treatment-emergent adverse events (TEAEs), serious adverse events 
(SAEs), and study discontinuation due to adverse events (AEs) or deaths from the time of first 
dose through end of safety follow up. Counts and proportions of subjects experiencing AEs will 
be reported for each treatment group, and Fisher’s exact test will be used to compare the 
treatment groups. For continuous laboratory analytes, summary statistics will be provided by 
visit, with statistical comparisons among treatment at each visit conducted using a mixed-model 
for repeated measures (MMRM) analysis.  Selected safety analyses may be conducted excluding 
data after introducing another anti-hyperglycemic therapy (for example, rescue therapy)
Additional details, including analysis of adverse events of special interest, will be provided in the 
SAP.

I 8 F-M C -G P H O ( a) Cli ni c al Pr ot o c ol
P a g e 1 3
L Y 3 2 9 8 1 7 6
2. S c h e d ul e of A cti viti e s
T he Sc he d ule o f Act i vities descri be d bel o w s h o ul d be f o ll owe d f or all pat ient s e nr olle d i n 
St u d y G P H O .  H o we ver, f or t h ose patie nts w h ose partici pati on i n t his st u d y is affecte d b y 
e xce pti o nal circ u msta nces ( rare e ve nts t hat ma y ca use disr u pti ons t o t he c o n d uct of t he 
st u d y, s uc h as pan de mics or nat ural disasters), please refer t o A p pe n di x 7 f or a d ditio nal 
i nstr uctio ns.

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Table GPHO.1.
Schedule of Activities
Study Period 
I
Study Period 
II
Study Period 
III
Screening/ 
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
ETb
801
Week of Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
4 weeks Post 
End of Tx
Allowable Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Informed consent
X
Randomization
X
Clinical Assessments
Medical historye
X
Physical examination
X
X
X
Height
X
Weightf
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
X
X
Vital signs (2 sitting 
BP and PR)g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dilated Fundoscopic 
Examinationh
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycemic 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPHO(a) Clinical Protocol
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LY3298176
Study Period
I
Study Period 
II
Study Period 
III
Screening 
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
4 weeks Post 
End of Tx
Allowable 
Deviation (days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Patient Education
Diabetes 
educationi, j
X
BG meter, SMBG 
trainingj
X
Dispense BG 
meter/supplies, as 
needed
X
X
X
X
X
X
X
X
X
X
X
Study drug 
injection trainingj
X
Hand out diary, 
instruct in usej
X
X
X
X
X
X
X
X
X
X
X
X
X
Remind patients 
about 7-point 
SMBGk
X
X
X
Review 7-point 
SMBG values 
collected in diary
X
X
X
Dispense study 
drug
X
X
X
X
X
X
X
X
Observe patient 
administer
tirzepatidel
X

I8F-MC-GPHO(a) Clinical Protocol
Page 16
LY3298176
Study Period
I
Study Period 
II
Study Period 
III
Screening 
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
4 weeks Post 
End of Tx
Allowable 
Deviation (days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Patient returns 
study drugs and 
injection supplies
X
X
X
X
X
X
X
X
X
Assess study drug 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review insulin 
dose and 
adjustment per 
TTT algorithmm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess compliance 
with insulin dose 
adjustment TTT 
algorithmm
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPHO(a) Clinical Protocol
Page 17
LY3298176
Study Period
I
Study Period
II
Study Period 
III
Screening
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
4 weeks Post 
End of Tx
Allowable 
Deviation (days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Laboratory Tests
Serum pregnancy 
testn
X
Urine pregnancy 
testo
X
X
X
X
Follicle-
stimulating 
hormone testp
X
Chemistry panel
Xq
X
X
X
X
X
Fasting serum 
glucose
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
Urinary albumin/ 
creatinine ratio
Xq
X
X
X
Serum creatinine, 
eGFR (CKD-EPI)r
Xq
X
X
X
X
Calcitonin
Xq
X
X
X
X
X
Hematology
Xq
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
Pancreatic 
amylase, lipase
Xq
X
X
X
X
X
Immunogenicitys
X
X
X
X
X
X
X
PK sample for 
Immunogenicityt
X
X
X
X
X
X
X

I8F-MC-GPHO(a) Clinical Protocol
Page 18
LY3298176
Study Period
I
Study Period
II
Study Period 
III
Screening
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
4 weeks Post 
End of Tx
Allowable 
Deviation (days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Anti-GAD 
antibody
X
Patient Reported Outcomesu
APPADL
X
X
X
EQ-5D-5L
X
X
X
IW-SP
X
X
X
DTSQs
X
DTSQc
X
X
Abbreviations:  APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-
Epidemiology; DTSQc = Diabetes Treatment Satisfaction Questionnaire change; DTSQs = Diabetes Treatment Satisfaction Questionnaire status; eGFR = 
estimated glomerular filtration rate; EQ-5D-5L = European Qualtiy of Life- dimensions; ET = early termination; F/U = follow-up; GAD = glutamic acid 
decarboxylase; HbA1c = hemoglobin A1c; PR = pulse rate; IW-SP = Impact of Weight on Self Perception; PK = pharmacokinetics; SMBG = self-monitored
blood glucose; TTT = treat to target; Tx = treatment.
a
Baseline assessments must be completed before processing in the interactive web-response system.
b
Patients who are unable or unwilling to continue in the study for any reason will perform an ET visit.  If the patient is discontinuing during an unscheduled visit, that visit 
should be performed as the ET visit.  If the patient is discontinuing during a scheduled visit, that visit should be performed as an ET visit.  Visit 801 (safety follow-up visit) 
should be performed 4 weeks after the ET visit as the final study visit.
c
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window).
d
On visits 3, 7, 11, 13, 15, 16, 17, 19 , ET, and at follow-up, patients should be reminded to report to the site in a fasting condition, after a period of approximately 8 hours 
without eating, drinking (except water), or any significant physical activity and before taking study drug(s), metformin and sulfonylurea (if used).
e
Medical history includes assessment of preexisting conditions (including history of gallbladder disease, cardiovascular disease, and medullary thyroid carcinoma) and 
substance usage (such as, alcohol and tobacco).

I8F-MC-GPHO(a) Clinical Protocol
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f
Weight measurements must be in kilograms.
g
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, at visits where required.  The 
participant should sit quietly for 5 minutes before vital sign measurements are taken.  For each parameter, 2 measurements will be taken using the same arm; the recordings 
should be taken at least 1 minute apart. BP must be taken with an automated blood pressure machine.
h
Dilated fundoscopic examination will be performed for all patients between Visit 2 and Visit 3, unless there is a contraindication to dilate the eye (ie. closed angle glaucoma).  
The diagnosis will be made by an eye care professional (ophthalmologist or optometrist) before Visit 3 to exclude patients with proliferative diabetic retinopathy and/or 
diabetic maculopathy or nonproliferative diabetic retinopathy that requires acute treatment. The results from this examination will be recorded on a specific retinopathy eCRF 
as a baseline measure of retinopathy.  Follow up dilated fundoscopic examination should be performed when clinically indicated, and the results recorded on the retinopathy 
eCRF.
i
Includes counseling on diet and exercise, symptoms and management of hypoglycemia, etc.
j
All training should be repeated as needed to ensure patient compliance. 
k
Patient is required to collect two 7-point SMBGs on nonconsecutive days prior to the next visit.  A 7-point SMBG consists of measurements before and 2 hours after each of 3 
main meals within the same day and at bedtime.  These SMBG profiles will be collected by the patient within 2 weeks prior to the assigned visits.  If 7-point SMBG is not 
performed, then data from the most recent nonconsecutive 4-point SMBG (3 before each meal and one at bedtime) profiles can be used.  If more than 2 SMBG profiles are 
available, the 2 most recent profiles on nonconsecutive days should be used.  In the weeks that the 7-point profiles are performed, the 4 –point SMBG profiles will not be 
needed.
l
Patients should administer their first dose of tirzepatide at the end of this visit, after all other study procedures and randomization.
m
During the first 8 weeks, the dose adjustment will be determined by the investigator in discussion with the patient by following a TTT algorithm.  After Week 8, the dose 
adjustment will be determined by the patient in a weekly manner and will be reviewed by the investigator at each office visit.  The dose adjustment will happen weekly during 
the first 16 weeks, and it is assumed that the dose will stay relatively stable from Week 16 onwards.  Assessment of the patient’s compliance to the TTT algorithm will be 
collected in the eCRF at Visits 7, 9, 11, 13, 15 and 19 for the period since the previous visit.  PIs will be reminded that the review of dose is based on daily FBG.
n
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only. Females of childbearing potential are those who are not surgically sterilized and 
between menarche and 1-year postmenopausal.
o
A urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first injection of study drug(s) for women of childbearing potential 
only.  Additional pregnancy tests will be performed at Visits 13, 17, and 19. Pregnancy tests may also be performed at the investigator’s discretion during the study.  If 
required per local regulations and/or institutional guidelines, pregnancy testing can also occur at other times during the study treatment period.
p
Follicle-stimulating hormone test performed at Visit 1 for potential postmenopausal women age 45 years or above with an intact uterus, not on hormone therapy or oral 
contraceptives, and who have had spontaneous amenorrhea for more than 6 months and less than 12 months and estradiol levels consistent with a postmenopausal state 
(FSH≥40 mIU/mL and estradiol <30 pg/mL).
q
Screening visit assessment will serve as baseline.
r
The CKD-EPI equation will be used by the central lab to estimate and report eGFR. 
s
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples will be collected including ADA, PK, and an exploratory 
immune safety sample.
t
PK samples for immunogenicity must be taken prior to drug administration.
u
All PROs should be completed before any other study procedures if the patient is not adversely affected by the fasting condition or completed after the patient has sufficiently 
recovered from the preceding visit procedures.

I8F-MC-GPHO(a) Clinical Protocol
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LY3298176
Note: Patients will be encouraged to collect a daily fasting BG and a weekly 4-point SMBG. Missing a fasting BG measurement will not be considered a protocol 
deviation.

I 8 F-M C -G P H O ( a) Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 3 2 9 8 1 7 6
3. I ntr o d u cti o n
3. 1.
St u d y R ati o n al e
T y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c h aracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y increase d i ns uli n resista nce a n d s uccessi ve beta -cell fail ure a n d c o nse q ue ntl y 
i na de q uate i ns uli n secreti on. T y pe 2 di a betes mellit us is ass ociate d wit h c o m o r bidi ties s uc h as 
i ncrease d wei g ht or o besity,  h y perte nsi o n, a n d i ncrease d bl o o d li p o pr otei n c o nce ntrati o ns, a n d a 
hi g her ri s k f or macr o a n d micr o vasc ular c o m plicati o ns. T o pre ve nt t hese c o m p licati o ns, ti g ht 
gl yce mic c o ntr ol is rec o m me n de d ( A D A 2 0 1 9 ).
T he treat me nt f or T 2 D M us uall y starts wit h lifestyle a n d diet c ha n ges f o ll owe d b y ste p wise 
a d ditio n of  O A Ms w he n pat ient s bec ome persiste ntl y h y per gl yce mic des pite treat me nt wit h 
lifestyle meas ures (I nz ucc hi et al 2 0 1 5). Wit h f urt her pr o gressi o n of t he disease, O A M will be 
i ns ufficie nt t o reac h a nd mai ntai n t he t hera p y  g o al of tar get gl yce mia, a n d ma n y patient s will 
e ve nt uall y re q uire i njecta ble t hera pies. Cli nical g ui deli nes ( A D A 2 0 1 9 ) c urre ntl y rec o m me n d a 
G L P -1 rece pt or a g o nist as t he first c h o ice, a hea d of i ns uli n. Basal i ns uli n al o ne is t he m ost 
c o n ve nie nt i nit ial i ns uli n re gi me n a n d ca n be a d de d t o metf or mi n a n d ot her oral a ge nts ( A D A 
2 0 1 9) . A de q uatel y titrate d glar gi ne t hera p y, i n c o m bi nati on wi t h or al tr e at me nt, fre q ue ntl y 
ac hie ves t he tar get gl yce mic le vel. Gl ar gi ne t hera p y, h o we ver, is fre q ue ntl y ass ociate d wit h
w ei g ht i ncrease a n d e ve nt ual h y p o gl yce mia.
I njecta ble i ncreti n-base d treat me nts (e. g., G L P -1 rece pt or a g o nists) are rec o me n de d as first 
i njecta ble use d i n c o m bi nat i on wi t h O A Ms t o ac hie ve a n d mai ntai n gl uc ose c o ntr ol  ( A D A 2 0 1 9).  
W hile ass ociate d wit h l o wer ris k f or h y p o gl yce mia a n d eit her wei g ht ne utral or wei g ht l oss 
effects, c urre nt pre parati o ns are directe d at a si n gle m o lec ular tar get ( G L P -1 rece pt ors) a n d 
pr o vi de d ose -de pe n de nt gl uc ose -l oweri n g ef fects, w hic h ca n be li mite d b y GI t olera bilit y ( Na uc k 
2 0 1 6).
T he m eta b o lic effects of G L P-1 rece pt or a g o nists ca n be e n ha nce d b y c o m bi ni n g t he m wit h t he 
actio ns of  ot her e nter o pa ncreatic h or m o nes. Gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pti de ( GI P) 
sti m ulates i ns uli n secreti o n i n a gl uc ose-de pe n de nt ma n ner, a n d ma y e xert s o me ot her acti o ns 
be y o n d i ts r ole as a n i ncreti n t hat c o ul d p ote ntiall y i m pr o ve t hera pe utic efficac y i n c o m bi nat i on 
wi t h G L P-1 rece pt or a g o nists al o ne (e. g. i m pr o ve d li pi d h o me o stasis a n d w h o le b o d y  e ner g y 
meta b o lis m) ( Na uc k 2 0 1 8, As mar 2 0 1 6).
T irze patid e is a 3 9-a mi n o aci d s y nt het ic pe pti de wit h a g o nist acti vity at b ot h t he GI P a n d G L P -1 
rece pt ors. Its str uct ure is base d o n t he GI P se q ue nce a n d i ncl u des a C 2 0 fatt y di-aci d moi et y  
 
. It is a d mi nistere d o nce-wee kl y ( Q W) b y s u bc uta ne o us ( S C) 
i njecti on ( C os k u n et al. 2 0 1 8). St u d y  I 8 F-M C -G P H O (G P H O ) is a P hase 3, m ultice nter, 
ra n d omize d, o pe n -label, parallel -gr o u p st u d y t hat will in vest i gate t he effects of treat me nt wit h 
tirze pati de 5 m g, 1 0 m g, a n d 1 5 m g Q W, c o m pare d wit h titrate d i ns uli n glar gi ne i n patient s wit h 
T 2 D M naï ve of i ns uli n treat me nt w h o ha ve i na de q uate gl yce mic c o ntr ol o n sta ble d oses of 
met f or mi n wit h or wi t ho ut a sulf o n yl urea .
C CI

I8F-MC-GPHO(a) Clinical Protocol
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LY3298176
3.2.
Background
Completed tirzepatide clinical trials include:  a Phase 1 study, Study I8F-MC-GPGA (GPGA), 
and 2 Phase 2 studies, Study I8F-MC-GPGB (GPGB) and I8F-MC-GPGF (GPGF).  
Phase 1 Study GPGA was a combination of single ascending dose (SAD) and multiple ascending 
dose study in healthy subjects and a multiple dose study in patients with T2DM.  Study GPGA 
investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of
tirzepatide administered as SC injections.  A total of 142 subjects (89 healthy subjects and 
53 patients with T2DM) received at least 1 dose of treatment.  Doses of tirzepatide ranged from 
0.25 mg to 8 mg in the SAD (with maximum tolerated dose achieved at 5 mg); multiple doses 
from 0.5 mg to 4.5 mg QW; and titrated doses up to 10 mg QW for 4 weeks in healthy subjects; 
and multiples doses at 0.5 mg and 5 mg QW and titrated to 15 mg QW for 4 weeks in patients 
with T2DM.
The safety and tolerability and PK/PD profiles of tirzepatide at doses and escalation regimens 
administered in this Phase 1 study supported further development of tirzepatide for QW dosing in 
patients with T2DM.
A 26-week Phase 2 study (GPGB) assessed the efficacy, tolerability, and safety of 4 doses (1 mg, 
5 mg, 10 mg, and 15 mg) of tirzepatide versus placebo and an active comparator (dulaglutide 1.5 
mg) in 318 patients with T2DM with inadequate glycemic control on diet and exercise alone or 
on a stable dose of metformin monotherapy.  
Study GPGB demonstrated that tirzepatide 5 mg, 10 mg, and 15 mg doses significantly lowered 
hemoglobin A1c (HbA1c) and body weight in a dose-dependent manner in patients with T2DM 
in comparison to placebo. In addition, reductions in HbA1c in the 5-, 10-, and 15-mg tirzepatide
doses were greater than with dulaglutide 1.5 mg QW.  Similar to the GLP-1 receptor agonist 
class and Study GPGA, most of the tirzepatide AEs were GI-related, consisting mainly of nausea, 
vomiting, and diarrhea, and were dose-dependent.  The GI AEs were usually mild to moderate in 
intensity. Serious AEs (SAEs) were balanced across the treatment groups and none of the groups 
in either study reported severe hypoglycemia (Frias et al. 2018).
As it was recognized that the titration scheme employed in Study GPGB was unlikely to be 
optimal to reduce the expected GI-related AEs with tirzepatide, a 12 week, placebo-controlled 
study (GPGF) was conducted to assess 3 different titration schemes. Study GPGF was designed 
to explore alternative titration schemes to reach doses up to 15 mg (longer intervals between dose 
escalations and different dose escalations) and assess the efficacy and safety in patients with 
T2DM to support evaluation of optimized dosing regimen(s) in Phase 3 clinical trials.These data 
support continued development of tirzepatide as a treatment for T2DM.  
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of tirzepatide are to be found in the 
Investigator’s Brochure (IB).

I8F-MC-GPHO(a) Clinical Protocol
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LY3298176
In addition, detailed information about the known and expected benefits and risks of insulin 
glargine may be found in the insulin glargine package insert.

I8F-MC-GPHO(a) Clinical Protocol
Page 24
LY3298176
4.
Objectives and Endpoints
Table GPHO.2 shows the objectives and endpoints of the study.
Table GPHO.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To demonstrate that once-weekly tirzepatide
10 mg and/or 15 mg is non-inferior to titrated 
insulin glargine as measured by change from 
baseline in hemoglobin A1c (HbA1c) at 40 
weeks

Mean change in HbA1c from baseline
Key Secondary (controlled for Type I error)
Efficacy

To demonstrate that once-weekly tirzepatide 5 
mg is noninferior to titrated insulin glargine 
for change from baseline in HbA1c at 40 
weeks 

Mean change in HbA1c from baseline

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior in weight 
loss to titrated insulin glargine at 40 weeks

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior to 
titrated insulin glargine for change from 
baseline in HbA1c at 40 weeks 

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior to 
titrated insulin glargine for the proportion of 
patients with HbA1c target value of <7.0% 
(53 mmol/mol) at 40 weeks

Mean change in body weight from baseline

Mean change in HbA1c from baseline

Proportion of patients achieving HbA1c target 
of <7.0% (53 mmol/mol)
Additonal Secondary (not controlled for type 1 
error)
Efficacy

To demonstrate that once-weekly tirzepatide 5 
mg, 10 mg, and/or 15 mg is superior to 
titrated insulin glargine at 40 weeks for:

Mean change in FSG (central lab) from 
baseline

Proportion of patients achieving an HbA1c 
target values of  ≤6.5% (48 mmol/mol) and 
<5.7% (39 mmol/mol)

Mean change in daily glucose average from 7-
point SMBG profiles from baseline

Proportion of patients who achieved weight 
loss ≥5%, ≥10%, and ≥15% from baseline

To compare tirzepatide 5 mg, 10 mg, and 15 
mg to titrated insulin glargine at 40 weeks for

Patient-reported outcomes:
o
Diabetes Treatment Satisfaction 
Questionnaire status/ Diabetes

I8F-MC-GPHO(a) Clinical Protocol
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LY3298176
Objectives
Endpoints
Treatment Satisfaction Questionnaire 
change 
Safety

To compare tirzepatide 5 mg, 10 mg, and 
15 mg to titrated insulin glargine for: 

TEAEs

Early discontinuation of study drug due to 
AEs

Adjudicated pancreatic AEs

Serum calcitonin

Incidence of allergic and hypersensitivity 
reactions 

Incidence of treatment-emergent anti-drug 
antibodies to tirzepatide

Mean change in systolic and diastolic blood 
pressure and pulse rate from baseline

Occurrence of hypoglycemic events 

Incidence of initiation of rescue therapy for 
severe persistent hyperglycemia
Exploratory

To compare tirzepatide 5 mg, 10 mg, and 15 
mg to titrated insulin glargine with respect for 
the following:

Change in lipids (total cholesterol, HDL, 
VLDL, and TG) 

Changes from baseline in mean body mass 
index (BMI)

Mean change in waist circumference

European Quality of Life- dimensions 
(EQ-5D-5L) scores

Impact of Weight on Self Perception

Ability to Perform Physical Activities of Daily 
Living
Abbreviations: HDL=high density lipoprotein; TG = triglycerides; VLDL = very low density lipoprotein

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5. Study Design
5.1.
Overall Design
Study GPHO is a Phase 3, multicenter, randomized, open-label, parallel-group study that will 
investigate the effects of treatment with tirzepatide 5 mg, 10 mg, and 15 mg QW compared with
titrated insulin glargine in patients with T2DM who have inadequate glycemic control on stable 
doses of metformin with or without a sulfonylurea.  The primary endpoint will be the mean 
change in HbA1c from baseline to 40 weeks.
Patients should be on a stable dose (no dose change for at least 2 months prior to screening) of 
metformin alone or metformin plus a sulfonylurea.  Section 2 provides a detailed schedule of 
activities of the study.  Eligible patients will be randomized at visit 3 in a 1:1:1:1 ratio 
(tirzepatide 5 mg QW, tirzepatide 10 mg QW, tirzepatide 15 mg QW, and insulin glargine once 
daily [QD]).  Patients will be stratified at randomization based on HbA1c (≤8.5%, >8.5% [69 
mmol/mol]), country, and use of concomitant oral antidiabetic treatments (metformin alone, 
metformin plus sulfonylurea).
Insulin glargine will be injected QD, as a single SC injection, always at bedtime at approximately 
the same time every night.  The initial dose of insulin glargine will be 6 IU/day for patients who 
have an average FBG concentration of ≥7.8 mmol/L (≥140 mg/dL). The initial dose of insulin 
glargine for patients with an average FBG concentration of <7.8 mmol/L (<140 mg/dL) may be 
reduced by 1-2 IU/day at the investigator’s discretion. All subsequent glargine dose adjustments
should be determined based on the algorithm (Kawamori et al. 2008).
Figure GPHO.1 illustrates the study design.

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Abbreviations:  QW = once weekly; QD = once daily; SU = sulfonylurea
a  Stable doses of metformin (metformin ≥1000 mg/day and no more than the maximum approved dose per country-specific 
label) and/or a sulfonylurea for 2 months prior to Visit 1, and during the Screening/Lead-in Period.
b  The initial dose of insulin glargine will be 6 IU/day for patients who have an average FBG concentration of ≥7.8 mmol/L (140 
mg/dL).  The initial dose of insulin glargine for patients with an average FBG concentration of <7.8 mmol/L (<140 mg/dL) may 
be reduced by 1-2 IU/day at the investigator’s discretion.  
*Telephone visits
Note: Patients will titrate insulin glargine dose in a weekly manner and will make the dose decision with the investigator for the 
first 8 weeks (phone or clinic visit). From Week 8 to Week 16 patients will continue the titration by a phone consultation or 
clinic visit every other week.  It is expected that the insulin dose will stay relatively stable from Week 16 onwards.
Figure GPHO.1.
Illustration of study design for Clinical Protocol I8F-MC-GPHO.
Study Period I (screening and lead-in)
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility at Visit 2. The patient 
will sign the informed consent form (ICF) before any study procedures are performed. 
Procedures at this visit will be performed as shown in the Study Schedule of Activities, Section 
2. Patients who meet all applicable inclusion criteria and none of the applicable exclusion 
criteria (Section 6) at Visit 1 will continue on their prestudy therapy between Visits 1 and 2.
Lead-in (Visit 2 to Visit 3)
At Visit 2, the screening laboratory results will be reviewed. For those patients meeting all other 
eligibility requirements, a dilated funduscopic examination performed by an ophthalmologist or 
optometrist, must be completed between Visit 2 and Visit 3 to ensure patients with proliferative 
diabetic retinopathy, diabetic maculopathy or non-proliferative diabetic retinopathy that requires 
acute treatment, are identified and not enrolled, unless there is a contraindication to dilate the eye 
(ie. closed angle glaucoma). Additionally, at visit 2, patients and their caregiver(s), if applicable, 

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will receive a glucometer, study diaries and training on how to perform self-monitoring of blood 
glucose (SMBG) and record BG values, hypoglycemic events, medications and adverse events.  
Patients will be provided diaries and will be trained as appropriate to record BG values, 
hypoglycemic events. During this period, patients should be on a stable dose of metformin 
(≥1000 mg/day and no more than the maximum approved dose per country-specific label) with 
or without a sulfonylurea (at least half of the maximum approved dose per country specific 
label).  Patients will also be trained on disease management and study procedures; this training 
can be repeated at subsequent visits as deemed appropriate.  If patients develop a condition that is 
a contraindication for the use of OAMs, they will be considered ineligible and must be 
discontinued from the trial before randomization.
Study Period II (40-week treatment period)
Randomization (Visit 3)
At Visit 3, eligible patients will perform all required baseline study procedures (including the 
collection of all baseline laboratory measures and ECG ) prior to randomization and prior to 
taking the first dose of study drug.  Patient should arrive to the clinic in the fasting state; the 
fasting state should have lasted at least 8 hours without having taken any doses of their study 
drug, metformin and sulfonylurea (if used).  The questionnaires (European Quality of Life [EQ-
5D-5L], Ability to Perform Physical Activities of Daily Living [APPADL], Impact of Weight on 
Self-Perception [IW-SP], and Diabetes Treatment Satisfaction Questionnaire status [DTSQs])
should be completed before any other study procedures if the patient is not adversely affected by 
the fasting condition or completed after the patient has sufficiently recovered from the preceding 
visit procedures.
Patients assigned to tirzepatide will be instructed on how to use the single-dose pen (SDP) and 
will inject their first dose of tirzepatide while in the clinic for Visit 3.  Patients randomized to the 
insulin glargine group will be trained on how to use the prefilled pen and will administer insulin 
glargine once daily ideally at bedtime. The date and time of the first dose of tirzepatide and the 
date of the first dose of insulin glargine should be recorded on the electronic case report form 
(eCRF).
Following randomization, patients will participate in a 40-week treatment period.  
Postrandomization period (end of Visit 3 to Visit 19):
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg 
QW, for the duration of the study in the 5 mg group.  For the 10-mg group, the starting dose of 
tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 
weeks (2.5 to 5 to 7.5 to 10 mg) until the 10-mg dose is reached and maintained for the duration 
of the study.  For the 15-mg group, the starting dose of tirzepatide will be 2.5 mg QW for 4 
weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 
15 mg) until the 15-mg dose is reached and maintained for the duration of the study.  
The initial dose of insulin glargine should be determined by the patient’s average plasma-
equivalent FBG concentration from the previous 2-4 days before Visit 3. The initial dose of 

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insulin glargine will be 6 IU/day for patients who have an average FBG concentration of ≥7.8 
mmol/L (≥140 mg/dL). The initial dose of insulin glargine for patients with an average FBG 
concentration of <7.8 mmol/L (<140mg/dL) may be reduced by 1-2 IU/day at the investigator’s 
discretion. All subsequent glargine dose adjustments should be determined based on the 
algorithm (Kawamori et al. 2008) (see section 7.2.1.2).
Most of the insulin glargine titration should occur during the first 16 weeks of the study, 
followed by a 24-week maintenance period.  The maintenance period is defined as a part of the 
titration period when the insulin glargine dose is expected to be stable and optimized (Weeks 
16-40 [Visits 15-19]).
During the first 8 weeks of treatment, patients should measure their prebreakfast FBG 
concentration every morning before any OAM have been taken and record the result in their 
study diary.  From week 8 onwards, patients are recommended to measure and record their 
prebreakfast FBG concentration everyday, if considered appropriate by the investigator. During 
the first 8 weeks, the insulin glargine dose adjustment will be determined by the investigator in 
discussion with the patient.  This time will be used as preparation and training for 
implementation of the patient self-titration according to the TTT algorithm (Section 7.2.1.2).  
From week 8 onwards, the decision of the titration will be made and implemented by the patient 
in a weekly manner.  Between Week 8 and Week 16, investigators or study site personnel will 
contact the patient every 2 weeks (office or telephone visit) and will review the insulin dose 
adjustment made by the patient at each of these visits.  Investigators may perform additional 
telephone visits if necessary, or perform additional office visits if the investigator deems 
additional training is necessary.  
During the treatment period, office visits will occur weekly or every other week during the first 
16 weeks, and thereafter, every 4 to 8 weeks to enable the site to properly monitor patients’ usage 
of the TTT algorithm.
At each of the 6 scheduled telephone visits, procedures will include assessments of SMBG, 
compliance with insulin titration algorithm, insulin dose, tirzepatide compliance (will be 
re-assessed at the office visit), hypoglycemic events, concomitant medications, and AEs (see 
Schedule of Activites Section 2).  The data obtained at these telephone visits will be entered into 
the electronic eCRFs at the next office visit.  
Throughout the treatment period, patients will collect all data on SMBG, insulin dose 
assessments, insulin doses administered, dates when study drug was administered, hypoglycemic 
events, in the patient diary to be reviewed with the study site personnel at the next office visit.  
For that purpose, at each visit, study diaries for the period after the previous office visit, will be 
collected, and instructions will be reviewed at each visit (new diaries will be dispensed for the 
next visit interval).  Study drug and injection supplies will be returned per the Schedule of 
Activities (Section 2) and according to local requirements.  New supplies will be dispensed as 
needed.  
Results of SMBG and hypoglycemic events will be used by the patient to assess insulin glargine
doses per the TTT algorithm.  Additional assessments may be requested by the investigator based 
on his/her clinical judgment.  Outcome of the assessment will be recorded in patient diaries.

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Compliance with the tirzepatide administration schedule and compliance with the insulin 
glargine TTT algorithm will be assessed at every office visit and collected in the eCRF at
prespecified visits (Section 2). Based on the outcome of these reviews, the site staff should 
discuss additional insulin glargine dose adjustments while the patient is still at the site and 
provide retraining, if needed.
Patients should be instructed to contact the investigative site for assistance as soon as possible if 
they experience any difficulties administering their study medication or with the TTT algorithm 
at any time during the study treatment period.  Patients should also be advised about the 
appropriate course of action in the event that study drug is not taken at the required time 
(late/missing doses).
Study Period III (safety follow-up period)
Safety follow-up (Visit 801) visits:
All patients who complete the treatment period are required to complete Visit 801, a safety 
follow-up visit approximately 4 weeks after their last dose.  Patients discontinuing the study early 
and performing an early termination (ET) visit will also be asked to perform the safety follow-up 
visit, so that the safety follow-up visit will be their final visit.  During the safety follow-up 
period, patients will not receive study drug.  Patients may be treated with another 
glucose-lowering intervention decided upon by the investigator. Initiation of new 
antihyperglycemic therapy for the safety follow-up period will not be classified as “rescue 
therapy”. Probihited anti-diabetes medications include GLP-1 receptor agonists, dipeptidyl 
peptidase (DPP-4) inhibitors, fixed-dose combination with component of GLP-1 receptor 
agonists or DPP-4 inhibitor, and pramlintide. Other basal insulin are also prohibited for patients 
assigned to insulin glargine. Patients are required to return any remaining study diaries to the 
study site at the end of this period.
Study Procedures
Patients will perform study procedures listed in the Schedule of Activities (Section 2). 
Patients will be permitted 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 treatments (Section 7.7).  Anti-hyperglycemic medications other than 
study drugs and metformin (and SU if used) are not allowed at any time during the study except 
as allowed for rescue therapy and/or after early study drug discontinuation.  Rescue therapy with 
other glucose-lowering agents, including prandial insulin, may be medically indicated in certain 
situations after randomization due to severe, persistent hyperglycemia or early discontinuation of 
study treatment.  GLP-1 receptor agonists, DPP-4 inhibitors, fixed-dose combination with 
component of GLP-1 receptor agonists or DPP-4 inhibitor, and pramlintide are prohibited 
medications and are not allowed as rescue therapies.  Use of other basal insulins will not be 
allowed in the insulin glargine group.  Use of glargine will not be allowed in the tirzepatide
groups.

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Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Sections 7.2.1.2 and 9.2.2.2) will receive a new glucose-lowering intervention (“rescue therapy”) 
and will also continue to administer study drug.  Patients who need hyperglycemic rescue therapy 
will continue in the trial until they complete all study visits.
Study governance considerations are described in detail in Appendix 3.
Self-Monitored Blood Glucose Profiles
The SMBG plan will include daily measurements of FBG, one weekly 4-point BG profile and 
two 7-point SMBG profiles done on 2 nonconsecutive days in the 2-week period prior to Visit 3 
(randomization), Visit 17 (Week 24), Visit 19 (end of treatment).  When required, patients (and 
their caregivers, if applicable) will measure and record their BG concentration on 7 occasions (7-
point SMBG): before breakfast (fasting), before lunch, before dinner, 2 hours after breakfast, 2 
hours after lunch, 2 hours after dinner, and at bedtime.  Pre-meal measurements should be taken 
before the patient begins eating the meal. Investigators will record the BG concentrations for the 
7-point SMBG profiles reported in the patients’ diaries in the patients’ eCRFs.
Patients will also be required to collect a weekly 4-point SMBG.  These 4-point SMBG profiles 
should include fasting (or pre-morning meal), pre-midday meal, pre-evening meal, and bedtime 
values.  In the weeks that the 7-point profiles are performed, the 4 –point SMBG profiles will not 
be needed.
5.2.
Number of Participants
A total of approximately 956 patients will be randomized in a 1:1:1:1 ratio:  

5 mg QW (239 patients), 

10 mg QW (239 patients), 

15 mg QW (239 patients), 

insulin glargine QD (239 patients).
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Study GPHO is designed to determine the comparative benefits and risks of once-weekly
tirzepatide 5 mg, 10 mg, or 15 mg versus titrated insulin glargine in patients with T2DM who 
have inadequate glycemic control on stable doses of metformin with or without a sulfonylurea.
An active comparator rather than placebo was selected for this trial because it includes patients 
with uncontrolled T2DM despite use of oral antihyperglycemic therapies (HbA1c ≥7.5% to 
≤11%). Insulin glargine was selected as the comparator because it is a widely used therapy 
prescribed in this patient population.  Metformin and sulfonylurea were chosen as the 
concomitant antihyperglycemic medication as they are commonly used individually or in 
combination in clinical practice, and its use in patients who initiate basal insulin therapy has been 

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applied.  To ensure a valid comparison of the randomized study treatments, it is important that 
insulin glargine is titrated optimally throughout the entire study.  Patients will be required to use 
a TTT algorithm, which has been shown to be effective in enabling a high proportion of patients 
with T2DM to achieve their therapeutic targets when treated with insulin glargine (Kawamori et 
al. 2008) as described in Section 7.2.1.2.  The frequency of clinic visits postrandomization is 
intended to allow patients and investigators frequent assessment of study treatments, including 
optimal insulin glargine dose adjustments as needed for the attainment of glycemic goals within a 
short time period.  
The parallel-group design for treatment comparison was chosen to avoid any interaction between 
treatments that may interfere with the interpretation of the trial outcome.  To minimize the 
potential confounding effect of changes to concomitant medications, patients will be permitted to 
use concomitant medications that they require during the study.  Medications that may interfere 
with the assessment of efficacy and safety characteristics of the study treatments will not be 
allowed (see Section 7.2.1.2).  An open-label design was chosen due to the different dosing 
frequencies, titration scheme of insulin glargine and injection devices compared to tirzepatide.
The planned duration of treatment for the primary endpoint at 40 weeks is considered appropriate 
to assess the full effects and benefit/risk of each maintenance dose of tirzepatide on both 
glycemic control and body weight.  Moreover, the duration of the study is considered sufficient 
and appropriate for patients to optimize dosing of insulin glargine for comparison with the 
tirzepatide treatment groups with respect to change in HbA1c.
5.5.
Justification for Dose
Tirzepatide doses of 5 mg, 10 mg, and 15 mg administered subcutaneously QW will be evaluated 
in this study. These doses and associated escalation schemes were selected based on assessment 
of safety, efficacy (glycemic and weight loss benefit), and GI tolerability data followed by 
exposure response modeling of data in T2DM patients in Phase 1 and 2 studies. Dosing 
algorithms starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5 mg increments 
every 4-week would permit time for development of tolerance to GI events and are predicted to 
minimize GI tolerability concerns.  The maximum proposed dose of 15 mg maintains an 
exposure multiple of 1.6 to 2.4 to the no-observed adverse effect level doses in 6-month monkey 
and rat toxicology studies.  The selected dose and escalation scheme would enable further 
evaluation of benefit/risk considerations for 5 mg, 10 mg, and 15 mg doses of tirzepatide.
This study will be conducted in China and at least 2 other countries/regions and the patient 
population will predominantly consist of Asian patients. Therefore, this study will use a simple
insulin glargine dosing algorithm (refer to Section 7.2.1.2) that has previously been found to be
safe and effective in Japanese patients in conjunction with glimepiride, resulting in a steady
improvement in glycemic control over 24 weeks without any serious adverse events (Kawamori
et al. 2008). However, the frequency of insulin glargine dose adjustments has been altered
slightly from the Kawamori schedule, such that it better reflects normal clinical practice in
China. In the study by Kawamori et al. (2008), the dose of insulin glargine was adjusted every 2-

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3 days, if necessary. In the current study, the dose of insulin glargine will be titrated weekly, 
with a more intensive follow-up during the first 16 weeks of treatment.  

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Type of Patient and Disease Characteristics
[1]
Have been diagnosed with type 2 diabetes based on the WHO classification or 
other locally applicable diagnostic standards
Patient Characteristics
[2]
Are on stable diabetes treatment with metformin with or without a 
Sulfonylurea (metformin ≥1000 mg/day and no more than the maximum 
approved dose per country-specific label; sulfonylurea should be at least half 
the maximum dose according to the specific country label information) for at 
least 2 months prior to Visit 1 and between Visit 1 and Visit 3.
[3]
Are insulin-naive (except for the use of insulin for treatment of gestational 
diabetes or short-term use [≤14 consecutive days] for acute conditions)
[4]
Have HbA1c ≥7.5% to ≤11.0%, as determined by the central laboratory at 
Visit 1
[5]
Are of stable weight (±5%) ≥3 months prior to Visit 1, and agree to not 
initiate a diet and/or exercise program during the study with the intent of 
reducing body weight other than the lifestyle and dietary measures for diabetes 
treatment
[6]
Have body mass index (BMI) ≥23 kg/m2 at Visit 1
[7]
Are ≥18 years old or of an acceptable age to provide informed consent 
according to local regulations, whichever is older
Male patients (see Appendix 6 for more details):

Male patients should be willing to use reliable contraceptive methods throughout 
the study and for at least 3 months after last injection 
Female patients:

Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation), congenital anomaly 
(ie. Mullerian agenesis) or menopause.
o
Women with an intact uterus are deemed postmenopausal if they are 45 
years old, and

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
have not taken hormones or oral contraceptives within the last year 
and had cessation of menses for at least 1 year,
OR

have had at least 6 months of spontaneous amenorrhea with 
follicle-stimulating hormone (FSH) and estradiol levels consistent 
with a postmenopausal state (FSH ≥40 mIU/mL and estradiol <30 
pg/mL).
o
Female patients of child-bearing potential (not surgically sterilized and
between menarche and 1-year postmenopausal) must:

test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
AND

if sexually active, agree to use two forms of effective 
contraception, where at least one form is highly effective for the 
duration of the trial and for 30 days thereafter 

not be breastfeeding
[8]
In the investigator’s opinion, are well-motivated, capable, and willing to: 
a) perform fingerstick BG monitoring, including scheduled BG profiles with up to 7 
measurements in 1 day
b) learn how to self-inject treatment (tirzepatide or insulin glargine), as required for 
this protocol (visually impaired persons who are not able to perform the injections 
must have the assistance of a sighted individual trained to inject the study drug; 
persons with physical limitations who are not able to perform the injections must 
have the assistance of an individual trained to inject the study drug) 
c) are willing and able to inject tirzepatide once-weekly or insulin glargine QD
d) maintain a study diary, as required for this protocol.
e) have a sufficient understanding of the primary language of the country such that 
they will be able to complete the patient questionnaires
Informed Consent
[9]
Have given written informed consent to participate in this study in accordance with 
local regulations and the Ethical Review Board (ERB) governing the study site
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Medical Conditions
[10] Have Type 1 diabetes mellitus (T1DM)

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[11] Had chronic or acute pancreatitis any time prior to study entry (Visit 1). 
[12] Have history of: 

proliferative diabetic retinopathy
or

diabetic maculopathy
or

nonproliferative diabetic retinopathy that requires acute treatment
(a dilated fundoscopic examination will be performed for all patients between 
Visit 2 and Visit 3, unless there is a contraindication to dilate the eye [ie. 
closed angle glaucoma].  The diagnosis will be made by an eye care 
professional [ophthalmologist or optometrist] before Visit 3 to confirm 
eligibility)
[13] Have a history of severe hypoglycemia and/or hypoglycemia unawareness 
within the 6 months prior to Visit 1
[14] Have a history of ketoacidosis or hyperosmolar state/coma
[15] Have a known clinically significant gastric emptying abnormality (for 
example, severe diabetic gastroparesis or gastric outlet obstruction), have 
undergone or plan to have during the course of the study: a gastric bypass 
(bariatric) surgery, or restrictive bariatric surgery (eg, Lap-Band®), or 
chronically take drugs that directly affect GI motility
[16] Have any of the following CV conditions within 2 months prior to Visit 1:  
acute myocardial infarction, or cerebrovascular accident (stroke) or 
hospitalization due to congestive heart failure (CHF)
[17] New York Heart Association Functional Classification III and IV CHF
[18] Have acute or chronic hepatitis, signs and symptoms of any other liver disease 
other than nonalcoholic fatty liver disease (NAFLD), or alanine 
aminotransferase (ALT) level >3.0 times the upper limit of the reference 
range, as determined by the central laboratory at study entry (visit 1); patients 
with NAFLD are eligible for participation in this trial only if their ALT level 
is ≤3.0 times the upper limit of normal (ULN) for the reference range
[19] Have an estimated glomerular filtration rate (eGFR) ≤45 mL/min/1.73 m2 (or 
lower than the country-specific threshold for using the protocol-required dose 
of metformin per local label), calculated by CKD-EPI, as determined by 
central laboratory at Visit 1
[20] Have evidence of a significant, uncontrolled endocrine abnormality (for 
example, thyrotoxicosis or adrenal crises), in the opinion of the investigator
[21] Have family or personal history of medullary thyroid carcinoma (MTC) or 
multiple endocrine neoplasia syndrome type 2 (MEN-2)

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[22] Have a serum calcitonin level of ≥35 ng/L (pg/mL), as determined by central 
laboratory at Visit 1
[23] Known or suspected hypersensitivity to trial product(s) or related products
[24] 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 12 
months
[25] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant
[26] Have a history of an active or untreated malignancy, or are in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 
5 years
[27] Have a history of any other condition (such as known drug or alcohol abuse or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
patient from following and completing the protocol
[28] Have any hematological condition that may interfere with HbA1c 
measurement (for example, hemolytic anemias, sickle-cell disease)
Prior/Concomitant Therapy
[29] Treatment with any glucose lowering agent(s) other than stated in the 
inclusion criteria # 2 in a period of 2 months prior to Visit 1 and between Visit 
1 and Visit 3
[30] Have been treated with prescription drugs that promote weight loss  
(e.g.,Saxenda  (liraglutide 3.0 mg), Xenical® [orlistat], Meridia® 
[sibutramine], Acutrim® [phenylpropanolamine], Sanorex® [mazindol], 
Apidex®[phentermine], BELVIQ® [lorcaserin], Qsymia™ 
[phentermine/topiramate combination], contrave® [naltrexone/bupropion] or 
similar other body weight loss medications including over-the-counter [OTC] 
medications [e.g., allī®]) within 3 months prior to Visit 1 and/or between 
study entry (Visit 1) and randomization (Visit 3)
[31] Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy 
(excluding topical, intra-ocular, intranasal, or inhaled preparations) or have 
received such therapy within 1 month of Visit 1; or between Visits 1 and 3
Prior/Concurrent Clinical Trial Experience
[32] 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

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[33] 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
[34] Have previously completed or withdrawn from this study or any other study 
investigating tirzepatide
Other Exclusions
[35] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[36] Are Lilly employees 
[37] Are unwilling or unable to comply with the use of a paper diary to directly 
record data from the subject
6.3.
Lifestyle Restrictions
Per the Schedule of Activities (Section 2), qualified medical staff will provide diabetes 
management counseling, which will include instructions on diet and exercise and education about 
the signs, symptoms, and treatment of hypoglycemia, should it occur.  
Patients 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.  Dietary 
counseling may be reviewed throughout the study, as needed.  Per inclusion criterion [5] (Section 
6.1), patients should not initiate during the study an organized diet and/or exercise weight 
reduction program other than the lifestyle and dietary measures for diabetes treatment.
Study participants should be instructed not to donate blood or blood products during the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) must not 
be rescreened.

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7. Treatments
7.1.
Treatments Administered
Patients will be randomized in a 1:1:1:1 ratio to receive tirzepatide 5 mg, 10 mg, 15 mg, or 
insulin glargine.  Tirzepatide will be administered QW as SC injection in patients with T2DM 
who are already treated with a stable dose of metformin alone or metformin plus a sulfonylurea.
Table GPHO.3 shows the randomized treatments for the entire treatment period.
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg 
QW, for the duration of the study for the 5-mg group.  For the 10-mg group, the starting dose of 
tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 
weeks (2.5 to 5 to 7.5 to 10 mg) until the 10-mg dose is reached and maintained for the duration 
of the study.  For the 15-mg group, the starting dose of tirzepatide will be 2.5 mg QW for 4 
weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 
15 mg) until the 15-mg dose is reached and maintained for the duration of the study.  
The starting dose of insulin glargine will be 6 IU/day at bedtime, titrated to a FBG between 72-
100 mg/dL, following a TTT algorithm (Kawamori et al. 2008.).  During the first 8 weeks, the 
insulin glargine dose adjustment will be determined by the investigator in discussion with the 
patient.  From week 8 onwards, the decision of the titration will be made and implemented by the 
patient in a weekly manner.  Between Week 8 and Week 16, investigators or study site personnel 
will contact the patient every 2 weeks (office or telephone visit) and will review the insulin dose 
adjustment made by the patient at each of these visits.
Table GPHO.3.
Treatment Regimens
Name of Study 
Drug
Dosage
Frequency
Drug Formulation
Route of 
Administration
Tirzepatide
5 mga
QW
Single-dose pen
SC
10 mga
QW
Single-dose pen
SC
15 mga
QW
Single-dose pen
SC
Insulin glargine
TTT dosingb
QD
prefilled pen
SC
Abbreviations:  QD = once daily; QW = once weekly; SC = subcutaneous; TTT = treat-to-target.
a
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg QW, for the 
duration of the study for the 5-mg group.  For the 10-mg group, the starting dose of tirzepatide will be 2.5 mg 
QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 mg) until the 
10-mg dose is reached and maintained for the duration of the study.  For the 15-mg group, the starting dose of 
tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 
7.5 to 10 to 12.5-15 mg) until the 15-mg dose is reached and maintained for the duration of the study. 
b The starting dose of insulin glargine will be 6 IU/day ideally at bedtime, titrated to a FBG between 72-100
mg/dL, following a TTT algorithm.  Insulin dose adjustments will be made in Study Period II per the TTT 
algorithm.
The investigator or his/her designee is responsible for the following:

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
Explaining the correct use of study drugs to the patient or patient representative, 
and SDP or insulin glargine training. For the SDP a demonstration device will be 
used.

Explaining the correct use of concomitant metformin, sulfonylurea (if used) to the 
patient, including any contraindications and appropriate dosing per country-
specific labeling

Verifying that instructions are followed properly

Maintaining accurate records of investigational product dispensing and collection
Patients should return all study drugs to the site according to the Schedule of Activities (Section 
2).  Patients should be instructed to discard all used SDPs and insulin glargine pens in a 
closeable, puncture-resistant container according to local regulations.
7.1.1. Packaging and Labelling
The sponsor will provide tirzepatide in prefilled pens (SDP) and insulin glargine in prefilled 
pens.  These will be dispensed via an interactive web-response system (IWRS).  Single-dose pens
and prefilled pens will be packaged in cartons to be dispensed.  Clinical study materials will be 
labeled according to the country’s regulatory requirements.
7.1.2. Medical Devices
The combination products provided for use in the study are tirzepatide investigational SDP and a 
marketed insulin glargine prefilled pen.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the study treatment 
groups at Visit 3.  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an IWRS.  Patients will be randomized in a 1:1:1:1 ratio to receive 5 mg 
tirzepatide , 10 mg tirzepatide, 15 mg tirzepatide, or insulin glargine.
7.2.1. Selection and Timing of Doses
7.2.1.1.
Tirzepatide
Assignment to tirzepatide (3 doses) or insulin glargine will occur at randomization.  
There are no restrictions on the time of day each weekly dose of tirzepatide is given, but it is 
advisable to administer the SC injections on the same day and same time each week.  The actual 
date and time of all dose administrations will be recorded by the patient.  If a dose of tirzepatide
is missed, the patient should take it as soon as possible unless it is within 72 hours of the next 
dose, in which case, that dose should be skipped and the next dose should be taken at the 
appropriate time.
7.2.1.2.
Insulin glargine
Patients in the insulin glargine group will start their insulin glargine treatment with a single SC
injection of insulin glargine  ideally at bedtime on the day of Visit 3. The initial dose of insulin
glargine should be determined by the patient’s average plasma-equivalent FBG concentration
from the previous 2-4 days before Visit 3. The initial dose of insulin glargine will be 6 IU/day

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for patients who have an average FBG concentration of ≥7.8 mmol/L (140 mg/dL). The initial
dose of insulin glargine for patients with an average FBG concentration of <7.8 mmol/L (<140
mg/dL) may be reduced by 1-2 IU/day at the investigator’s discretion. All subsequent glargine
dose adjustments should be determined based on the algorithm in Table GPHO.4. 
Table GPHO.4.
Dosing Titration Schedule for Once-Daily Insulin Glargine (TTT 
Algorithm)
Average of self-monitored plasma-equivalent FBG 
measurements from the previous 2-4 days
Change in insulin glargine dose (IU/day)
≥6.1 mmol/L (≥110 mg/dL)
+2
5.6 – 6.1 mmol/L (101 – 109 mg/dL)
+1 or +2 (at the investigator’s discretion)
4.0 – 5.6 mmol/L (72 – 100 mg/dL)
No change in dosage
3.3 – 3.9 mmol/L (60 – 71 mg/dL)
-1
<3.3 mmol/L (<60 mg/dL)
-2
Notes:  The FBG concentrations listed above refer to fasting plasma glucose concentrations obtained from a
laboratory or FBG concentrations obtained using an International Federation of Clinical Chemistry (IFCC) plasma-
equivalent BG meter.  If only one prebreakfast SMBG value is available, the patient should contact the investigator 
site for instructions on adjusting insulin dose.
Source: Kawamori et al. 2008.
Regular FBG measurements are required during the study treatment period for the purpose of
adjusting the dose of insulin glargine, if necessary, and monitoring patient safety. Patients
should monitor their FBG concentrations using the plasma-equivalent BG meter provided to
them for this study. During the first 8 weeks of treatment, patients should measure their 
prebreakfast FBG concentration every morning before any OAM have been taken and record the
result in their study diary.  From week 8 onwards, patients are recommended to measure and 
record their prebreakfast FBG concentration everyday, if considered appropriate by the 
investigator. During the first 8 weeks, the insulin glargine dose adjustment will be determined by 
the investigator in discussion with the patient.  From week 8 onwards, the decision of the titration 
will be made and implemented by the patient in a weekly manner.  The investigator and/or 
patients will titrate the dose of insulin glargine every week according to the patient’s average 
FBG concentration for the previous 2-4 days. The target FBG range is between 4.0-5.6 mmol/L 
(72-100 mg/dL).
Patients should be instructed not to make up missing doses. If they forget to take their dose of
insulin glargine on a particular day, they should record this in their patient diary and take their
next dose as scheduled on the following day (that is, the dose is not doubled to make up for the
missing dose on the previous day).
7.3.
Blinding
This trial is an open-label study due to the differences in dosing schedule, titration, and devices 
between once-weekly tirzepatide and once-daily insulin glargine. It is not blinded between 
different doses of tirzepatide.

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7.4.
Dosage Modification
7.4.1. Study drugs
Details about dose administration of tirzepatide during the study are described in Sections 7.2.1
and 8.1.2.  Insulin glargine will be adjusted according to the TTT algorithm (see Section 7.2.1.2).
7.4.2. Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications
After randomization, discontinuation of metformin or a sulfonylurea (if used) or change in
dosage is not permitted, except in the following situations:
1) In the event of a hypoglycemic episode(s) (clinical symptoms of hypoglycemia and/or 
blood glucose (BG)-confirmed symptomatic hypoglycemia [glucose concentration 
≤3.0 mmol/L {54mg/dL}]):

Patients in the tirzepatide groups on dual oral treatment of metformin and 
sulfonylurea may reduce/discontinue the dose of either metformin or sulfonylurea, but 
are recommended to reduce/discontinue the dose of sulfonylurea first. When 
hypoglycemia develops in patients on tirzepatide and metformin monotherapy, the 
dose of metformin may be reduced or discontinued.

Patients in the insulin glargine group must adjust the dose of insulin glargine 
following the TTT algorithm (section 7.2.1.2).  In the event of recurrent 
hypoglycemic episodes despite reductions of the insulin dose, the investigator may 
consider a reduction in the dose of the OAMs.  In that case, patients on dual oral 
treatment of metformin and sulfonylurea may reduce/discontinue the dose of either 
metformin or sulfonylurea, but are recommended to reduce/discontinue the dose of 
sulfonylurea first. If the patient is on metformin monotherapy, the dose of metformin
may be reduced or discontinued.
2) In certain situations that require short-term discontinuation in line with the product(s) 
labeling for each respective country (for example: for metformin: severe dehydration, 
elective surgery, or need for radiologic exam involving IV iodinated contrast dye).
Once the situation that led to temporary discontinuation of the drug resolved, treatment 
should be restarted at investigator discretion.
3) If a patient develops contraindications to metformin or sulfonylurea (if used), such that 
the use of the drug is contraindicated according to the country-specific label, the drug 
should be discontinued; in this case, the insulin glargine dose may need to be further 
adjusted.
A patient will be considered noncompliant with the protocol (protocol deviation) if he/she
changes the dose or discontinues metformin or sulfonylurea (if used) for reasons other than 
those described here. In the case of noncompliance that lasts >14 days during the treatment 
period, the patient will not be included in the per-protocol (PP) analyses.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

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
confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments 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 site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
The study site must store the study drug in a locked and secure environment.  Please refer to the 
study drug label for specific storage conditions.  Patients will receive insulated bags with cooling 
gel packs for use in transporting the study drug carton from the site to home. 
Study site staff must regularly assess whether the patient is correctly administering the assigned 
study drug and storing the study drug according to the provided instructions.
7.6.
Treatment Compliance
Study drug compliance will be determined by the following: 

Study drug administration data will be recorded by the patient and reviewed by 
the investigator at each study visit.

The patients will be instructed to return any unused study drug and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability.
In the 3 tirzepatide treatment groups, treatment compliance is defined as taking at least 75% of 
the required doses of study drug.  In the insulin glargine group, a patient will be considered to be 
significantly noncompliant if they miss their daily dose of insulin glargine for more than 7 
consecutive days or for more than 7 days within a month (that is, a patient is considered to be 
compliant if they are ≥75% compliant with their required insulin glargine therapy).  Similarly, a 
patient will be considered significantly noncompliant if he or she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.  
In addition to the assessment of a patient’s compliance with the study drug administration, other 
aspects of compliance with the study treatments will be assessed at each visit based on the 
patient’s adherence to the visit schedule, compliance with the concomitant antihyperglycemic 
medication regimen, completion of study diaries, the results of home BG monitoring, and any 
other parameters the investigator considers necessary.
Patients considered to be poorly compliant with their medication and/or the study procedures will 
receive additional training and instruction, as required, and will be reminded of the importance of 
complying with the protocol.

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7.7.
Concomitant Therapy
Patients will be permitted 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 treatments (Table GPHO.5). 
Investigative site staff will inform patients that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study.  This 
may not be possible when initiated for treatment of medical emergencies, in which case the 
patient will inform the investigator or a designated site staff member as soon as possible.  Any 
additional medication initiated during the course of the study (including over-the-counter [OTC] 
drugs, such as paracetamol or aspirin) must be documented, and the name of the drug and the 
date(s) of administration must be recorded on the “Concomitant Medications” section of the 
eCRF. 
Anti-hyperglycemic medications other than study drugs and protocol allowed concomitant 
antihyperglycemic medications are not allowed at any time during the study except as allowed 
for rescue therapy, and/or after early study drug discontinuation.  Rescue therapy with other 
glucose-lowering agents, including prandial insulin, may be medically indicated in certain 
situations after randomization due to severe, persistent hyperglycemia or early discontinuation of 
study treatment.  GLP-1 receptor agonists, DPP-4 inhibitors, fixed-dose combination with 
component of GLP-1 receptor agonists or DPP-4 inhibitor, and pramlintide are prohibited 
medications and are not allowed as rescue therapies.  Use of other basal insulins will not be 
allowed in the insulin glargine group.  Use of glargine will not be allowed in the tirzepatide
groups.
All non-study medications will be recorded on source documents at all visits.
Nonstudy medications taken by patients who are screened but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.
Table GPHO.5.
Use of Concomitant Medications that May Interfere with Efficacy 
and Safety Assessments in Study GPHO
Drug Class
Use During 
Screening/Lead-In
Conditions for Use after Randomization
Acute 
therapya
Rescue 
therapy 
During Safety 
Follow-Up Period
Drugs with approved weight loss 
indicationb
Excluded
N
N/A
Y
Systemic glucocorticoid therapyc
Excluded except for 
acute therapya
Y
N/A
Y
Antihyperglycemia medications
Other GLP-1 RAs and related
fixed-dose combination
Excluded
N
N
N
DPP-4 inhibitors and related
fixed-dose combination
Excluded
N
N
N
Pramlintide
Excluded
N
N
N

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Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; N = no; N/A 
= not applicable; SGLT2 = sodium-glucose co-transporter 2; Y = yes
a
Acute therapy = treatment for up to 14 days.  For acute therapy, rescue therapy and therapy during safety follow-
up period, use of other basal insulins will not be allowed in the insulin glargine group; use of glargine will not be 
allowed in the tirzepatide group.
b
Includes Saxenda® (liraglutide 3.0 mg), Xenical® (orlistat), Meridia® (sibutramine), Sanorex® (mazindol), 
Apidex® (phentermine), BELVIQ® (lorcaserin), Qsymia® (phentermine/topiramate combination), Contrave®
(naltrexone/buproprion), or similar other body weight loss medications including over-the-counter medications 
(eg, allī®) within 3 months prior to Visit 1 or any time during the trial. 
c
Chronic systemic glucocorticoid therapy = treatment for up to 14 days. From 1 months prior to Visit 1 or 
between Visits 1 and 3; does not apply to topical, intraocular, intranasal, intra-articular, or inhaled preparations.
d
Switching metformin manufacturers is allowed as long as the dosage is the same.  Changing to a metformin 
formulation with a different action profile (for example, from short-acting to long-acting metformin) is not 
permitted.
e
For rescue therapy, metformin dose can be increased if the dose is below maximum approved dose per 
country-specific label and is well tolerated.
7.7.1. Management of Patients with Gastrointestinal Symptoms
In the Phase 2 program, the most commonly reported treatment-emergent adverse events for 
patients receiving tirzepatide were nausea, vomiting, and diarrhea.  
The tirzepatide dose escalation scheme has been designed to minimize the development of 
intolerable GI symptoms.  The escalation period is considered to be 24 weeks, which allows 20 
weeks to escalate to 15 mg and  additional 4 weeks to reach steady state.  During the dose 
escalation period, every effort should be made by the investigator to be able to escalate and 
maintain patients on the corresponding study drug dosage. 
To mitigate GI symptoms and manage patients with intolerable GI AEs, the investigator should:

Advise patients to eat smaller meals, for example, splitting 3 daily meals into 4 or 
more smaller meals, and to stop eating when they feel full.

Prescribe symptomatic medication (for example, anti-emetic or anti-diarrheal 
medication) per local country availability and individual patient needs. Use of 
symptomatic medication should be captured as concomitant medication in the 
eCRF.

Temporarily interrupt tirzepatide (omit 1 dose, the patient will take 3 of 4 doses at 
that dose level). The data related to temporary interruption of study treatment 
should be documented in source documents and entered on the eCRF.  
SGLT-2i
         Excluded
N
Y
Y
Insulinsa
Excluded
Y
Y
Y
Meglitinides
Excluded
N
Y
Y
Alpha-glucosidase inhibitors
Excluded
N
Y
Y
Sulphonylureas
Allowed
N
Y
Y
Thiazolidinediones
Excluded
N
Y
Y
Metformind
Required
N/A
Ye
Y

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
After the interruption, restart at the same dose with the patient taking medication 
to alleviate their GI symptoms (Section 8.1.2).   
If intolerable GI symptoms or events persist despite the above measures, the investigator may 
decide to continue treatment at a lower, tolerated maintenance dose of tirzepatide (5 mg or 10 
mg).  

Patients at 5mg or lower will be discontinued from tirzepatide.

Patients at 7.5mg or 10mg will decrease the dose to 5mg.

Patients at 12.5mg or 15mg will decrease the dose to 10mg.
If de-escalation of the tirzepatide dose is necessary, the investigator will use the interactive 
web-response system (IWRS) to receive the appropriate tirzepatide dispensing information.  If 
de-escalation is needed between scheduled visits, the IWRS will have unscheduled visits (for 
example, Visit 13a) dedicated to provide dispensing information for patients whose dose has 
been de-escalated.  Those patients who have their dose de-escalated, will not be escalated again. 
The dose can be de-escalated only once.  After that, the patients will have to discontinue 
tirzepatide if intolerable GI AE persists and stay in the study.  
If intolerable persistent GI symptoms occur after Week 24, the investigator should take the above 
measures to keep the patient on study treatment.  However, after the escalation period (Week 24), 
dose decreases will not be allowed.
7.7.2. Severe, Persistent Hyperglycemia
Add-on glycemic rescue therapy will be allowed for patients who meet prespecified criteria for 
severe, persistent hyperglycemia described below and no intercurrent cause of the hyperglycemia 
could be identified (investigators should first confirm that the patient is fully compliant with the 
assigned therapeutic regimen and that he or she does not have an acute condition causing severe 
hyperglycemia): 
(a) average daily BG from the once-weekly 4-point SMBG profile >270 mg/dL (>15.0 
mmol/L) over at least a consecutive 2-week period any time during the first 8 weeks 
post randomization; 
OR
(b) average daily BG from the once-weekly 4-point SMBG profile >240 mg/dL (>13.3 
mmol/L) over a consecutive 2-week period at any time 9 to 16 weeks post 
randomization; 
OR
(c) average daily BG from the once-weekly 4-point SMBG profile >200 mg/dL (>11.1 
mmol/L) over a consecutive 2-week period at any time beyond the first 16 weeks post 
randomization;
OR

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(d) HbA1c ≥8.5% at 24 weeks, with inadequate response to the existing regimen defined 
as improvement in HbA1c over the last 3 months (week 12 to week 24) that is <0.3%.
Rescue therapy option:
For the insulin glargine group, patients can further titrate the insulin glargine.  The criteria 
described above for severe, persistent hyperglycemia will only be applicable after Week 16.  The 
first choice before initiating any rescue therapy for those patients during the initial 16 weeks will 
be to follow the TTT algorithm to increase the dose of insulin glargine. 
Rescue treatment with GLP-1 receptor agonists, DPP-4 inhibitors, fixed-dose combination with 
component of GLP-1 receptor agonists or DPP-4 inhibitors, or pramlintide will not be allowed.  
Additionally, use of other basal insulins will not be allowed in the insulin glargine group.  Use of 
glargine will not be allowed in the tirzepatide groups.
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion 
Tirzepatide will not be made available after conclusion of the study to patients.
7.8.2. Special Treatment Considerations 
Investigators will be trained on how to apply decision criteria for the timing and method of 
intervention in patients who do not reach glycemic targets during the treatment period.  An 
additional therapeutic intervention should be considered for patients with persistent 
hyperglycemia as described in Section 9.2.2.2.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:
Patient Decision
o
The patient requests to discontinue investigational product.
Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via the electronic case report form 
(eCRF).
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:

ALT or aspartate aminotransferase (AST) >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio (INR) >1.5 

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, patients will be discontinued from the investigational product in the following 
circumstances:

If a patient is inadvertently enrolled and it is determined that continued treatment with 
study drug would not be medically appropriate, see Section 8.1.3

Acute or chronic pancreatitis 

If a patient is diagnosed with MTC after randomization, or has a postrandomization
calcitonin value ≥35 ng/mL that has increased at least 50% over baseline

If a patient is diagnosed with an active or untreated malignancy (other than basal or 
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization

Any significant study drug-related hypersensitivity reaction

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
Any other TEAE, SAE, or clinically significant laboratory value for which the 
investigator believes that permanent study drug discontinuation is the appropriate 
measure to be taken

If female patient becomes pregnant

If a patient is diagnosed with T1DM
Patients who stop the study drug permanently will receive another glucose-lowering intervention
(Section 7.4.2) and will continue participating in the trial according to the protocol to collect all
planned efficacy and safety measurements.
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 Schedule of Activities, Section 9.2
Adverse Event, and Section 9.4 Safety of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
In certain situations after randomization, the investigator may need to temporarily interrupt study 
drug.  Every effort should be made by the investigator to maintain patients on study drug and to 
restart study drug after any temporary interruption, as soon as it is safe to do so.  

If the number of doses missed is equal or less than 2, the treatment can be restarted at the 
same dose, if the drug was well tolerated prior to discontinuation.

If the number of missed doses is equal or greater than 3, then the treatment should be 
restarted at 5 mg irrespective of the dose the patient was receiving before the interruption 
and subsequently escalated as required by protocol.
If study drug interruption is due to an AE, the event is to be documented and followed according 
to the procedures in Section 9.2 of this protocol.  If the study drug interruption is due to 
intolerable persistent GI AE (for example, nausea, vomiting, or diarrhea), the patients should be 
treated as suggested in Section 7.7.1.  Investigators should inform the sponsor that study drug has 
been temporarily interrupted.  
The data related to temporary interruption of study treatment will be documented in source 
documents and entered on the eCRF.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor CRP agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. Safety follow up is as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.

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8.2.
Discontinuation from the Study
In order to minimize the amount of missing data and to enable assessment of study objectives as 
planned in the study protocol, every attempt will be made to keep patients in the study 
irrespective of the following:

adherence to study drug

adherence to visit schedule

missing assessments

study drug discontinuation due to AE 

development of comorbidities

development of clinical outcomes
The circumstances listed above are not valid reasons for discontinuation from the study. 
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically 
or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

If a female patient becomes pregnant

If a patient is diagnosed with T1DM

patient decision requests to be withdrawn from the study
Patients who agree to provide information relevant to any trial endpoint at the end of the study 
are not considered to have discontinued from the study.
A patient who withdraws consent and clearly indicates that there will be no further contact of any 
kind with the site will be considered to have discontinued from the study.
Prior to early study discontinuation, the patient will discontinue study drug and will have end-of-
study procedures (ET visit) performed as shown in the Schedule of Activities (Section 2).  
During the ET visit, the patient will be prescribed an appropriate glucose-lowering regimen and 
glucose self-monitoring plan.  Visit 801 (safety follow-up visit) should be performed 
approximately 4 weeks after the ET visit as the final study visit.
Patients discontinuing from the study prematurely for any reason should complete adverse event 
and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), 
and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient 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.  Every attempt will be made to minimize the 

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number of patients considered lost to follow-up at the end of the study.  Patients will be informed 
about the importance of completing the study and providing updated contact information to the 
study site when necessary.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments and Procedures
The primary efficacy measurement in this study is mean change in HbA1c from baseline to 
40 weeks, as determined by the central laboratory.  Blood samples for HbA1c measurements will 
be collected at specific clinic visits as summarized in the Study Schedule, Section 2.
9.1.2. Secondary Efficacy Assessments and Procedures
The following secondary efficacy measures will be assessed at 40 weeks based on data collected 
at the times shown in the Study Schedule.

Change in HbA1c from baseline

Change in weight from baseline

Proportion of patients achieving a target HbA1c <7% (53 mmol/mol)

Change in fasting serum glucose from baseline measured in the central laboratory

Proportion of patients achieving an HbA1c target values of ≤6.5% (48 mmol/mol) and 
<5.7% (39 mmol/mol)

Change in 7-point self-monitored blood glucose (SMBG) profiles 

Proportion of patients who achieved weight loss ≥5%, ≥10%, and ≥15% from baseline

Patient-reported outcomes:
o
Diabetes Treatment Satisfaction Questionnaire status and Diabetes Treatment 
Satisfaction Questionnaire change
9.1.3. Exploratory Efficacy Assessments and Procedures
The following efficacy measures will be calculated based on data collected at the times shown in 
the Study Schedule.

Change in lipids (total cholesterol, HDL, VLDL, and TG)

Change in waist circumference

Change from baseline in mean BMI

European Quality of Life dimensions (EQ-5D-5L) scores

Impact of Weight on Self Perception

Ability to Perform Physical Activities of Daily Living

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9.1.4. Appropriateness of Assessments
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2DM.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product
(tirzepatide) before completing the study.  The patient should be followed until the event 
resolves, stabilizes with appropriate diagnostic evaluation, or is reasonably explained. For events 
that are not anticipated to resolve or stabilize, the patient should be followed until the treating 
physician (in consultation with the sponsor) determines that appropriate follow-up has been 
completed.  The frequency of follow-up evaluations of the AE is left to the discretion of the 
investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via the 
electronic case report form (eCRF) the occurrence of each patient’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study.  
In addition, site personnel will record any change in the condition(s) and any new conditions as 
AEs. For each AE, the onset and duration, the seriousness and severity, and the actions taken 
with respect to study treatment will be recorded. Investigators should record their assessment of 
the potential relatedness of each AE to protocol procedure, investigational product, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility of 
being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.

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If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Patients with a serious hepatic adverse event should have additional data collected 
using the eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.

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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia
Patients will collect information on episodes of hypoglycemia after signing ICF until the last 
study visit (Follow up Visit or Early Termination Visit).  For that purpose, patients will be 
trained 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 
Schedule of Activities.  Site personnel will enter this information into the eCRF hypoglycemia 
page at each visit. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia:  (the PG values in this section refer to 
values determined by a laboratory or International Federation of Clinical Chemistry and 
Laboratory Medicine plasma-equivalent glucose meters and strips) (ADA 2017):
Glucose Alert Value (Level 1):
Documented symptomatic hypoglycemia is defined as any time a patient feels that
he or she is experiencing symptoms and/or signs associated with hypoglycemia, and has
a PG level of ≤70 mg/dL (≤3.9 mmol/L).
Documented asymptomatic hypoglycemia is defined as any event not accompanied
by typical symptoms of hypoglycemia, but with a measured PG ≤70 mg/dL
(≤3.9 mmol/L).
Documented unspecified hypoglycemia is defined as any event with no information
about symptoms of hypoglycemia available, but with a measured PG ≤70 mg/dL
(≤3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):
Documented symptomatic hypoglycemia is defined as any time a patient feels that
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has
a PG level of <54 mg/dL (<3.0 mmol/L).
Documented asymptomatic hypoglycemia is defined as any event not accompanied
by typical symptoms of hypoglycemia, but with a measured PG <54 mg/dL
(<3.0 mmol/L).
Documented unspecified hypoglycemia is defined as any event with no information
about symptoms of hypoglycemia available, but with a measured PG <54 mg/dL

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(<3.0 mmol/L).
Severe hypoglycemia (Level 3):
Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, glucagon, 
or other resuscitative actions.  These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. Blood glucose measurements may not be 
available during such an event, but neurological recovery attributable to the restoration of 
BG to normal is considered sufficient evidence that the event was induced by a low BG 
concentration.
Other hypoglycemia categories:
Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between
bedtime and waking.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the AE 
eCRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive BG values ≤70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event 
(Weinberg et al. 2010; Danne et al. 2013).  
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated.  The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established.  The patient should receive additional 
education, if deemed appropriate.  The dose of concomitant antihyperglycemic medications may 
need to be reduced as outlined in section 7.4.2.
9.2.2.2.
Severe, Persistent Hyperglycemia
Severe, persistent hyperglycemia will be collected during the trial to assess the risk of extreme 
imbalance in glycemic control.
Investigators will be trained on the application of criteria for deciding when and how to intervene 
with patients who do not reach glycemic targets.  An additional therapeutic intervention should 
be considered in patients who develop severe, persistent hyperglycemia after randomization at 
the discretion of investigator in accordance with American Diabetes Association/European 
Association for the Study of Diabetes guidance.  Rescue medication will be prescribed as add-on 
to randomized treatment, and patients will continue to follow the protocol-specified visit 
schedule.
Add-on glycemic rescue therapy will be allowed for patients who meet prespecified criteria for 
severe, persistent hyperglycemia in section 7.7.2 and no intercurrent cause of the hyperglycemia 
could be identified (investigators should first confirm that the patient is fully compliant with the 

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assigned therapeutic regimen and that he or she does not have an acute condition causing severe 
hyperglycemia).
9.2.2.3.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide including this trial.  
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases [Banks 
and Freeman 2006; Koizumi et al. 2006]; the pain is often associated with 
nausea and vomiting);

serum amylase (total and/or pancreatic) and/or lipase ≥3×ULN

characteristic findings of acute pancreatitis on computed tomography (CT) 
scan or magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed).  
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed.  If laboratory values and/or abdominal imaging support the 
diagnosis of acute pancreatitis, the patient must discontinue therapy with investigational 
product(s) but will continue in the study on another glucose-lowering regimen.  The most 
appropriate diabetes therapeutic regimen will be decided by the investigator, based on the 
patient’s clinical status.  A review of the patient’s concomitant medications should be conducted 
to assess any potential causal relationship with pancreatitis.
Each case of AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE.  For a potential case that 
does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to study drug(s).
Each patient will have measurements of p-amylase and lipase (assessed at the central laboratory) 
as shown on the Schedule of Activities (Section 2) to assess the effects of the investigational 
doses of tirzepatide on pancreatic enzyme levels. Serial measures of pancreatic enzymes have 
limited clinical value for predicting episodes of acute pancreatitis in asymptomatic patients 
(Nauck et al. 2017; Steinberg et al. 2017a; Steinberg et al. 2017b). Thus, further diagnostic 
follow-up of cases of asymptomatic pancreatic hyperenzymemia (lipase and/or pancreatic 
amylase ≥3X ULN) is not mandated but may be performed based on the investigator’s clinical 
judgment and assessment of the patient’s overall clinical condition. Only cases of pancreatic 
hyperenzymemia that undergo additional diagnostic follow-up and/or are accompanied by 
symptoms suggestive of pancreatitis will be submitted for adjudication.

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All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent clinical 
endpoint committee (CEC). In addition, AEs of severe or serious abdominal pain of unknown 
etiology will also be submitted to the adjudication committee to assess for possible pancreatitis 
or other pancreatic disease. Relevant data from patients with acute or chronic pancreatitis and 
those with severe or serious abdominal pain will be entered into a specifically designed eCRF 
page by study site or Lilly staff. The adjudication committee representative will enter the results 
of adjudication in a corresponding eCRF page.
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the 
study.  The assessment of thyroid safety during the trial will include reporting of any case of 
thyroid malignancy including MTC and papillary carcinoma and measurements of calcitonin. 
This data will be captured in specific eCRFs. The purpose of calcitonin measurements is to 
assess the potential of tirzepatide to affect thyroid C-cell function, which may indicate 
development of C-cell hyperplasia and neoplasms. Tirzepatide should be discontinued (after first 
confirming the value) if post randomization calcitonin value is ≥35 ng/L (pg/mL) and has 
increased at least 50% over baseline.  A consultation with a thyroid specialist (if not available, an 
endocrinologist) should be obtained.
If the increased calcitonin value (≥35 pg/mL and increases by ≥50% compared to baseline) is 
observed in a patient who has administered a medication that is known to increase serum 
calcitonin, this medication should be stopped and calcitonin levels should be measured after an 
appropriate wash out period.  If the confirmed calcitonin value is <35 pg/mL, tirzepatide should 
be restarted when it is safe to do so.
9.2.2.5.
Major Adverse Cardiovascular Events
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise.  The nonfatal CV AEs to be adjudicated include:  

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention)

cerebrovascular events, including cerebrovascular accident (stroke) and transient
ischemic attack
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment emergent cardiac conduction disorders will be further evaluated.  Patients who 
develop any event from this group of disorders should undergo an ECG which should be 
submitted to the central reading center. Additional diagnostic tests to determine exact diagnosis 
should be performed, as needed. The specific diagnosis will be recorded as an AE. Events that 
meet criteria for serious conditions as described in Section 9.2.1 must be reported as SAEs.

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9.2.2.7.
Hypersensitivity Events
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Additional data, such as type of reaction and treatment 
received, will be collected on any AEs or SAEs that the investigator deems related to study 
drug(s) via a CRF created for this purpose.  Additional samples should also be collected as 
outlined in Section 9.4.4. Study drug(s) should be temporarily interrupted in any individual
suspected of having a severe or serious allergic reaction to study drug(s).  Study drug(s) may be 
restarted when/if it is safe to do so, in the opinion of the investigator.  If study drug(s) is 
permanently discontinued, the patient will receive another glucose-lowering treatment, judged by 
the investigator to be appropriate based on the patient’s clinical status, and will continue in the 
trial to collect all planed efficacy and safety measurements.
9.2.2.7.1. Injection Site Reactions
Injection site reactions will be collected on the eCRF separate from the hypersensitivity reaction 
eCRF.  At the time of AE occurrence in the tirzepatide group, samples may be collected if 
possible for measurement of tirzepatide ADA and tirzepatide concentration.
9.2.2.7.2. Anti-Drug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 9.4.4.
9.2.2.8.
Diabetic Retinopathy Complications
Dilated retinal fundoscopic exam will be diagnosed by a qualified eye care professional 
(ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 to exclude patients 
with proliferative retinopathy, or maculopathy, or nonproliferative retinopathy that requires acute 
treatment .  The results from this exam will be recorded on a specific retinopathy eCRF as a 
baseline measure of retinopathy.
A follow up dilated fundoscopic exam should be performed when clinically indicated (by any 
adverse event suspected of worsening retinopathy and the findings should be recorded on the 
retinopathy eCRF.
9.2.2.9.
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 
9.4.5.1 and Appendix 4.
9.2.2.10. Severe Gastrointestinal Adverse Events
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea.  Information about 
severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE form.  
For detailed information concerning the management of GI AEs, please refer to Section 7.7.1.
9.2.2.11. Acute Renal Events
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 failure.  GI AEs have been 
reported with tirzepatide, including nausea, diarrhea, and vomiting.  This is consistent with other 
GLP-1 receptor agonists (Aroda and Ratner 2011).  The events may lead to dehydration, which 

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could cause a deterioration in renal function, including acute renal failure.  Patients should be 
advised to notify investigators in case of severe nausea, frequent vomiting, or symptoms of 
dehydration.
9.2.2.12. Metabolic Acidosis, including Diabetic Ketoacidosis
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been 
reported rarely in patients with T2DM.  Patients who present with signs and symptoms consistent 
with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood 
glucose levels, as ketoacidosis may be present even if blood glucose levels are less than 250 
mg/dL.  If ketoacidosis is suspected, patient should be evaluated, and prompt treatment should be 
instituted.  Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
Lactic acidosis has been reported rarely in patients with T2DM associated with use of metformin, 
excessive alcohol intake and decrease renal function.  Routine bicarbonate assessment will be 
performed during the course of the study.  If lactic acidosis is suspected, metformin should be 
temporarily discontinued until the resolution of the event.
9.2.2.13. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as an AE.
9.2.2.14. Major Depressive Disorder/Suicidal Ideation
The prevalence of depressive symptoms and disorders is increased in patients  with T1DM or T2DM 
(ADA Guideline, 2017).  Any adverse event of major depressive disorder or suicidal ideation should 
be reported.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Study drug overdose (more than the specified number of injections) will be reported as an AE.  
In the event of overdose, refer to the IB for tirzepatide and/or Product Label for insulin glargine
(glargine USPI, 2015 [WWW]).
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, electrocardiograms (ECGs) should be collected according to the Schedule of 
Activities (Section 2).  
Electrocardiograms will initially be interpreted by a qualified physician (the investigator or 
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 

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while the patient is still present, for immediate subject management, should any clinically 
relevant findings be identified.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the patient receives the first dose of the investigational treatment 
should be reported to Lilly or its designee as an AE via the eCRF.
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database. At a future time, the stored ECG data may be overread by a 
cardiologist at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements. The machine-read ECG intervals and heart rate may be used 
for data analysis and report-writing purposes, unless a cardiologist overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would 
be used).
9.4.2. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2).
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.4. Immunogenicity Assessments
Where local regulations and ERBs allow, blood samples for immunogenicity testing will be 
collected to determine antibody production against tirzepatide as specified in the Schedule of 
Activities (Section 2).
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against the tirzepatide.  To interpret the results 
of immunogenicity, a PK sample will be collected at the same time points as the immunogenicity 
sample.  All samples for immunogenicity should be taken predose when applicable and possible. 
In the event of drug hypersensitivity reactions (immediate or non-immediate), additional samples 
will be collected as close to the onset of the event as possible, at the resolution of the event, and 
30 days following the event.  Instructions for the collection and handling of blood samples will 
be provided by the sponsor.  Sample collected at Visit 801 will assess immunogenicity at 
washout of tirzepatide (5 half-lives post end of treatment).

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Treatment-emergent antidrug antibodies (ADAs) are defined in Section 10.3.6.  
Samples with tirzepatide ADA detected will be titered and evaluated for their ability to neutralize 
the activity of assigned treatment (tirzepatide-neutralizing antibodies). Samples with tirzepatide
ADA detected will also be tested for cross-reactive binding to native GIP and GLP-1, and, if 
such is detected, then for neutralizing antibodies against native GIP and GLP-1, respectively.
9.4.5. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.5.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels. 
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be a SAE
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Biomarkers
Not applicable.

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9.9.
Health Economics
The following questionnaires will be completed by the patients at specific clinic visits according 
to the Schedule of Events (Section 2). At these visits, the questionnaires should be completed 
before the patient has discussed their medical condition or progress in the study with the 
investigator and/or site staff and before any other study procedures if the patient is not adversely 
affected by their fasting condition.
9.9.1. Diabetes Treatment Satisfaction Questionnaire (DTSQ)
The status (s) and change (c) versions of the Diabetes Treatment Satisfaction Questionnaire 
(DTSQ) will be used during the study to assess the patients’ satisfaction with their diabetes 
treatment and the perceived frequency of hyperglycemia and hypoglycemia.  The questionnaire 
contains 8 items (Bradley 1994).  Each item is rated on a 7-point Likert scale.  Six items (1 and 4 
through 8) are summed to produce a measure of treatment satisfaction ranging from 0 “very 
dissatisfied” to 6 “very satisfied.”  The remaining 2 items (2 and 3) are treated individually.  Item 
2 measures the perceived frequency of hyperglycemia on a scale ranging from 0 “none of the 
time” to 6 “most of the time,” and Item 3 measures the perceived frequency of hypoglycemia on 
the same scale.  The change version has the same 8 items as the status version with a small 
alteration of the wording of Item 7. The DTSQc response options differ from those of the 
DTSQs to produce measures of relative change rather than absolute satisfaction.
9.9.2. Impact of Weight on Self-Perception Questionnaire 
The Impact of Weight on Self-Perception (IW-SP) questionnaire contains 3 items that assess how 
often the patients’ body weight affects how happy they are with their appearance and how often 
they feel self-conscious when out in public (Hayes and DeLozier 2015).  Each item is rated on a 
5-point scale ranging from “always” to “never.”  Total scores for the IW-SP are derived by 
summing the item scores and dividing by the number of items.  The score can also be
transformed to a range from 0 to 100.  Higher IW-SP scores correspond to better self-perception 
(Hayes and DeLozier 2015).
9.9.3. Ability to Perform Physical Activities of Daily Living 
The Ability to Perform Physical Activities of Daily Living (APPADL) questionnaire contains 7 
items that assess how difficult it is for patients to engage in certain activities considered to be 
integral to normal daily life, such as walking, standing, and climbing stairs (Hayes et al. 2011; 
Hayes et al. 2012).  Items are scored on a 5-point numeric rating scale, where 5 = “not at all 
difficult” and 1 = “unable to do.”  A raw overall score is calculated by simply summing the 
scores of the 7 items, and a transformed overall score is obtained by linearly transforming the 
raw overall score to a 0 to 100 scale.  A higher raw overall score and a higher transformed 
overall score are indicative of better ability to perform activities of daily living.  
9.9.4. European Quality of Life
Generic HR-QoL will be assessed using the EQ-5D-5L (EQ-5D; EuroQoL Group 2015).  The 
EQ-5D-5L is a standardized 5-item instrument for use as a measure of health outcome.  It 

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provides a simple descriptive profile and a single index value for health status that can be used in 
the clinical and economic evaluation of health care as well as population health surveys.  The 
EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3251 possible health states.  In addition to the 
health profile, a single health state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension. This index value ranges between less than 0 
(where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1 
(perfect health).  In addition, the EQ Visual Analog Scale records the respondent’s self-rated 
health status on a vertical graduated (0 to 100) visual analog scale.  In conjunction with the 
health state data, it provides a composite picture of the respondent’s health status.  
The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015).

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10. Statistical Considerations
10.1. Sample Size Determination
Although the primary objective of the trial is to demonstrate that once-weekly tirzepatide 10 mg 
and/or 15mg doses are  non-inferior to titrated insulin glargine relative to mean change in HbA1c 
from baseline, the trial is powered to assess superiority of tirzepatide 10 mg and 15mg, each 
tested in parallel against titrated insulin glargine at two-sided significance level of 0.025, relative 
to the primary endpoint (mean change in HbA1c from baseline at 40 weeks), under the following 
assumptions: use of 2-sample t-test utilizing HbA1c data collected before initiation of any rescue 
medication or premature treatment discontinuation with no more than 25% subjects initiating any 
rescue medication or premature treatment discontinuation in each treatment group; 0.45% greater 
mean reduction in HbA1c from baseline for 10mg and 15mg tirzepatide compared to insulin 
glargine; 1:1:1:1 randomization; and a common standard deviation (SD) of 1.2%. On the basis of 
these assumptions, approximately 956 patients (80% from China, 20% from other 
countries/regions) with type 2 diabetes will be enrolled into this study to ensure at least 90% 
power to demonstrate that tirzepatide 10mg and/or 15mg are superior to insulin glargine relative 
to the primary endpoint. China patients would provide 82% power to demonstrate the superiority.

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10.2. Populations for Analyses
For purposes of analysis, the following populations are defined in Table GPHO.6:
Table GPHO.6.
Description of Analysis Sets
Analysis Set
Description
Screened patients
All participants who sign informed consent
Randomized patients
All patients who are randomly assigned a treatment group
modified intent-to-treat (mITT) 
set
All randomly assigned participants who are exposed to at least 1 dose of study 
drug.  In the event of a treatment error, participants will be analyzed according 
to the treatment they were randomized.
Efficacy analysis set (EAS)
Data obtained during Study Period II from the mITT set, excluding data after 
initiating rescue antihyperglycemic medication or stopping study drug.
Full analysis set (FAS)
Data obtained during Study Period II from the mITT set, regardless of adherence 
to study drug or initiation of rescue antihyperglycemic medication
Safety analysis set (SAS)
Data obtained during Study Periods II or III from the mITT set, regardless of 
adherence to study drug or initiation of rescue antihyperglycemic medication.
Per Protocol
Patients included in the randomized population who have completed Week 40 of 
study treatment without permanent discontinuation of IP and without significant 
protocol deviations through Week 40 that would significantly impact the 
primary objective.  
Treatment group will be defined on the basis of the treatment the patients 
actually receive.
10.3. Statistical Analyses
10.3.1. General Statistical 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 (SAP) or the clinical study report (CSR).  Additional exploratory 
analyses of the data may be conducted as deemed appropriate.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval (CI) will be calculated at 95%, 2-sided.  In statistical summaries 
and analyses, patients will be analyzed as randomized.
The primary analysis is for the treatment period through Week 40.  The primary endpoint is the 
HbA1c measurement obtained at Week 40 (Visit 19).
Efficacy and safety will be assessed using the modified intent-to-treat (mITT) population, which 
consists of all randomly assigned participants who are exposed to at least one dose of study drug. 
Efficacy analyses, including the analyses for the primary and multiplicity adjusted objectives,
will be performed on data obtained before the initiation of any rescue therapy and before 
premature treatment discontinuation. When change from baseline is included as a response 
variable of analysis models, the patient will be included in the analysis only if he/she has a 

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baseline and a postbaseline measurement.  Selected efficacy analyses will also be conducted 
using the Per-Protocol (PP).  
Safety assessment will be based on all available data, irrespective of whether they were obtained 
while the participants had discontinued the study drug or whether the participant had been given 
rescue medication. Selected safety anlaysis (e.g. hypoglycemia, GI events) will be conducted 
after excluding data on rescue therapy. 
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model to make comparisons among treatment groups 
relative to continuous measurements assessed over time will be a mixed model for repeated 
measures (MMRM), with terms: treatment, visit, and treatment-by-visit interaction, country, 
sulfonylurea use (Yes or No), and baseline measurement as a covariate.  An unstructured 
covariance structure will model the relationship of within-patient errors.
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time, and cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments.
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages.  Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes.  Logisitic regression may be used to examine the 
treatment difference in binary efficacy outcomes.  Summary statistics for discrete count measures 
will include sample size, mean, SD, median, minimum and maximum.  The negative binomial 
regression model will be used for the treatment comparison of discrete count measures.
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
Frequency counts and percentages of all patients randomized, and receiving at least 1 dose of 
study drug will be presented by treatment groups.  A listing of randomized patients not receiving 
study drug will be provided.  Of the patients in the mITT set, frequency, counts and percentages 
of patients completing the study, prematurely discontinuing the study, including the reason for 
premature discontinuation, will be presented by treatment groups.  A Kaplan-Meier analysis of 
time from randomization to premature discontinuation from study by treatment group will be 
provided.
10.3.2.2. Patient Characteristics
Demographics, medical history, and concomitant illness will be summarized by treatment group 
using the mITT set.
10.3.2.3. Concomitant Therapy
Concomitant medications, including previous therapy for diabetes, will be summarized by 
anatomical therapeutic chemical classification and treatment groups using the mITT set.  In 

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particular, the incidence of initiation of rescue therapy for severe, persistent hyperglycemia will 
be analyzed as an exploratory safety endpoint.  Dose modifications of oral antihyperglycemic 
therapy, antidiarrheal and aniemetic Rx will also be compared between treatment groups.
10.3.2.4. Treatment Compliance
Of the patients in the mITT set, frequency counts and percentages of patients prematurely 
discontinuing study drug, including reason for premature discontinuation, will be presented by 
treatment group.  A Kaplan-Meier analysis of time from randomization to premature study drug 
discontinuation by treatment group will be provided.
Treatment compliance, overall, is defined as taking at least 75% of the total required injections of 
study drugs. Frequency counts and percentages of patients compliant to study drug will be 
summarized by treatment groups and visits using the mITT set.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to establish noninferiority of 10 mg tirzepatide and/or 15 
mg tirzepatide to insulin glargine relative to mean change in HbA1c from baseline to the 40-
week visit.
The primary efficacy analysis will be based on the contrast from the MMRM analysisusing EAS. 
The response variable of MMRM will be change in HbA1c from baseline values obtained at each 
scheduled postbaseline visit.  The independent variables of the MMRM model are treatment 
group (5 mg tirzepatide, 10 mg tirzepatide, 15 mg tirzepatide, and insulin glargine), visit, and 
treatment-by-visit interaction, country, sulfonylurea use (Yes or No), and baseline HbA1c as a 
covariate.  An unstructured covariance structure will model relationship of within-patient errors.  
If the analysis fails to converge, the following variance-covariance matrices will be used (in 
order) until convergence is achieved: heterogeneous compound symmetry, compound symmetry, 
and first-order autoregressive.  The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.  With the aid of the MMRM analysis, 2-sided 97.5% CIs for 
the difference in mean change in HbA1c from baseline to the 40-week visit between 10 mg 
tirzepatide and insulin glargine well as between 15 mg tirzepatide and insulin glargine will be 
constructed.  If the upper limit of the CI is below 0.4%, the tirzepatide dose will be declared 
noninferior to insulin glargine.
Additional details, including analysis methods for key secondary endpoints and a strategy for 
controlling the overall family-wise type 1 error rate at an alpha of 0.05 for primary and key 
secondary endpoint evaluation will be provided in the SAP.
Additional Analysis for the Primary Endpoint
The primary analysis model, MMRM, will be repeated using the PP populations to check the 
sensitivity of the analysis.  If the conclusion differs from that of all randomized patients, the data 
and analyses will be further investigated.  Details for the analysis conducted on PP population 
will be included in SAP.

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A secondary analysis model will be an ANCOVA for HbA1c change from baseline to Week 40 
(Visit 19), with treatment group, country, sulfonylurea use (Yes or No) as fixed effects and 
baseline HbA1c as a covariate.  The ANCOVA analysis will be conducted using the Full 
Analysis Set (FAS), which consists of all available changes from baseline in HbA1c data at week 
40, irrespective of whether they were obtained while the participants had discontinued the 
investigational product or whether the participant had been given rescue medication.  
Additionally, data for subjects with missing values will be imputed, based on observed data in
the same treatment group from subjects who had their efficacy measure at Week 40 assessed 
after early discontinuation of investigational product and/or initiation of rescue medication 
(retrieved dropouts). Analysis will be conducted with multiple imputations and statistical 
inference over multiple imputations will be guided by the method proposed by Rubin (Rubin 
1987).
10.3.3.2. Secondary Analyses
The secondary study objectives subject to type 1 error rate control are as follows:

noninferiority of the 5 mg tirzepatide dose to insulin glargine relative to mean change in 
HbA1c from baseline to the 40-week visit

superiority of each tirzepatide dose to insulin glargine relative to mean change in body 
weight from baseline to the 40-week visit

superiority of each tirzepatide dose to insulin glargine relative to mean change in HbA1c 
from baseline to the 40-week visit

superiority of each tirzepatide dose to insulin glargine relative to proportion of patients 
achieving the target value of HbA1c < 7% at the 40-week visit
The type I error-contolled strategy for the primary and secondary endpoints will be described in 
the SAP.  
Analysis of change from baseline in body weight at the 40-week visit will be conducted in a 
manner similar to the primary efficacy analyses with change in weight from baseline as the 
response variable and baseline body weight as a covariate.
Comparisons among treatments relative to the proportion of patients achieving the HbA1c target 
value of < 7.0% (53 mmol/mol) at the 40-week visit will be conducted using a logistic regression 
analysis with terms of treatment, country, sulfonylurea use (Yes or No), and baseline HbA1c as a 
covariate. 
10.3.3.3. Tertiary/Exploratory Analyses
All exploratory efficacy analyses will be conducted using the EAS.  Details will be provided in 
the SAP.
10.3.4. Safety Analyses
Unless specified otherwise, safety assessments will compare safety of tirzepatide doses with 
insulin glargine irrespective of adherence to study drug or initiation of rescue therapy. Thus, the 
safety analysis will be conducted using the Safety Analysis Set (SAS). Selected safety analyses
will be conducted after excluding data on rescue therapy. 

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Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Selected 
notable AEs of interest may be reported using high-level terms or Standardized MedDRA 
Queries.  Summary statistics will be provided for incidence of TEAEs, serious adverse events 
(SAEs), study discontinuation due to AEs, study drug discontinuation due to AEs, deaths, and 
other CV endpoints.  Counts and proportions of subjects experiencing AEs will be reported for 
each treatment group, and Fisher’s exact test will be used to compare the treatment groups.
10.3.4.1. Hypoglycemic Events
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia in each 
category (either total or nocturnal) will be compared between tirzepatide doses and insulin 
glargine using negative binomial regression analysis.  Selected safety analyses may be conducted
excluding data after introducing another anti-hyperglycemic therapy (for example,rescue 
therapy).
10.3.4.2. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment group.
10.3.4.3. Adjudicated Cardiovascular Events
Listings of deaths, myocardial infarctions, strokes, and hospitalization for unstable angina 
confirmed by an independent CEC will be provided.  The dates of randomization, event, first 
dose and last dose of study drug, and time from randomization to the event will be listed.
10.3.4.4. Central Laboratory Measures, Vital Signs, and Electrocardiograms
Values and change from baseline to postbaseline values of central laboratory measures, vital 
signs, and selected ECG parameters will be summarized at each scheduled visit.  The analysis 
model to make comparisons among treatment groups relative to continuous change from baseline 
values assessed over time will be an MMRM similar to the primary efficacy analysis and with 
baseline measurement as a covariate.  An unstructured covariance structure will model 
relationship of within-patient errors.
The percentages of patients with treatment-emergent abnormal, high, or low laboratory measures 
at any time will be summarized and compared between treatment groups by using Fisher’s exact 
test.  A treatment-emergent abnormal value is defined as a change from normal value at baseline
to a value greater than the high limit at any time during Periods II and III.  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 Periods II and III.  The high and low limits will 
be provided in the SAP.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.

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10.3.6. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting ADA, with TE ADA, and with 
neutralizing TE ADA to tirzepatide will be tabulated by tirzepatide dose. Treatment-emergent 
ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimum required 
dilution if no ADAs were detected at baseline (treatment-induced ADA) or those with a 4-fold (2 
dilutions) increase in titer compared to baseline if ADAs were detected at baseline (treatment-
boosted ADA).  For the TE ADA patients the distribution of maximum titers will be described.  
The frequency of neutralizing antibodies to tirzepatide and/or cross-reactive and neutralizing 
antibodies to endogenous couterparts will be tabulated in TE ADA patients.
The relationship between the presence of antibodies and tirzepatide safety and efficacy may be 
assessed.
10.3.7. Other Analyses
10.3.7.1. Health Economics
Analyses of actual and change from baseline in patient-reported outcome (PRO) scores will be 
conducted using linear models with baseline PRO scores, treatment and other factors that may be 
considered relevant.  These variables will be specified in the SAP.
10.3.7.2. Subgroup Analyses
Subgroup analyses of mean change in HbA1c from baseline to Visit 19 will be provided by age, 
race, ethnicity, gender, duration of diabetes, baseline HbA1c (≤8.5%, >8.5%), and baseline 
sulfonylurea.  These variables will be specified in the SAP.
10.3.8. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.

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11.
References
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
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American Diabetes Association. Standards of Medical Care in Diabetes—2019. Diabetes Care. 
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Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
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Bradley C. The diabetes treatment satisfaction questionnaire: DTSQ. In: Bradley C, editor.
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Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
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EuroQoL Group. EQ-5D-5L User guide: basic information on how to use the EQ-5D-5L 
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5L_UserGuide_2015.pdf. Published April 2015. Accessed August 6, 2018.
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Self-Perceptions Questionnaire (IW-SP) in individuals with type 2 diabetes and obesity. 
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Hayes RP, Nelson DR, Meldahl ML, Curtis BH. Ability to perform daily physical activities in 
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Hayes RP, Schultz EM, Naegeli AN, Curtis BH. Test-retest, responsiveness, and minimal 
important change of the ability to perform physical activities of daily living questionnaire in 
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Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas 
A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a 
patient-centered approach: update to a position statement of the American Diabetes 
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Kawamori R, Eliaschewitz FG, Takayama H, Hayashida CY. Efficacy of insulin glargine and 
glimepiride in controlling blood glucose of ethnic Japanese patients with type 2 diabetes 
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Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN. JPN Guidelines for the management 

I 8 F-M C -G P H O ( a) Cli ni c al Pr ot o c ol
P a g e 7 3
L Y 3 2 9 8 1 7 6
of  ac ute pa ncreatitis: dia g n ostic criteria f or ac ute pa ncreatitis. J He p at o bili ary P a ncre at S ur g . 
2 0 0 6; 1 3( 1): 2 5 - 3 2.
Na uc k M. I ncreti n t hera pies: hi g hli g ht i n g c om m o n feat ures a n d differe nces i n t he m o des of 
actio n of  gl uca g o n-li ke pe pti de-1 a g o nists a n d di pe pti d yl pe pti dase -4 i n hi bit ors. Di a betes O bes 
Met a b.
2 0 1 6; 1 8( 3): 2 0 3 - 2 1 6.
R u bi n D B. M ult i ple i m p utati o n f or n o nres p o nse in s ur ve ys. Ne w Y or k: J o h n Wile y & S o ns 
I nc.; 1 9 8 7.
Stei n ber g W M, B use J B, G h or ba ni M L M, Ørste d D D , Na uc k M A; L E A D E R Steeri n g 
C o m mittee; L E A D E R Tri al I n vest i gat ors. A m ylase, li pase, a n d ac ute p a ncreat itis i n p e o ple 
w ith ty pe 2 d ia betes treate d w ith lira gl utide: res ults fr o m t he L E A D E R Ra n d omize d Trial.
Di a betes C are 2 0 1 7a; 4 0( 7): 9 6 6 - 9 7 2.
Stei n ber g W M, R ose nst oc k J, Wa d de n T A, D o ns mar k M, Je nse n C B, De Vries J H. I m pact of 
lira glut i de o n a m ylase, li pase, a n d ac ute pa ncreatitis i n partici pa nts wit h o ver weig ht/ o besit y 
a n d n or m o gl yce mia, pre dia betes, or t ype 2 di a betes: sec o n dar y a nal yses of p o ole d data fr o m 
t he S C A L E cli nical de vel o p me nt pr o gra m. Di a betes C are . 2 0 1 7 b ; 4 0( 7): 8 3 9- 8 4 8.
V ora J, C o he n N, E va ns M, H oc ke y  A, S p eig ht J, W hatel y -S mi t h C.  I nte nsif yi n g i ns uli n 
re gi me n after basal i ns uli n o pti mizati on i n a d ults wit h t ype 2 dia betes: a 2 4 -wee k, ra n d o mize d, 
o pe n -label tri al c o mpari n g i ns uli n glar gi ne pl us i ns uli n gl ulisi ne wit h bi p hasic i ns uli n as part 
( La n Sca pe). Di a betes, O besity a n d Met a b . 2 0 1 5; 1 7( 1 2): 1 13 3- 1 1 4 1 .
Wei n ber g M E, Bacc hetti P, R us ha k o ff RJ. Fre q ue ntl y re peate d gluc ose m eas ure me nts 
o veresti mate t he i nci de nce of i n patie nt h y p o gl yce mia a n d se vere h y per gl yce mia. J Di a betes 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CIOMS
Council for International Organizations of Medical Sciences
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.
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
ECG
electrocardiogram
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.

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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 authorized form.
ITT
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intent to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
patients 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.
IVRS/IWRS
interactive voice-response system/interactive web-response system
OAM
PK/PD
pharmacokinetics/pharmacodynamics
PP
per-protocol 
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SUSARs
suspected unexpected serious adverse reactions
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.

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Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, fasting
Urinalysis
Albumin
Creatinine
Pregnancy Test (females only)b
Follicle-stimilating hormone (FSH)c
Estradiolc
HbA1c
Endocrine
eGFR (calculated by CKD-EPI equation)d
Calcitonin
Immunogenicity
Tirzepatide anti-drug antibody
Pancreas (exocrine)
Serum pancreatic amylase
Serum lipase
Lipid Panel (fasting)
Total cholesterol
LDL
HDL
VLDL
Triglycerides
Abbreviations:  CKD-EPI = Chronic Kidney Disease-Epidemiology; eGFR = estimated glomerular filtration rate; 
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; 
VLDL = very low-density lipoprotein cholesterol.

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a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential; a
urine pregnancy test must be performed at Visit 3. Urine pregnancy tests may also be performed at the 
investigator’s discretion during the study. A local laboratory may be used for urine pregnancy tests.
c
Follicle-stimulating hormone test performed at Visit 1 for potential postmenopausal women age 45 years or 
above with an intact uterus, not on hormone therapy or oral contraceptives, and who have had spontaneous 
amenorrhea for more than 6 months and less than 12 months and estradiol levels consistent with a 
postmenopausal state (FSH≥40 mIU/mL and estradiol <30 pg/mL).
d
Estimated glomerular filtration rate will be calculated by the central laboratory at all visits and included in lab
result reports.

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Appendix 3.
Study Governance Considerations

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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

ensuring that informed consent is given by each patient or legal 
representative.  This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patients willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study

informed consent form

other relevant documents (for example, curricula vitae, advertisements)

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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, cardiology, nephrology, internal medicine, 
family medicine, general medicine, or any other specialty physician who has experience treating 
Type 2 Diabetes with clinical research experience will participate as investigators in this clinical 
trial.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
A qualified investigator will serve as the CSR coordinating investigator.  If this investigator is 
unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion of 
the eCRFs, and study procedures

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
make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory tests, 
medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture 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, clinical outcome assessment (COA) data (scales, self-reported diary data) will be 
collected by the subject/investigator site personnel, via a paper source document and will be 
transcribed by the investigator site personnel into the EDC system.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I8F-MC-GPHO is described in the Clinical Trial Agreement.

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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised ratio; 
RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
World Health Organization Classification 
of Diabetes and Diagnostic Criteria
Type 1 Diabetes:  Type 1 diabetes is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment is 
necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death.
Type 2 Diabetes:  Type 2 diabetes, although often asymptomatic, may also present with classical 
hyperglycemic symptoms (thirst, polyuria, weight loss), but despite hyperglycemia, ketone 
bodies are present in only low concentrations in the blood and urine.  Coma is rare in type 2 
diabetes but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis or 
ketoacidosis can also occur in fulminating illness (for example, severe infection or mesenteric 
artery thrombosis) due to an acute increase in insulin requirements, but spontaneous ketosis does 
not occur.  Some patients with type 2 diabetes later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998).

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Appendix 6.
Classification of Contraceptive Methods
Highly Effective Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle).  
Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception

Vasectomy – for men in clinical trials
Effective Methods of Contraception (must use combination of 2 methods):

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
Men, regardless of their fertility status, with non-pregnant women of child bearing potential 
partners must agree to either remain abstinent (if this is their preferred and usual lifestyle) or use 
condoms plus one additional highly effective (less than 1% failure rate) method of contraception 
(such as combination oral contraceptives, implanted contraceptives or intrauterine device) or 
effective method of contraception, (such as diaphragms with spermicide or cervical sponge) for 
the duration of the study and for at least 3 months after the last injection.
Men with pregnant partners should use condoms during intercourse for the duration of the study 
and until the end of estimated relevant potential exposure in women of childbearing potential. 
Men who are in exclusively same sex relationships (as their preferred and usual lifestyle) are not 
required to use contraception.

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Appendix 7.
Changes to Study Procedures due to 
Exceptional Circumstances
The changes to procedures described in this appendix are temporary measures intended to be 
used only during exceptional circumstances as directed by the sponsor in partnership with the 
investigator.
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.  
In such a situation, please follow the guidance below:
1) Patients should come for the primary endpoint visit (Visit 19) at the originally planned 
40-week (±7 days) schedule whenever possible and safe to do so, at the investigator's 
discretion.  However, in order to maximize the ability for onsite visits for Visit 19, 
minimize missing data, and preserve the intended conduct of the study, the visit window 
for Visit 19 may be brought forward no sooner than 14 days (Week 38) or extended up to 
28 days (Week 44).  The subsequent safety follow-up visit (Visit 801) should take place 
4 weeks ±7 days after Visit 19.

Study team approval for this V19 change will be given case by case for sites/patients 
being impacted by exceptional circumstances provided that patient is able to attend 
the office Visit 19 during the extended treatment period.
2) For patients requiring an extension for Visit 19 up to Week 44, additional IP will be 
provided to allow patients to remain on study drug uninterrupted during the extended 
treatment period, to ensure patient safety, and to maintain the overall integrity of the trial. 
3) The sites will need to document the details of how all patients and visits were affected by 
exceptional circumstances.
4) 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 on-site study visit 

asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 

arranging delivery of study supplies from site to participant. 
These requirements must be met before action is taken: 

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
Alternate delivery of study intervention should be performed in a manner that ensures 
product integrity. The existing protocol requirements for product accountability 
remain unchanged, including verification of participant’s receipt of study supplies. 

When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt).

Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies.
5) Additional consent from the patient per local regulations will be obtained for those 
patients who will be dispensed additional IP during the extended treatment period and
from whom provision of their personal information is required prior to alternate delivery 
of study intervention and other supplies.

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Appendix 8.
Protocol Amendment [I8F-MC-GPHO(a)] 
Summary [A Randomized, Phase 3, Open-label Trial 
Comparing the Effect of Tirzepatide Once Weekly Versus 
Titrated Insulin Glargine on Glycemic Control in Patients 
with Type 2 Diabetes on Metformin with or without a 
Sulfonylurea]
Overview
Protocol I8F-MC-GPHO titled “A Randomized, Phase 3, Open-label Trial Comparing the Effect 
of Tirzepatide Once Weekly Versus Titrated Insulin Glargine on Glycemic Control in Patients 
with Type 2 Diabetes on Metformin with or without a Sulfonylurea” has been amended.  The 
new protocol is indicated by amendment (a) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table.

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Amendment Summary for Protocol I8F-MC-GPHO Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Section 2 Schedule 
of Activities
Added language to direct readers to 
Appendix 7 in case of patients whose 
participation in this study is affected by 
restrictions due to the exceptional 
circumstances. 
This enables patients and investigators to 
adjust the Visit 19 window and to ensure 
patient safety and trial integrity.
Appendix 7. 
Changes to Study 
Procedures due to 
the exceptional 
circumstances
An appendix was added to provide 
guidance for Visit 19 on:
1)
Adjusting the Visit 19 window to 
be brought forward no sooner than 
14 days (Week 38) or extended up 
to 28 days (Week 44),
2)
Additional IP dispensed for Visit 
19, and
3)
Consent from the patients for the 
additional IP needed for Visit 19
4)
Documents regarding details to 
consider and actions regarding 
study supplies.
This enables patients and investigators to 
adjust the timing of Visit 19 (primary 
endpoint) and to ensure patient safety and trial
integrity.
Section 2 Schedule 
of Activities
Removed the activities of patients 
returning study drugs at Week 2 and Week 
6 to clarify that patients can skip Week 2 
and Week 6 for returning study drugs and 
injection supplies, and they can return them 
in Week 4 and Week 8.
The study drugs are being dispensed to the 
patients every 4 weeks, so the patients will 
have to return used drugs in Week 2 / Week 6, 
and return the remaining drugs in Week 4 / 
Week 8, which is inconvenient for clinical 
practice.
Section 5.1 Overall 
Design
Changed wordings to clarify that the date 
and time of the first dose of tirzepatide 
should be recorded on the electronic case 
report form (eCRF), while only the date
(without time) of the first dose of insulin 
glargine should be recorded on the eCRF.
This is a team decision.
Section 1 Synopsis
Section 2 Schedule 
of Activities
Section 4 Objectives 
and Endpoints
Changed heart rate (HR) to pulse rate (PR)
to clarify that pulse rate will be collected in 
vital sign measurements in this protocol.
This is a team decision.
List of Tables
Changed GPGH to GPHO.
Correct spelling errors in the original protocol.

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Section 10.2

L e o  D o c u m e n t  I D  =  b 8 8 5 b 0 3 4 - 7 4 a 8 - 4 4 8 d - b e 2 1 - 8 c d b 9 1 1 8 1 e 7 d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 3 - F e b - 2 0 2 1  1 0 : 3 7 : 2 9  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :
A p p r o v a l  D a t e  &  T i m e :  2 3 - F e b - 2 0 2 1  1 3 : 0 7 : 3 1  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D