A Phase 3, Long-Term Safety Study of Tirzepatide in Combination With Monotherapy of Oral Antihyperglycemic Medications in Patients With Type 2 Diabetes Mellitus (SURPASS J-combo)
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Protocol I8F-JE-GPGP (a) 
 
A Phase 3, Long-Term Safety Study of Tirzepatide in Combination with Monotherapy of Oral 
Antihyperglycemic Medications in Patients with Type 2 Diabetes Mellitus (SURPASS J-combo) 
 
NCT03861039 
 
Approval Date: 17-Jan-2019 

I 8 F-J E -G P G P( 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-J E -G P G P ( a)
A P h a s e 3, L o n g -T er m S af et y  St u d y of Tir z e p ati d e i n 
C o m bi n ati o n wit h M o n ot h er a p y  of Or al Anti h y p er gl y c e mi c 
M e di c ati o n s i n P ati e nt s wit h T y p e 2 Di a b et e s M e llitu s
(S U R P A S S J -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 i nt 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 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 ( L Y 3 2 9 8 1 7 6), u nl e s s s u c h p er s o 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 ut 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 J a p a n K. K.
K o b e , H y o g o J a p a n
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: 1 1 D e c 2 0 1 8
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: 1 7- J a n- 2 0 1 9 G M T

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Table of Contents
Section
Page
Protocol I8F-JE-GPGP(a) A Phase 3, Long-Term Safety Study of 
Tirzepatide in Combination with Monotherapy of Oral 
Antihyperglycemic Medications in Patients with Type 2 Diabetes 
Mellitus (SURPASS J-combo) ............................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
5.2.
Number of Participants.................................................................................................23
5.3.
End of Study Definition ...............................................................................................23
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................25
6.1.
Inclusion Criteria..........................................................................................................25
6.2.
Exclusion Criteria ........................................................................................................26
6.3.
Lifestyle Restrictions....................................................................................................29
6.4.
Screen Failures.............................................................................................................29
7.
Treatments........................................................................................................................30
7.1.
Treatments Administered .............................................................................................30
7.1.1.
Packaging and Labeling .......................................................................................30
7.1.2.
Medical Devices...................................................................................................30
7.2.
Method of Treatment Assignment ................................................................................31
7.2.1.
Selection and Timing of Doses.............................................................................31
7.3.
Blinding .......................................................................................................................31
7.4.
Dosage Modification....................................................................................................31
7.4.1.
Tirzepatide...........................................................................................................31
7.4.1.1.
Management of Patients with Gastrointestinal Symptoms...............................31

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7.4.2.
Oral Antihyperglycemic Medications...................................................................32
7.4.2.1.
Dose Adjustments in the Event of Hypoglycemia ...........................................32
7.4.2.2.
Dose Adjustments in the Event of Severe, Persistent 
Hyperglycemia ...............................................................................................32
7.5.
Preparation/Handling/Storage/Accountability...............................................................33
7.6.
Treatment Compliance .................................................................................................33
7.7.
Concomitant Therapy...................................................................................................34
7.8.
Treatment after the End of the Study............................................................................34
7.8.1.
Treatment after Study Completion........................................................................34
7.8.2.
Special Treatment Considerations ........................................................................35
8.
Discontinuation Criteria ....................................................................................................36
8.1.
Discontinuation from Study Treatment.........................................................................36
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................36
8.1.2.
Temporary Interruption of Study Treatment .........................................................37
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................37
8.2.
Discontinuation from the Study....................................................................................38
8.3.
Lost to Follow-Up........................................................................................................39
9.
Study Assessments and Procedures ...................................................................................40
9.1.
Efficacy Assessments...................................................................................................40
9.1.1.
Efficacy Assessments...........................................................................................40
9.1.1.1.
7-Point Self-Monitored Blood Glucose Profiles ..............................................40
9.1.2.
Appropriateness of Assessments ..........................................................................40
9.2.
Adverse Events ............................................................................................................40
9.2.1.
Serious Adverse Events........................................................................................41
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................42
9.2.2.
Adverse Events of Special Interest .......................................................................42
9.2.2.1.
Hypoglycemia ................................................................................................42
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................44
9.2.2.3.
Pancreatitis.....................................................................................................44
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia................................................46
9.2.2.5.
Major Adverse Cardiovascular Events............................................................46
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................46
9.2.2.7.
Hypersensitivity Events..................................................................................46
9.2.2.7.1.
Injection Site Reactions ............................................................................47
9.2.2.7.2.
Anti-Drug Antibodies ...............................................................................47
9.2.2.8.
Diabetic Retinopathy Complications...............................................................47
9.2.2.9.
Hepatobiliary Disorders..................................................................................47

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9.2.2.10.
Severe Gastrointestinal Adverse Events..........................................................47
9.2.2.11.
Acute Renal Events ........................................................................................47
9.2.2.12.
Metabolic Acidosis, Including Diabetic Ketoacidosis .....................................47
9.2.2.13.
Amputation/Peripheral Revascularization .......................................................48
9.2.2.14.
Major Depressive Disorder/Suicidal Ideation..................................................48
9.2.2.15.
Individual Clinical Events Adjudication..........................................................48
9.2.3.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................49
9.4.1.
Electrocardiograms ..............................................................................................49
9.4.2.
Vital Signs ...........................................................................................................49
9.4.3.
Laboratory Tests ..................................................................................................49
9.4.4.
Immunogenicity Assessments ..............................................................................50
9.4.5.
Safety Monitoring ................................................................................................50
9.4.5.1.
Hepatic Safety Monitoring..............................................................................50
9.5.
Pharmacokinetics .........................................................................................................51
9.6.
Pharmacodynamics ......................................................................................................51
9.7.
Pharmacogenomics ......................................................................................................51
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................51
9.8.
Biomarkers...................................................................................................................52
9.9.
Health Economics ........................................................................................................53
9.9.1.
European Quality of Life – 5 Dimension – 5 Level (EQ-5D-
5L).......................................................................................................................53
9.9.2.
Diabetes Treatment Satisfaction Questionnaire (DTSQ).......................................53
10.
Statistical Considerations ..................................................................................................54
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................54
10.3. Statistical Analyses ......................................................................................................54
10.3.1.
General Statistical Considerations ........................................................................54
10.3.2.
Treatment Group Comparability...........................................................................55
10.3.2.1.
Patient Disposition..........................................................................................55
10.3.2.2.
Patient Characteristics ....................................................................................56
10.3.2.3.
Concomitant Therapy .....................................................................................56
10.3.2.4.
Treatment Compliance....................................................................................56
10.3.3.
Efficacy Analyses ................................................................................................56
10.3.4.
Safety Analyses....................................................................................................57
10.3.4.1.
Hypoglycemic Events.....................................................................................57
10.3.4.2.
Gastrointestinal Events...................................................................................57

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10.3.4.3.
Adjudicated Cardiovascular Events ................................................................57
10.3.4.4.
Central Laboratory Measures, Vital Signs, and 
Electrocardiograms.........................................................................................57
10.3.5.
Evaluation of Immunogenicity .............................................................................58
10.3.6.
Other Analyses.....................................................................................................58
10.3.6.1.
Health Economics...........................................................................................58
10.3.6.2.
Subgroup Analyses.........................................................................................58
10.3.7.
Interim Analyses..................................................................................................58
11.
References ........................................................................................................................59
12.
Appendices .......................................................................................................................61

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List of Tables
Table
Page
Table GPGP.1.
Schedule of Activities....................................................................................13
Table GPGP.2.
Objectives and Endpoints...............................................................................19
Table GPGP.3.
Tirzepatide Treatment Regimens ...................................................................30

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List of Figures
Figure
Page
Figure GPGP.1. Illustration of study design for Clinical Protocol I8F-JE-GPGP......................23

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................62
Appendix 2.
Protocol GPGP Clinical Laboratory Tests......................................................66
Appendix 3.
Study Governance Considerations..................................................................68
Appendix 4.
Protocol GPGP Oral Antihyperglycemic Medication (OAM) Daily 
Dose..............................................................................................................73
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................74
Appendix 6.
World Health Organization Classification of Diabetes and Diagnostic 
Criteria ..........................................................................................................75
Appendix 7.
Classification of Contraceptive Methods........................................................76
Appendix 8.
Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period......................................................................................77
Appendix 9.
Protocol Amendment I8F-JE-GPGP(a) Summary A Phase 3, Long-
Term Safety Study of Tirzepatide in Combination with Monotherapy of 
Oral Antihyperglycemic Medications in Patients with Type 2 Diabetes 
Mellitus (SURPASS J-combo).......................................................................78

I 8 F-J E -G P G P( 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 P hase 3, L o n g -Ter m  S afet y St u d y  of Ti rze pati de i n C om bi nat i on wi t h M o n ot hera p y of Or al 
A nt i h y per gl yce mic Me dicati ons i n Patie nts wit h T y pe 2 Dia betes Mellit us ( S U R P A S S J-c o m b o) .
R ati o n ale: 
Ti rze patid e is a o nce- wee kl y d ual gl uc ose-de pe n de nt i n s uli n otr o pic p ol y pe ptide ( GI P)/ gl uca g o n 
li ke pe pti de-1 ( 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 with a g o nist 
acti vit y at b ot h t he GI P a n d G L P -1 rece pt ors.  T he str uct ure of tirze patide 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 t hat 
  
T irze patid e is a d mi nistere d b y s u bc uta ne o us a d mi nistrati o n.
St u d y  I 8 F-J E-G P G P ( G P G P) is a m ult ice nter, ra n d o mize d, P hase 3, l o n g-t er m, a d d-o n treat m e nt
st u d y desi g ne d t o assess t he safety a n d efficac y of o nce -wee kl y tirze pati de (5, 1 0, or 1 5 m g ), 
a d mi nistere d s u bc uta ne o usl y i n patient s wit h t ype 2 dia betes m ellit us ( T 2 D M) ta ki n g t hera pe utic 
d oses of vari o us oral a nt i h y per gl yce mic me dicati ons ( O A Ms): s ulf o n yl ureas ( S Us), big ua ni des, 
alp ha- gl uc osi dase i n hi bit ors (a -GI s), t hiaz oli di ne di o ne ( T Z D), gli ni des, or s o di u m-gl uc ose 
c otra ns p orter t ype 2 i n hi bit ors ( S G L T - 2i’s).  T he pri mar y  e n d p oi nt will be t o assess t he safety 
a n d t olera bilit y of tirze patid e d uri n g 5 2 wee ks of treat me nt as a n a d d-o n t hera p y  t o S Us, 
bi g ua ni des, T Z D, a -GI s, gli ni des, or S G L T - 2i’s i n t he treat me nt of T 2 D M, base d o n G ui deli ne 
f or Cli nical E val uati on of Oral H y p o gl yce mic A ge nts ( P har mace utical a n d F o o d Safet y 
B urea u /E val uat i on a n d Lice nsi n g Di visi o n N otificati o n N o. 0 7 0 9 - 1. 2 0 1 2).
O bjecti ve(s)/ E n d p oi nts:   
O bjecti ves
E n d p oi nts
Pri m ar y

T o assess safet y a n d t olera bilit y of o nce -
wee kl y tirze pati de d uri n g 5 2 wee ks of
treat me nt as a n a d d-o n  t hera p y t o SUs , 
bi g ua ni des, T Z D, a -GI s, gli ni des or S G L T -
2i ’s i n t he treat me nt of T 2 D M i n ter ms of 
T E A Es .

I nci de nce of T E A Es
Sec o n d ar y

T o assess safet y a n d t olera bilit y of o nce -
wee kl y tirze pati de d uri n g 5 2 wee ks of 
treat me nt as a n a d d-o n  t hera p y t o S Us, 
bi g ua ni des, T Z D, a -GI s, gli ni des, or S G L T -
2i ’s i n t he treat me nt of T 2 D M..

Earl y  disc o nti n uati o ns of i n vesti gati o nal 
pr o d uct d ue t o A Es

A dj u dicate d all deat hs a n d n o nfatal maj or C V 
e ve nts

A dj u dicate d pa ncreatic A Es

Ser u m calcit o ni n 

Inci de nce of aller gic a n d h y perse nsiti vit y 
reacti o ns 

I nci de nce of i njecti o n site reacti o ns

I nci de nce of treat me nt -e mer ge nt A D A t o 
tirze pati de

T he c ha n ge i n s yst olic a n d diast olic bl o o d 
C CI

I8F-JE-GPGP(a) Clinical Protocol
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LY3298176
pressure, and heart rate from baseline 

Occurrence of hypoglycemic episodes 

Time to initiation of rescue therapy for severe 
persistent hyperglycemia

To assess the efficacy of once-weekly
tirzepatide as an add-on therapy to SUs, 
biguanides, TZD, a-GIs, glinides, or SGLT-
2i’s in the treatment of T2DM at 52 weeks.

Mean change in HbA1c

Proportion of patients who achieve HbA1c 
<7%, ≤6.5%, and <5.7%

Mean change in FSG

Mean change in daily average 7-point SMBG 
profiles

Mean change in body weight

Proportion of patients who achieve weight 
loss of ≥5%, ≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in HOMA-2
Abbreviations:  a-GIs = alpha-glucosidase inhibitors; ADA = anti-drug antibodies; AE = adverse event; FSG = fasting 
serum glucose; HOMA-2 = Updated Homeostasis Model Assessment; HbA1c = hemoglobin A1c; SGLT-2i’s = 
sodium-glucose cotransporter type 2 inhibitors; SMBG = self-monitored blood glucose; SUs = sulfonylureas; 
T2DM = type 2 diabetes mellitus; TEAE = treatment-emergent adverse event; TZD = thiazolidinedione.
Summary of Study Design:  
Study GPGP is a multicenter, randomized, Phase 3, long-term, add-on treatment study, which 
will assess the safety and efficacy of tirzepatide (5, 10, or 15 mg) in patients with T2DM taking 
therapeutic doses of various OAMs; SUs, biguanides, a-GIs, TZD, glinides, or SGLT-2i’s.
Approximately 441 patients who have been taking SUs (126 patients), or biguanides, TZD, a-
GIs, glinides, or SGLT-2i (63 patients each) monotherapy will be randomized.
Treatment Arms and Duration:  
Study GPGP will consist of 4 periods: a 2-week screening period, a 2-week lead-in period, a 
52-week treatment period, and a 4-week safety follow-up period.  Patients will be randomized in 
a 1:1:1 ratio (tirzepatide 5, 10, and 15 mg).  Randomization will be stratified by OAM classes
(SUs, biguanides, TZD, a-GIs, glinides, or SGLT-2i’s).
Number of Patients:
A total of approximately 441 patients (126 patients in combination with SUs and 63 patients 
each in combination with biguanides, TZD, a-GIs, glinides, or SGLT-2i’s) will be randomized.
Statistical Analysis:
Sample size
Because the primary objective is to assess the safety of long-term treatment of tirzepatide and no 
formal hypothesis testing on the efficacy measures is planned, statistically derived power 
calculations were not considered for the determination of sample size.  The sample size of the 

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study was based on the Guideline for Clinical Evaluation of Oral Hypoglycemic Agents 
(Pharmaceutical and Food Safety Bureau/Evaluation and Licensing Division Notification No. 
0709-1. 2012).  The guideline requires long-term safety data of 1 year of treatment with
combination therapy using other antihyperglycemic medications. At least 100 patients treated 
for 1 year in combination with SUs and at least 50 patients in combination with each of the other 
agents are required. By taking into account the overall drop-out rate of approximately 20%, 
126 patients receiving combination treatment with SUs and 63 patients receiving combination 
treatment with other agents are planned to be randomized; therefore, a total of 441 patients are 
planned to be randomized.
General Consideration
Safety and efficacy will be assessed using the modified intention-to-treat (mITT) population, 
which consists of all randomly assigned participants who are exposed to at least 1 dose of 
investigational product.  A statistical summary will be performed for each combination therapy,
as well as overall.  
Safety Analysis
Safety assessment will be based on all available data, irrespective of whether they were obtained 
while the participants had discontinued the investigational product 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 first dose to the 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.  A selected safety analysis (eg, hypoglycemia) will 
be conducted after excluding data while on rescue therapy or data after starting another permitted 
antihyperglycemic medication following permanent discontinuation of investigational drug.
Additional details, including analysis of AEs of special interest, will be provided in the statistical 
analysis plan (SAP).
Efficacy Analyses
The efficacy measure is mean change in glycated hemoglobin (HbA1c) from baseline to 52 week 
visit. The “efficacy” estimand, represents efficacy prior to discontinuation of investigational 
product without confounding effects of rescue therapy for persistent severe hyperglycemia. 
The efficacy assessment, guided by the “efficacy” estimand, will use Efficacy Analysis Set
(EAS), which consists of 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” as fixed effects, and “baseline HbA1c”
as a covariate. An unstructured covariance structure will model the relationship of within-patient 
errors.

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2. Schedule of Activities

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Table GPGP.1.
Schedule of Activities
Screening
Lead-in
Treatment
Follow-up
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
ETa
801b
Week of Treatment
-4
-2
0
4
8
12
16
20
24
32
40
48
52
―
56
Visit Window (days)
±7
±7
―
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
―
±7
Fasting Visit c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Assessments
Informed consent
X
Medical history
X
Demographics
X
Previous diabetes therapy
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dilated fundoscopic examinationd
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (2 sitting BP and HR)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single 12-lead ECGf
X
X
X
X
X
X
Adverse events
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
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
Pregnancy test (serum)g
X
Pregnancy test (urine)h
X
X
X
X
X
X
FSH test, estradioli
X
HbA1c
X
X
X
X
X
X
X
X
Fasting Serum Glucose
X
X
X
X
X
X
X
Insulin
X
X
X
X
X
X
C-peptide
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Chemistry panel
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
Urinary albumin/creatinine ratio
X
X
X
X
X
eGFR (CKD-EPI)
X
X
X
X
Lipase, pancreatic amylase
X
X
X
X
X
X
X
X
Calcitonin
X
X
X
X
X
X
X
Review screening lab test results
X

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Schedule of Activities
Screening
Lead-in
Treatment
Follow-
up
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
ETa
801b
Week of Treatment
-4
-2
0
4
8
12
16
20
24
32
40
48
52
―
56
Visit Window (days)
±7
±7
―
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
―
±7
Fasting Visit c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
Nonpharmacogenetic samples 
for storage
X
X
X
X
X
X
X
Pharmacogenetics samplej
X
Immunogenicity (ADA)k
X
X
X
X
X
X
X
X
PK sample for immunogenicityl
X
X
X
X
X
X
X
X
Patient Education and Supplies
Dispensing of SMBG 
meter/supplies
X
X
X
X
X
X
X
X
X
X
X
SMBG meter training
X
Weekly fasting SMBG 
measurementm
X
X
X
X
X
X
X
X
X
X
X
X
7-point SMBG measurementn
X
X
Dispensing of study diary and 
instruct in use
X
X
X
X
X
X
X
X
X
X
X
Study diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
Subcutaneous injection training/
injection site inspection/ review 
of technique
X
Dispensing of investigational 
product and injection supplies
X
X
X
X
X
X
X
X
X
X
Return of used investigational 
product containers, unused study 
medication, and study diary
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of investigational 
product compliance 
X
X
X
X
X
X
X
X
X
X
X
X
Patient-Reported Outcomes 
EQ-5D-5L
X
X
X
DTSQs
X
DTSQc
X
X

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Abbreviations: ADA = anti-drug antibodies; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; DTSQc = Diabetes Treatment 
Satisfaction Questionnaire (change); DTSQs = Diabetes Treatment Satisfaction Questionnaire (status); ECG = electrocardiogram; eCRF = electronic case 
report form; eGFR = estimated glomerular filtration rate; EQ-5D-5L = European Quality of Life – 5 Dimension – 5 Level; ET = early termination; 
FSH = follicle-stimulating hormone; HbA1c = glycated hemoglobin; HR = heart rate; OAM = oral antihyperglycemic medication; PK = pharmacokinetics; 
SMBG = self-monitored blood glucose.
a
Early termination (ET) visit is conducted within 14 days after the decision of study discontinuation.
b
Visit 801 should be 4 weeks after Visit 13 or 4 weeks after early termination.  
c
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 investigational product.
d
Dilated fundoscopic examination will be performed by an eye-care professional (ophthalmologist or optometrist) for all patients between Visit 2 and 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 (See exclusion criterion #11 Section 6.2).
e
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. Blood pressure must be taken with an automated BP machine.
f
A single 12-lead ECG will be recorded, after the patient has been supine for 5 minutes.  A local ECG will be performed at screening.  The ECGs during the 
treatment period will be electronically transmitted via modem to the centralized ECG vendor designated by Lilly.
g
Serum pregnancy test to be performed by the central laboratory at Visit 1 for women of childbearing potential only. 
h
Urine pregnancy tests can be performed as required at local laboratories. A urine pregnancy test must be performed at Visit 3 with the result available prior to 
randomization and first injection of investigational product(s) for women of childbearing potential only. Additional pregnancy tests will be performed at 
Visits 6, 9, 11, 13 and ET.  Pregnancy tests may also be performed, at the investigator’s discretion, during the study.
i
FSH test performed at Visit 1 for postmenopausal women at least 45 years of age with an intact uterus, not on hormone therapy, 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).
j
The blood sample should be collected at Visit 3 before any investigational product has been given to the patient.
k
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples will be collected including ADA, PK, and 
exploratory immune safety sample.
l
PK samples for immunogenicity must be taken prior to drug administration.
m The patients are required to measure their fasting (pre-breakfast) blood glucose (FBG) concentration at least once a week at approximately the same time of 
day before OAMs have been taken.  By the investigator’s decision, the frequency of measurement of FBG could be increased.
n
7-point SMBG profiles (glucose measurements before breakfast, lunch, dinner, and at bedtime and 2-hours after breakfast, lunch, and dinner) should be 
performed on 2 days within the 2 weeks prior to Visit 3 (0 weeks), and Visit 13 (52 weeks).

I 8 F-J E -G P G P( a) Cli ni c al Pr ot o c ol
P a g e 1 6
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 irze patid e is a o nce- wee kl y d ual gl uc ose-de pe n de nt i n s uli n otr o pic p ol y pe pti de ( GI P)/ gl uca g o n 
li ke pe pti de-1 ( 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 with a g o nist 
acti vit y at b ot h t he GI P a n d G L P -1 rece pt ors.  T he str uct ure of tirze patide 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 t hat 
  
Ti rze patid e is a d mi nistere d b y s u bc uta ne o us ( S C) a d mi nistrati o n.
St u d y  I 8 F-J E-G P G P ( G P G P) is a P hase 3 st u d y  d esig ne d t o assess t he safet y a n d efficac y of 
o nce -wee kl y tirze pati de ( 5, 1 0, or 1 5 m g), a d mi nistere d S C i n patie nts wit h ty pe 2 dia betes 
mellit us ( T 2 D M) ta ki n g t hera pe ut ic d oses of vari ous oral  a nti h y per gl yce mic me dicati ons 
( O A Ms): s ulf on yl ureas ( S U s), big ua ni des, al p ha- gl uc osi dase i n hi bit ors (a -GI s), 
t hiaz o li di ne di one ( T Z D), gli ni d es, or s o diu m -gl uc ose c otra ns p orter t y pe 2 i n hi bit ors ( S G L T -
2i ’s).  T he pri mar y e n d p o i nt will be t o assess safet y a n d t olera bility of  tirze pati de d uri n g 5 2 
wee ks of treat me nt as a n a d d-o n t hera p y  t o S Us, bi g ua ni des, T Z D, a-GI s, gli ni des, or S G L T - 2i’s
i n t he tr e at me nt of T 2 D M, base d o n G ui deli ne f or Cli nical E val uati o n of Oral H y p o gl yce mic 
A ge nts (P har mace ut ical a n d F o o d Safet y B urea u /E val uat i on a n d Lice nsi n g Di visi o n N otificat i on 
N o. 0 7 0 9 - 1. 2 01 2).
T he data fr o m t his trial, t o get her wit h t he data fr o m ot her P hase 3 trials, are e x pecte d t o pr o vi de 
r o b ust be nefit/ris k pr ofiles of i n di vi d ual d oses of tirze patide , as re q uire d b y re g ulat or y a ge ncies 
f or r e g ulat or y s u b missio n  a n d mar keti n g a p pr o val.
3. 2.
B a c k gr o u n d
T irze patid e is c urre ntl y bei n g i n vesti gate d f or its p ote ntial use i n t he treat me nt of h y per gl yce mia 
i n T 2 D M. I n n or mal p h ysiol o g y , t he i ncret i ns GI P a n d G L P-1 are secrete d fr o m e nter oe n d ocri ne 
cells i n t he g ut f o llo wi n g a m eal, a n d t hese i ncret i ns e n ha nce t he p h ysi ol ogical res p o nse t o f o o d, 
i ncl u di n g se nsati o n of satiety,  i ns uli n secreti on, a n d n utrie nt dis p osal ( Ba g gi o a n d Dr uc ker 
2 0 0 7). Patie nts wit h T 2 D M ha ve i m paire d i ncret i n res p o nses ( Ba g gi o a n d Dr uc ker 2 0 0 7).  
I ncreti n-base d treat me nts t hat are c urre ntl y  a vaila ble fall withi n 2 classes: G L P - 1 rece pt or
a g o nists a n d di pe pt i dyl pe pt i dase-4 ( D P P - 4) i n hi bit ors ( Ne u miller 2 0 1 5). M ost G L P -1 rece pt or
a g o nists ha ve a be neficial effect o n gl uc ose meta b olis m t hr o u g h t h e e n ha nce me nt of gl uc ose -
de pe n de nt i ns uli n secret i on, re d ucti o n of  ina p pr o priatel y ele vate d gl uca g o n le vels, a n d a dela y  in 
gastri c e m pt yi n g. Di pe pt i dyl pe pti dase -4 i n hi bit ors i n direct l y e xert a n i ncreti n effect b y 
pre ve nt i n g t he pr ote ol ytic brea k d o w n a n d i nacti vati on of e n d o ge n o us a g o nists of gastric 
i n hi bit or y p ol y pe pti de rece pt or (GI P R ) a n d G L P- 1 rece pt or a g o nists. Eac h class has its 
t hera pe utic li mit atio ns .  F or e xa m ple, d osi n g of G L P - 1 rece pt or a g o nists ma y be li mite d b y 
gastr oi ntesti nal ( GI) a d verse effects a n d D P P- 4 i n hi bit ors are li mite d i n efficac y b y t he fact t he y 
i n hi bit de gra dati o n of e n d o ge n o us i ncreti ns, b ut, e ve n w he n pr otecte d fr o m de gra dat i on, t he 
e n d o ge n o us i ncret i ns d o n ot reac h plas ma le vels si milar t o w hat is attai ne d wit h e x o ge n o us 
i ncreti n a nal o g treat me nt. As a d ual  rece pt or a g o nist, tirze pati de bi n ds b ot h GI P a n d G L P - 1 
rece pt ors a n d c o m bi nes t he si g nali n g of eac h rece pt or f or i m pr o ve d gl yce mic c o ntr ol. B y  virt ue 
of  bei n g a G I P/ G L P d ual rece pt or a g o nist, tirze pati de has t he p ote ntial of reac hi n g hi g her 
C CI

I8F-JE-GPGP(a) Clinical Protocol
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efficacy in target tissues such as the insulin-producing pancreatic ß-cells that express both GIP 
and GLP-1 receptors before reaching its therapeutic limitation. Tirzepatide may, furthermore,
attain additional efficacy by recruiting metabolically active tissues not targeted by classical GLP-
1 analogs (for example, adipose tissue as indicated by the observation of increased energy 
utilization [Baggio and Drucker 2007]).
Three tirzepatide clinical trials have completed dosing and analysis:  a Phase 1 study, 
Study I8F-MC-GPGA (GPGA), and 2 Phase 2 studies, Study I8F-MC-GPGB (GPGB) and 
I8F-MC-GPGF (GPGF).  One Phase 1 study, Study I8F-JE-GPGC (GPGC) is ongoing in Japan.
The safety and tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profiles of 
tirzepatide at doses and escalation regimens administered in Study GPGA supported further 
development of tirzepatide for once-weekly (QW) dosing in patients with T2DM.
Phase 2 studies have evaluated the efficacy, tolerability, and safety of tirzepatide in patients with 
T2DM with inadequate glycemic control on diet and exercise alone or on a stable dose of 
metformin monotherapy.  Study GPGB, a 26-week Phase 2 study, compared the efficacy, 
tolerability, and safety of 4 doses (1, 5, and 10 mg [titrated]; and 15 mg [titrated]), of QW 
tirzepatide compared with QW dulaglutide 1.5 mg and QW placebo in 318 patients with T2DM,
with inadequate glycemic control on diet and exercise alone or on a stable dose of metformin 
monotherapy.  Tirzepatide 5mg, 10mg, and 15-mg significantly lowered glycated hemoglobin 
(HbA1c) and body weight in a dose-dependent manner, in comparison to placebo. In addition, 
reductions in HbA1c for the tirzepatide 5-, 10-, and 15-mg doses were greater than with 
dulaglutide 1.5 mg QW. Similar to adverse events (AEs) observed with the GLP-1 receptor 
agonist class and the Phase 1 Study GPGA, most of the tirzepatide AEs were gastrointestinal 
(GI)-related, consisting mainly of nausea, vomiting, and diarrhea, which were mild-to-moderate 
in intensity and dose-dependent.  Serious AEs (SAEs) were balanced across the treatment 
groups, and none of the groups in the study reported severe hypoglycemia (Frias et al. 2018).
Study GPGF, a 3-month Phase 2 study, was designed to examine the efficacy, safety, and 
tolerability of QW tirzepatide administered in 3 different titration schemes (longer time intervals 
between dose escalations and different dose escalations), to reach the highest tirzepatide planned 
doses of 12 mg and 15 mg, compared with placebo, in patients with T2DM who have inadequate 
glycemic control with diet and exercise alone or with a stable dose of metformin monotherapy
and was designed to support evaluation of optimized dosing regimen(s) in Phase 3.
In addition, the safety, tolerability, and PK/PD of tirzepatide are being evaluated in the ongoing 
Study GPGC; a Phase 1, 8-week multiple ascending dose (MAD) study in Japanese patients with 
T2DM. This study involves a comparison of 3 once-weekly SC dose levels of tirzepatide
(2.5 mg to 10 mg titration regimen for Cohort 1; 5 mg to 15 mg titration regimen for Cohort 2;
and 5 mg fixed dose for Cohort 3), or placebo. The interim safety and tolerability data of Study 
GPGC supports the use of doses up to 15 mg of tirzepatide in Japanese patients.  

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3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of tirzepatide are to be found in the Investigator’s Brochure (IB).
In addition, detailed information about the known and expected benefits and risks of OAMs
administered with tirzepatide may be found in each of their respective package inserts.

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4.
Objectives and Endpoints
Table GPGP.2 shows the objectives and endpoints of the study.
Table GPGP.2.
Objectives and Endpoints  
Objectives
Endpoints
Primary

To assess safety and tolerability of once-weekly
tirzepatide during 52 weeks of treatment as an 
add-on therapy to SUs, biguanides, TZD, a-GIs, 
glinides or SGLT-2i’s in the treatment of 
T2DM in terms of incidence of TEAEs.

Incidence of TEAEs
Secondary

To assess safety and tolerability of once-weekly
tirzepatide during 52 weeks of treatment as an 
add-on therapy to SUs, biguanides, TZD, a-GIs, 
glinides, or SGLT-2i’s in the treatment of 
T2DM.

Early discontinuations of investigational 
product due to AEs

Adjudicated all deaths and nonfatal major CV 
events

Adjudicated pancreatic AEs

Serum calcitonin 

Incidence of allergic and hypersensitivity 
reactions 

Incidence of injection site reactions

Incidence of treatment-emergent ADA to 
tirzepatide

The change in systolic and diastolic blood 
pressure, and heart rate from baseline 

Occurrence of hypoglycemic episodes 

Time to initiation of rescue therapy for severe 
persistent hyperglycemia

To assess the efficacy of once-weekly
tirzepatide as an add-on therapy to SUs, 
biguanides, TZD, a-GIs, glinides, or SGLT-2i’s
in the treatment of T2DM at 52 weeks.

Mean change in HbA1c

Proportion of patients who achieve HbA1c 
<7%, ≤6.5%, and <5.7%

Mean change in FSG

Mean change in daily average 7-point SMBG 
profiles

Mean change in body weight

Proportion of patients who achieve weight loss 
of ≥5%,≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in HOMA-2

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Objectives and Endpoints
Abbreviations:  a-GIs = alpha-glucosidase inhibitors; ADA = anti-drug antibodies; AE = adverse event; 
CV = cardiovascular; FSG = fasting serum glucose; HbA1c = glycated hemoglobin; HOMA-2 = Updated 
Homeostasis Model Assessment; SGLT-2i’s = sodium-glucose cotransporter type 2 inhibitors; SMBG = self-
monitored blood glucose; SUs = sulfonylureas; T2DM = type 2 diabetes mellitus; TEAE = treatment-emergent 
adverse event; TZD = thiazolidinedione.

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5. Study Design
5.1.
Overall Design
Study GPGP is a multicenter, randomized, Phase 3, long-term, add-on treatment study which 
will assess the safety and efficacy of tirzepatide (5, 10, or 15 mg), in patients with T2DM taking 
therapeutic doses of various OAMs; SUs, biguanides, a-GIs, TZD, glinides, or SGLT-2i’s.  
Approximately 441 patients who have been taking SUs (126 patients), or biguanides, TZD, a-
GIs, glinides, or SGLT-2i (63 patients each) monotherapy will be randomized.
Study GPGP will consist of 4 periods (see Figure GPGP.1):

2-week screening period  

2-week lead-in period 

52-week treatment period 

4-week safety follow-up period 
Screening procedures and patient training (disease monitoring and management procedures, 
study diaries, and study procedures) will be performed at Visits 1 and 2 (screening and lead-in 
periods).  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.  
At Visit 2, the screening laboratory results will be reviewed.  For those patients meeting all other 
eligibility requirements, a dilated fundoscopic 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 excluded.
At Visit 3, patients will perform all required baseline study procedures (including the collection 
of all baseline laboratory measures) prior to randomization and prior to taking the first dose of 
investigational product.  Patients will be randomized in a 1:1:1 ratio (tirzepatide 5 mg, 10 mg, 
and 15 mg).  Following randomization, the patient will inject the first dose of investigational 
product at the study site, according to the dose escalation regimen.  The date and time of the first 
dose of investigational product should be recorded on the electronic case report form (eCRF).  
Beginning at randomization, all patients will receive investigational product according to the 
randomized treatment arm for the duration of the 52-week treatment period.  Patients should be 
maintained on stable doses of their OAM, unless dose modifications are required in the event of 
hypoglycemia (See Section 7.4.2.1).  A safety follow-up visit will occur approximately 4 weeks 
following the last dose of the investigational product.
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 tirzepatide 5-mg arm.  For the 10-mg arm, 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 arm, 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.

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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). 
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) must be documented, and the name of the drug(s) and the date(s) of administration must 
be recorded in the patient’s diary and on the “Concomitant Medications” section of the eCRF. 
Antihyperglycemic medications other than investigational product are not allowed at any time 
during the study, except as allowed for rescue therapy, after early investigational product
discontinuation or short term insulin use. No changes to background therapy can be made from 
Visit 1 to Visit 3 with the exception of rescue therapy.  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 therapy with
antihyperglycemic medications, including insulins, will be allowed in certain situations after 
randomization due to severe, persistent hyperglycemia. In this case, GLP-1 receptor agonists
and DPP-4 inhibitors are not allowed as rescue therapies.
After early discontinuation of study treatment, any antihyperglycemic medications, except for 
GLP-1 receptor agonists may be allowed. Short-term insulin use for up to 14 days is allowed for 
certain clinical situations (eg, elective surgery, during hospitalization, hyperosmolar states). If 
insulin is prescribed as a rescue therapy, it must be differentiated from short-term use of insulin
therapy for medical emergencies when reported in the eCRF.
All nonstudy medications will be recorded on source documents at all visits.
Study governance considerations are described in detail in Appendix 3.
Figure GPGP.1 illustrates the study design.  

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Abbreviations: AGI = alpha-glucosidase inhibitor; BG = biguanide; GLN = glinide;
OAM = oral antihyperglycemic medication; QW = once weekly; SGLT-2i = sodium-
glucose cotransporter type 2 inhibitor, SU = sulfonylurea, TZD = thiazolidinedione.
Note:  All doses will be administered QW subcutaneously using single-use pens.  
Patients who have been taking each OAM monotherapy will be randomized to 
tirzepatide (5-, 10-, or 15-mg arm).
Figure GPGP.1.
Illustration of study design for Clinical Protocol I8F-JE-GPGP.
5.2.
Number of Participants
Because the primary objective is to assess the safety of long-term treatment of tirzepatide and no 
formal hypothesis testing on the efficacy measures are planned, statistically derived power 
calculations were not considered for the determination of sample size.  The sample size of the 
study was based on the Guideline for Clinical Evaluation of Oral Hypoglycemic Agents 
(Pharmaceutical and Food Safety Bureau/Evaluation and Licensing Division Notification No. 
0709-1. 2012).  The guideline requires long-term safety data of 1 year of treatment with
combination therapy using other antihyperglycemic medications.  At least 100 patients treated 
for 1 year in combination with SUs and at least 50 patients in combination with each of the other 
agents are required.  By taking into account the overall drop-out rate of approximately 20%, 
126 patients for the combination with SUs and 63 patients for the combination with each of the 
other agents are planned to be randomized; therefore, a total of 441 patients are planned to be 
randomized. 
5.3.
End of Study Definition
End of study is the date of the last patient visit or the last scheduled procedure shown in the 
Schedule of Activities (Section 2).

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5.4.
Scientific Rationale for Study Design
This study has been primarily designed to assess the safety of long-term treatment of QW 
tirzepatide as an add-on therapy for T2DM in patients who have inadequate glycemic control 
with monotherapy of OAM.
Study treatment will continue for up to 52 weeks to collect 1 year of safety data in combination 
with monotherapy of OAM. Sulfonylureas, biguanides, TZD, a-GIs, glinides, or SGLT-2i’s have 
been chosen as combination therapy because they have a different mechanism of action from 
tirzepatide and are expected to be combined with tirzepatide in the clinical setting of T2DM in 
Japan. The investigators will be instructed to maintain patients on stable doses of their OAM 
(SUs, biguanides, TZD, a-GIs, glinides, or SGLT-2i’s) during the study. However, OAM dose 
modifications may be required in the event of hypoglycemia (refer to Section 7.4).
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 weeks would permit adequate 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-, 10-, and 15-mg doses of tirzepatide.
Based on interim data in Study GPGC, there were no clinically meaningful difference in the PK, 
PD, and safety profile between Japanese patients and non-Japanese patients. Hence, the doses 
and associated escalation schemes chosen for this Phase 3 study GPGP are the same as that 
chosen for global studies.

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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.  
Subjects who do not qualify based upon Visit 1 laboratory measurements will have an 
opportunity to have 1 additional screening visit with repeat screening laboratory tests.
Type of Patient and Disease Characteristics
[1]
Have been diagnosed with T2DM based on the World Health Organization 
classification before the screening visit (Visit 1)
Patient Characteristics
[2]
Have body mass index (BMI) of ≥23 kg/m2 at Visit 1
[3]
Have been taking SUs (glibenclamide, gliclazide, glimepiride), biguanides, 
TZD, a-GIs, glinides, or SGLT-2i monotherapy for at least 3 months before 
Visit 1 and have been on the following dose for at least 8 weeks before Visit 1 
(OAM daily doses are provided in Appendix 4)
[4]
Have HbA1c ≥7.0% to <11.0%, as determined by the central laboratory at 
Visit 1 
[5]
Are of stable weight (±5%) during 3 months preceding Visit 1; and agree to 
not initiate an intensive 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]
20 years or older at the time of signing informed consent
[6a] Male patients (see Appendix 7 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.
[6b] Female patients:
Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation) congenital 
anomaly (ie, Müllerian agenesis) or menopause.
Women with an intact uterus are deemed postmenopausal if they are 
45 years old, and

have not taken hormones or oral contraceptives within the last 
year and had cessation of menses for at least 1 year,
OR

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
have had at least 6 months of amenorrhea with follicle-stimulating 
hormone (FSH) and estradiol levels consistent with a 
postmenopausal state (FSH ≥40 mIU/mL and estradiol <30 pg/mL).
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 2 forms of effective contraception, 
where at least 1 form is highly effective for the duration of the 
trial and for 30 days, thereafter 

not be breastfeeding
[7]
In the investigator’s opinion, are well-motivated, capable, and willing to: 
a)
perform 7-point self-monitored blood glucose (SMBG) testing 
b)
learn how to self-inject treatment, as required for this protocol 
(visually impaired persons who are not able to perform the injections 
must have the assistance of a sighted individual trained to inject the 
investigational product; persons with physical limitations who are not 
able to perform the injections must have the assistance of an 
individual trained to inject the investigational product) 
c)
are willing and able to inject investigational product QW
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
[8]
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:
Medical Conditions  
[9]
Have type 1 diabetes mellitus
[10] Had chronic or acute pancreatitis any time prior to study entry (Visit 1)
[11] Have a history of 

proliferative diabetic retinopathy 

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or 

diabetic maculopathy
or 

nonproliferative diabetic retinopathy that requires acute treatment
(a dilated fundoscopic exam, performed by an ophthalmologist or optometrist 
between Visit 2 and Visit 3, is required to confirm eligibility) 
[12] Have a history of severe hypoglycemia and/or hypoglycemia unawareness 
within the 6 months prior to Visit 1 
[13] Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma 
requiring hospitalization within the 6 months prior to Visit 1
[14] Have a known clinically significant gastric emptying abnormality (eg, severe 
diabetic gastroparesis or gastric outlet obstruction), have undergone or plan to 
have during the course of the study: gastric bypass (bariatric) surgery, or 
restrictive bariatric surgery (eg, Lap-Band®), or chronically take drugs that 
directly affect GI motility
[15] Have any of the following cardiovascular conditions within 2 months prior to 
Visit 1: acute myocardial infarction, cerebrovascular accident (stroke), or 
hospitalization due to heart failure
[16] Have a history of New York Heart Association Functional Classification IV 
congestive heart failure
[17] 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; patients with 
NAFLD are eligible to participate only if their ALT level is ≤3.0 times the 
upper limit of normal (ULN) for the reference range
[18] Have an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2
(<45 mL/min/1.73 m2 for patients who take biguanides and SGLT-2i’s), 
calculated by Chronic Kidney Disease-Epidemiology (CKD-EPI) as 
determined by central laboratory at Visit 1
[19] Have evidence of a significant, uncontrolled endocrine abnormality 
(eg, thyrotoxicosis or adrenal crises), in the opinion of the investigator
[20] Have family or personal history of medullary thyroid carcinoma or multiple 
endocrine neoplasia syndrome type 2 (MEN-2) 
[21] Have a serum calcitonin level of ≥35 ng/L at Visit 1
[22] Have evidence of a significant, active autoimmune abnormality (eg, 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

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[23] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant
[24] 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
[25] 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
[26] Have any hematological condition that may interfere with HbA1c 
measurement (eg, hemolytic anemias, sickle-cell disease)
Prior/Concomitant Therapy  
[27] Have history of use of any injectable therapy for T2DM treatment (GLP-1
receptor agonists and insulin) within 3 months prior to Visit 1
[28] 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 prior to Visit 1 and/or between study 
entry (Visits 1) and randomization (Visit 3)
[29] Have been treated with drugs that promote weight loss (eg, Sanorex®
[mazindol]) within 3 months prior to Visit 1 and/or between study entry 
(Visit 1) and randomization (Visit 3)
Prior/Concurrent Clinical Trial Experience  
[30] Are currently enrolled in, or discontinued within the last 30 days from, a 
clinical trial involving an investigational drug or device or off-label use of a 
drug or device (other than the investigational product/device used in this 
study), or are concurrently 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
[31] Have participated, within the last 30 days, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 30 days or 5 half-lives (whichever is longer) should have passed
[32] Have previously completed or withdrawn from this study or any other study 
investigating tirzepatide
Other Exclusions  
[33] 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
[34] are Lilly employees 

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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
Subjects who do not qualify, based upon Visit 1 laboratory measurements, will have an 
opportunity to have 1 additional screening visit with repeat screening laboratory tests.

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7. Treatments
7.1.
Treatments Administered
In this study, patients will receive treatment with 1 of the 3 doses of tirzepatide (5, 10, 15 mg), 
each administered QW as SC injection(s) in patients with T2DM. Patients should continue 
taking their usual OAM (SUs, biguanides, TZD, a-GIs, glinides, or SGLT-2i’s) dose and regimen 
throughout the active treatment period, unless dose modifications are required in the event of 
hypoglycemia (refer to Section 7.4).
Table GPGP.3 shows the randomized treatments for the entire treatment period.
Table GPGP.3.
Tirzepatide Treatment Regimens
Name of Drug
Dosage
Frequency
Drug Formulation
Route of
Administration
Investigational Compound
Tirzepatide
5 mga
QW
Single-use pen
SC
10 mga
QW
Single-use pen
SC
15 mga
QW
Single-use pen
SC
Abbreviations: QW = once weekly; SC = subcutaneous.
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 in the tirzepatide 5-mg arm.  For the 10-mg arm, 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 arm, 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 investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational product to the patient 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection,
as well as records of interruptions in investigational product administration

instructing the patient to discard all used single-use pens for tirzepatide in a closeable, 
puncture-resistant container and dispose according to local regulations
7.1.1.
Packaging and Labeling
Tirzepatide will be supplied by Lilly in single-use pens which 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 manufactured medical device provided for use in the study is the tirzepatide single-use pen.

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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the study treatment arms 
at Visit 3.  Assignment to treatment arms will be determined by a computer-generated random 
sequence using an interactive web response system (IWRS).  Patients will be randomized in a 
1:1:1 ratio to receive 5 mg tirzepatide, 10 mg tirzepatide, or 15 mg tirzepatide.  
7.2.1.
Selection and Timing of Doses
Assignment to 1 of the 3 tirzepatide doses will occur at randomization.  There are no restrictions 
on the time of day each weekly dose is given, but it is advisable to administer SC injections on 
the same day and same time each week.  The actual date and time of all dose administrations will 
be recorded in the subject’s eCRF.  If a dose of investigational product, including 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 taken at the appropriate time.
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
7.4.1.
Tirzepatide
Tirzepatide will be increased based on the schedule (refer to Figure GPGP.1)  De-escalation will 
be allowed ONLY ONCE, IF patients experience intolerable GI AEs which persist after all the 
measures mentioned in Section 7.4.1.1 have been implemented (refer to Section 7.4.1.1 for 
details).
7.4.1.1.
Management of Patients with Gastrointestinal Symptoms
In the Phase 2 program, the most commonly reported treatment-emergent adverse events 
(TEAEs) for patients receiving tirzepatide were nausea, vomiting, and diarrhea. The tirzepatide
dose escalation scheme has been designed to improve GI tolerability. The escalation period is 
considered to be 24 weeks, which allows 20 weeks to escalate to 15 mg and an 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 investigational 
product dosage. 
To mitigate GI symptoms and manage patients with intolerable GI AEs, the investigator should:

Advise patients to eat smaller meals (eg, splitting 3 daily meals into 4 or more smaller 
meals) and to stop eating when they feel full.

Prescribe symptomatic medication (eg, 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.  The data related to temporary interruption of study 
treatment should be documented in source documents and entered into the eCRF.

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
After the interruption, restart at the same dose with the patient taking medication to 
alleviate his/her 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 5 mg or lower will be discontinued from tirzepatide.

Patients at 7.5 mg or 10 mg will decrease the dose to 5 mg.

Patients at 12.5 mg or 15 mg will decrease the dose to 10 mg.
If de-escalation of the tirzepatide dose is necessary, the investigator will use the IWRS to receive 
the appropriate tirzepatide dispensing information.  If de-escalation is needed between scheduled 
visits, the IWRS will have unscheduled visits (eg, Visit 13a) dedicated to provide dispensing 
information for patients whose dose has been de-escalated.  Those patients who have their doses
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 AEs persist.  
7.4.2.
Oral Antihyperglycemic Medications
7.4.2.1.
Dose Adjustments in the Event of Hypoglycemia
Throughout the study, the investigator should maintain patients on stable doses of their OAM 
(SUs, biguanides, TZD, a-GIs, glinides, or SGLT-2i’s).  However, only if a patient requires a 
reduction of the dosage of his/her OAM due to occurrence of hypoglycemia without interrupting 
study treatment, the dose of OAMs may be reduced by the investigator’s decision.  
In this case, the reason and details of the dose reduction will be recorded on source documents 
and will be entered in the appropriate section of the eCRF.
7.4.2.2.
Dose Adjustments in the Event of Severe, Persistent Hyperglycemia
Throughout the study, the investigator should maintain patients on stable doses of their OAM 
(SUs, biguanides, TZD, a-GIs, glinides, or SGLT-2i’s). Therefore, increasing the dose of the 
concomitant OAM is not permitted. When a patient experiences hyperglycemia, rescue therapy 
with basal or rapid acting insulins, may be medically indicated (see Appendix 8). The 
investigator should first determine whether there are any possible causes for the patient’s 
hyperglycemia (eg, excess food consumption, a change in dietary habits, illness, 
pharmacological treatments, or poor compliance with OAMs or study treatment). If any possible 
causes are identified, the investigator should address these issues first and encourage the patient 
to comply with any necessary behavioral changes to prevent hyperglycemia before prescribing a 
rescue therapy.
Patients on allowed rescue therapy for hyperglycemia will remain in the study (unless a 
discontinuation criterion of study was met) and will continue to administer investigational 
product.

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7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

Confirming that 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.

Ensuring that 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 investigational product in a locked and secure environment.  Please 
refer to the investigational product label for specific storage conditions.  Patients will receive 
insulated bags with cooling gel packs for use in transporting the investigational product from the 
site to home.
Temperature logs must be maintained to verify correct storage conditions at the investigator site, 
throughout the study.  Patients should be instructed to store the investigational product in their 
refrigerators, but are not required to maintain temperature logs. 
Study site staff must regularly assess whether the patient is correctly administering the assigned 
investigational product and storing the investigational product according to the provided 
instructions. 
7.6.
Treatment Compliance
Investigational product compliance will be determined by the following: 

Investigational product 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 investigational product and/or 
empty cartons at the next visit to the study site for the purpose of performing drug 
accountability.
In the 3 tirzepatide treatment arms, treatment compliance overall is defined as taking at least 
75% of the total required doses of investigational product.  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 investigational product
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 

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antihyperglycemic medication regimen, completion of study diaries, the results of home blood
glucose (BG) monitoring, and any other parameters the investigator considers necessary.
Initially, 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. 
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. Prohibited medications include following;

Any antihyperglycemic medications, except for concomitant OAMs

Any medications that promote weight loss (eg, Sanorex® [mazindol])

Any chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, 
intra-ocular, intranasal, or inhaled preparations)
Short-term insulin use is allowed for certain clinical situations (eg, elective surgery, during 
hospitalization, hyperosmolar states).  Rescue therapy with antihyperglycemic medications 
including insulins will be allowed in certain situations after randomization due to severe, 
persistent hyperglycemia (see Appendix 8).  In this case, GLP-1 receptor agonists and DPP-4 
inhibitors are not allowed as rescue therapies.  After early discontinuation of study treatment, any 
antihyperglycemic medications, except for GLP-1 receptor agonists may be allowed. If insulin is 
prescribed as a rescue therapy, it must be differentiated from short-term use of insulin therapy for 
medical emergencies when reported in the eCRF.  
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 OTC drugs) must be 
documented, and the name of the drug and the date(s) of administration must be recorded in the 
patient’s diary and on the “Concomitant Medications” section of the eCRF. 
All nonstudy medications will be recorded on the eCRF at all visits.
Nonstudy medications taken by patients who are screened, but not randomized, will not be 
reported to Lilly, unless an SAE occurs.
7.8.
Treatment after the End of the Study
7.8.1.
Treatment after Study Completion 
Tirzepatide will not be made available to patients after the conclusion of the study.

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7.8.2.
Special Treatment Considerations 
An additional therapeutic intervention should be considered for patients with persistent 
hyperglycemia, as described in Appendix 8.

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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 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:
o
ALT or aspartate aminotransferase (AST) >8X ULN
o
ALT or AST >5X ULN for more than 2 weeks
o
ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio (INR) >1.5
o
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)
o
alkaline phosphatase (ALP) >3X ULN
o
ALP >2.5X ULN and TBL >2X ULN
o
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:
o
If a patient is inadvertently enrolled and it is determined that continued treatment 
with investigational product would not be medically appropriate (see 
Section 8.1.3)
o
Acute or chronic pancreatitis 
o
If a patient is diagnosed with medullary thyroid cancer (MTC) after 
randomization
o
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
o
Any significant investigational product-related hypersensitivity reaction

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o
Any other TEAE, SAE, or clinically significant laboratory value for which the 
investigator believes that permanent investigational product discontinuation is the 
appropriate measure to be taken
o
If female patient becomes pregnant
o
If a patient is diagnosed with type 1 diabetes mellitus (T1DM)
o
Temporary discontinuation of concomitant OAM ≥14 days
Patients who stop the investigational product permanently may receive another 
antihyperglycemic medication, except for GLP-1 receptor agonists, and will continue 
participating in the trial, according to the protocol, to collect all planned safety and efficacy 
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 Events), and Section 9.4 (Safety) of this protocol.
8.1.2.
Temporary Interruption of Study Treatment 
Temporary discontinuation of concomitant antihyperglycemic medications <14 consecutive days 
is allowed for certain clinical situations (eg, severe dehydration, elective surgery, or need for 
radiologic exam involving intravenous [IV] iodinated contrast dye).In certain situations after 
randomization, the investigator may need to temporarily interrupt investigational product. Every 
effort should be made by the investigator to maintain patients on investigational product and to 
restart investigational product after any temporary interruption, as soon as it is safe to do so.  

If the number of consecutive doses missed is ≤2, the treatment can be restarted at the 
same dose, if the drug was well-tolerated prior to discontinuation. 

If the number of consecutive doses missed is ≥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 (See Manual of Operations for further 
details).
If investigational product 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 investigational 
product interruption is due to intolerable persistent GI AE (eg, nausea, vomiting, or diarrhea), the 
patients should be treated, as suggested in Section 7.4.1.1.  The data related to temporary 
interruption of study treatment will be 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 clinical research physician (CRP)/clinical 
research scientist (CRS) agree it is medically appropriate to continue, the investigator must 
obtain documented approval from the Sponsor CRP/CRS to allow the inadvertently enrolled 
patient to continue in the study with or without treatment with investigational product. Safety 

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follow up is as outlined in Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of the protocol.
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 investigational product

adherence to visit schedule

missing assessments

investigational product discontinuation due to AE (Section 8.1.1)

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

investigator decision
o
the investigator decides that the patient should be discontinued from the 
study

patient decision
o
the patient 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 investigational product and will 
have end-of-study procedures (early termination [ET] visit) performed as shown in the Schedule 
of Activities (Section 2).  During the ET visit, the patient will be prescribed an appropriate 
antihyperglycemic medication 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.

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Patients discontinuing from the study prematurely for any reason should complete AE 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 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.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1.
Efficacy Assessments
The following efficacy parameters at Week 52 will be assessed in this study  

Mean change in HbA1c

Proportion of patients who achieve HbA1c <7%, ≤6.5%, and <5.7%

Mean change in fasting serum glucose (FSG)

Mean change in daily average 7-point SMBG profiles

Mean change in body weight

Proportion of patients who achieve weight loss of ≥5%, ≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in Updated Homeostasis Model Assessment (HOMA-2)
9.1.1.1.
7-Point Self-Monitored Blood Glucose Profiles
Patients will be asked to perform a 7-point SMBG profile on 2 days during the 2 weeks before 
Visits 3 and 13 (refer to the Schedule of Activities in Section 2). Patients will test and record 
SMBG concentrations in their study diaries before each meal (breakfast, lunch, and dinner) and 
approximately 2 hours after the start of each meal, and at bedtime. The 7-point SMBG profiles 
will be entered into eCRF and analyzed.
9.1.2.
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.

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Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate healthcare option: 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patientto discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  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 eCRF the 
occurrence and nature 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. Investigators should 
record their assessment of the potential relatedness of each AE to study procedure,
investigational product via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to investigational product 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 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.
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.

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
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 AE should have additional data collected using the 
eCRF (Section 9.4.5.1).
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 patients once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient 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.
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(s) 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 in the study diary regarding episodes of hypoglycemia, starting 
from Visit 1 until the last study visit.  For that purpose, patients will be trained about signs and 
symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect appropriate 

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information for each episode of hypoglycemia in the study according to the Schedule of 
Activities (Section 2).  
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia: (the BG values in this section refer to 
values determined by a laboratory or International Federation of Clinical Chemistry and 
Laboratory Medicine blood-equivalent glucose meters and strips) in accordance with the 2017 
American Diabetes Association position statement on glycemic targets (American Diabetes 
Association 2017):
Glucose Alert Value (Level 1):

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 
BG 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 BG ≤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 BG ≤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 
BG 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 BG <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 BG <54 mg/dL 
(<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. Plasma 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.
Nocturnal hypoglycemia:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between 
bedtime and waking.
If a hypoglycemic event meets the criteria of severe, it should be recorded as serious on the AE 
eCRF and reported to Lilly as an SAE.

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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).  
9.2.2.2.
Severe, Persistent Hyperglycemia
Add-on glycemic rescue therapy will be allowed for patients who meet any of the following 
prespecified criteria for severe, persistent hyperglycemia.  In this case, the investigator 
determines if a new intervention is warranted, after noncompliance with the assigned therapeutic 
regimen is ruled out as the reason for hyperglycemia.  Patients should continue administering 
assigned investigational products.  The criteria are as follows: 
a) Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>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) Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>240 mg/dL (>13.3 mmol/L) over at least a consecutive 2-week period at any time 9-16 
weeks post-randomization; 
OR 
c) Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>200 mg/dL (>11.1 mmol/L) over a consecutive 2-week period at any time beyond the 
first 16 weeks post-randomization. 
OR 
d) HbA1c ≥8.5% (69 mmol/mol) 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%.  
Investigators should first confirm that the patient is fully compliant with the assigned therapeutic 
regimen and that he/she does not have an acute condition that is raising his/her BG.  For patients 
who meet criteria for severe persistent hyperglycemia, the investigator will decide, in 
consultation with the patient, on an appropriate antihyperglycemic medication (rescue therapy). 
Investigators should follow national standards of care for diabetes management in respective 
participating countries or the American Diabetes Association/European Association for the Study 
of Diabetes guidance (Inzucchi et al. 2015). Antihyperglycemic medications including insulins
will be allowed as the rescue intervention. In this case, GLP-1 receptor agonists and DPP-4 
inhibitors are not allowed as rescue therapies.  Patients who receive a new intervention should 
also continue administering investigational products for the remaining period in the trial.
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 

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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 ≥3X 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 tirzepatide, but will 
continue in the study on another antihyperglycemic medication.  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 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 investigational products.
Each patient will have measurements of pancreatic 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 lipase ≥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.
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
Clinical Events Classification (CEC) committee. 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. The adjudication committee representative will 
enter the results of adjudication in a corresponding eCRF page.

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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 postrandomization 
calcitonin value is ≥35 ng/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 ng/mL and increases by ≥50%, compared with 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 
washout period. If the confirmed calcitonin value is <35 ng/mL, tirzepatide should be restarted 
when it is safe to do so.
9.2.2.5.
Major Adverse Cardiovascular Events
Deaths and nonfatal cardiovascular (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 (MI); hospitalization for unstable angina; hospitalization for heart failure; 
coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention); and cerebrovascular events, including cerebrovascular accident (stroke) and 
transient ischemic attack. Relevant data from patients who experienced death or nonfatal CV 
AEs will be entered into a specifically designed eCRF page by study site. 
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 electrocardiogram (ECG)
which should be submitted to the central reading center. Additional diagnostic tests to determine 
the 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. 
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 
investigational product(s) via an eCRF created for this purpose.  Additional samples should also 
be collected, as outlined in Section 9.4.4.  Investigational product(s) should be temporarily 
interrupted in any individual suspected of having a severe or serious allergic reaction to
investigational product.  Investigational product may be restarted when/if it is safe to do so, in 
the opinion of the investigator.  If the investigational product is permanently discontinued, the 
patient will receive another antihyperglycemic medication, judged by the investigator to be 

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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 arm, samples will be collected for 
measurement of tirzepatide anti-drug antibodies (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 examination will be performed by an eye-care professional 
(ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 to exclude patients 
with proliferative retinopathy and/or maculopathy.  The results from this exam will be recorded 
on a specific retinopathy eCRF as a baseline measure of retinopathy.  
A follow-up, dilated fundoscopic examination should be performed, when clinically indicated by 
any AE 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 5.
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.  
For detailed information concerning the management of GI AEs, please refer to Section 7.4.1.1.
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 and chronic renal failure.  Gastrointestinal 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 
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 <250 mg/dL.  
If ketoacidosis is suspected, SGLT-2i’s should be discontinued (if used), patients should be 

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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 decreased renal function.  Routine bicarbonate 
assessment will be performed during the course of the study.  If lactic acidosis is suspected, 
metformin should temporarily be discontinued (if used) until the resolution of the event.
9.2.2.13. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as AEs.
9.2.2.14. Major Depressive Disorder/Suicidal Ideation 
The prevalence of depressive symptoms and disorders is increased in patients with T1DM or 
T2DM (American Diabetes Association 2017).  Any AE of major depressive disorder or suicidal 
ideation should be reported. 
9.2.2.15. Individual Clinical Events Adjudication

All AEs of acute or chronic pancreatitis, as well as cases of pancreatic hyperenzymemia 
only that undergo additional diagnostic follow-up and/or are accompanied by symptoms 
suggestive of pancreatitis will be adjudicated by an independent committee of expert 
physicians.  

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:  MI; 
hospitalization for unstable angina; hospitalization for heart failure; coronary 
interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention); and cerebrovascular events, including cerebrovascular accident (stroke) 
and transient ischemic attack.
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 or drug delivery system so that the 
situation can be assessed.
9.3.
Treatment of Overdose
Investigational product 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.

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9.4.
Safety
9.4.1.
Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2).  
Electrocardiograms should be recorded according to the study-specific recommendations 
included in the Manual of Operations for the study.  
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 
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, except for the screening ECG,
which will be performed locally.  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 (systolic blood pressure, diastolic blood pressure, and 
heart rate), height, weight, and waist circumference should be conducted according to the 
Schedule of Activities (Section 2) and following the study-specific recommendations included in 
the Manual of Operations for the study.
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 the 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.

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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 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 nonimmediate), additional samples 
will be collected (including ADAs, PK, and, exploratory immune safety samples), as close to the 
onset of the event as possible, at the resolution of the event, and 30 days following the onset of 
the event.  Instructions for the collection and handling of blood samples will be provided by the 
Sponsor.  The actual date and time (24-hour clock time) of each sampling will be recorded.  
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of the tirzepatide at a laboratory approved by the Sponsor.  Samples collected at Visit 801 will 
assess immunogenicity at washout of tirzepatide (5 half-lives post-end of treatment).
Treatment-emergent ADAs are defined in Section 10.3.5.  
Samples with tirzepatide ADAs 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.
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the Sponsor.  The duration 
allows the Sponsor to respond to future regulatory requests related to tirzepatide.  Any samples 
remaining after 15 years will be destroyed. 
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 5) 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.

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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
A PK sample will be collected at the same time points as the immunogenicity sample per the 
Study Schedule of Activities (Section 2).  All samples for PK assessment should be taken 
predose.  
The date and time of SC injection must be recorded on the eCRF from the study diaries.
The date and time at which each sample was drawn must be recorded on the laboratory 
requisition form. 
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry (LC/MS) method.
Bioanalytical samples collected to measure tirzepatide concentrations will be retained for a 
maximum of 1 year following last patient visit for the study.
9.6.
Pharmacodynamics
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section. 
Samples collected to measure PD will be identified by the patient number (coded) and retained at 
a facility selected by Lilly or its designee for a maximum of 15 years following last patient visit 
for the study at a facility selected by Lilly or its designee.
9.7.
Pharmacogenomics
9.7.1.
Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to tirzepatide and to 

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investigate genetic variants thought to play a role in T2DM.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards (IRBs) impose shorter time limits. This retention period 
enables use of new technologies, response to regulatory questions, and investigation of variable 
response that may not be observed until later in the development of tirzepatide or after 
tirzepatide becomes commercially available.
Molecular technologies are expected to improve during the 15-year storage period and, therefore,
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements.
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2), where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
investigational products, pathways associated with T2DM, mechanism of action of 
investigational products, and/or research method or in validating diagnostic tools or assay(s) 
related to T2DM.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of tirzepatide or after tirzepatide becomes commercially available.  Any 
samples remaining after 15 years will be destroyed.

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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 his/her 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 his/her fasting condition.
9.9.1.
European Quality of Life – 5 Dimension – 5 Level (EQ-5D-5L)
Generic HR-QoL will be assessed using the EQ-5D-5L (EuroQoL 2015).  The EQ-5D-5L is a 
standardized 5-item instrument for use as a measure of health outcome.  It provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of healthcare, 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 3125 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 2015). 
9.9.2.
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 his/her 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.

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10. Statistical Considerations
10.1. Sample Size Determination
Because the primary objective is to assess the safety of long-term treatment of tirzepatide and no 
formal hypothesis testing on the efficacy measures is planned, statistically derived power 
calculations were not considered for the determination of sample size.  The sample size of the 
study was based on the requirement of the Japanese guideline for oral hypoglycemic agents;
Guideline for Clinical Evaluation of Oral Hypoglycemic Agents (Pharmaceutical and Food 
Safety Bureau/Evaluation and Licensing Division Notification No. 0709-1. 2012).  The guideline 
requires long-term safety data of 1 year of treatment with combination therapy using other 
antihyperglycemic medications. At least 100 patients treated for 1 year in combination with an 
SU, and at least 50 patients in combination with each of the other agents (SUs, biguanides, TZD, 
a-GIs, glinides, or SGLT-2i’s) is required. By taking into account the overall drop-out rate of 
approximately 20%, 126 patients receiving combination treatment with an SU and 63 patients 
receiving combination treatment with other agents are planned to be randomized, resulting in a
total of 441 patients that are planned to be randomized.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Randomized
All patients who are randomly assigned a treatment arm
Modified intention-to-treat (mITT)
All randomly assigned participants who are exposed to at least 1 dose of 
investigational product
Efficacy analysis set (EAS)
Data obtained during Study Period II from mITT, excluding data after 
initiating rescue antihyperglycemic medication or stopping investigational 
product (last dose date + 7 days). In the event of a treatment error, 
participants will be analyzed according to the treatment to which they were 
randomized.
Safety analysis set (SAS)
Data obtained during both Study Period II and III from mITT, regardless of 
adherence to investigationalroduct or initiation of rescue antihyperglycemic 
medication.
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 
SAP or the clinical study report (CSR).  Additional exploratory data analyses may be conducted,
as deemed appropriate.

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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 efficacy measure is mean change in HbA1c from baseline to 52 week visit. The “efficacy” 
estimand represents efficacy prior to discontinuation of investigational product without 
confounding effects of rescue therapy for persistent severe hyperglycemia. 
The efficacy assessment, guided by the “treatment-regimen” estimand will be conducted as 
supplemental analyses. The “treatment-regimen” estimand represents the efficacy irrespective of 
adherence to investigational product or initiation of rescue antihyperglycemic medications, 
which will be conducted using mITT set. Because no formal hypothesis testing on the efficacy 
measures is planned, no multiplicity adjustments will be made for conducting 2 efficacy 
assessments.  Unless specified otherwise, safety assessments will be guided by an estimand 
comparing safety of tirzepatide doses, irrespective of adherence to investigational product or 
initiation of antihyperglycemic rescue medication.  Thus, safety analysis will be conducted using 
safety analysis set (SAS).  A selected safety analyses (eg, hypoglycemia) will be conducted after 
excluding data while on rescue therapy or data after starting another permitted antihyperglycemic 
medication following permanent discontinuation of investigational product.  Unless specified 
otherwise, summary statistics will be presented by treatment groups (3 different tirzepatide
doses) and overall within each of the combination therapies.
Summary statistics for continuous measures will include sample size, mean, standard deviation 
[SD], median, minimum, and maximum. Dose-response relationship will be assessed, if 
appropriate. 
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time for each treatment.
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. Summary statistics for discrete count measures 
will include sample size, mean, SD, median, minimum, and maximum. Dose response 
relationship will be assessed if appropriate.
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 screened, randomized, and receiving at least 
1 dose of investigational product will be presented by treatment groups.  A listing of randomized 
patients not receiving investigational product will be provided.  Of the patients in the mITT set, 
frequency counts and percentages of patients completing the study or prematurely discontinuing 
the study (including reason for premature discontinuation) will be presented by treatment groups.  

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A Kaplan-Meier analysis of time from randomization to premature discontinuation from study by 
treatment group will be provided.  Patients with important protocol deviations will be listed.
A detailed description of patient disposition will be provided at the end of the study. 
10.3.2.2. Patient Characteristics
Demographic, medical history, and preexisting conditions will be descriptively summarized by 
treatment groups, 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 particular, the time to initiation of rescue therapy for severe, persistent hyperglycemia will be 
analyzed as an exploratory safety endpoint.  Dose modifications of oral antihyperglycemic 
medications will also be described by treatment groups.
The frequencies and percentages of patients taking concomitant medications before and after 
allocation (Visit 3) will be summarized. Patient listings for the use of concomitant medications 
will be provided.
10.3.2.4. Treatment Compliance 
Treatment compliance, overall, is defined as taking at least 75% of the total required injections 
of investigational product.  Frequency counts and percentages of patients compliant to 
investigational product will be summarized by treatment groups and visits using the mITT set.
10.3.3.
Efficacy Analyses
The efficacy assessment, guided by the “efficacy” estimand, will use Efficacy Analysis Set 
(EAS) which consists of 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 an MMRM with the following terms: “treatment”, “visit”, and 
“treatment-by-visit interaction” as fixed effects; and “baseline HbA1c” as a covariate. An 
unstructured covariance structure will model the relationship of within-patient errors.
The following efficacy measures will be summarized through 52 weeks.

Mean change in HbA1c

Proportion of patients who achieve HbA1c <7%, ≤6.5%, and <5.7%

Mean change in FSG

Mean change in daily average 7-point SMBG profiles

Mean change in body weight

Proportion of patients who achieve weight loss of ≥5%, ≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in HOMA-2
The efficacy assessment for selected efficacy measures, guided by the “treatment regimen” 
estimand, will be based on the mITT population and data irrespective of adherence to 

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investigational product, initiation of rescue therapy and premature treatment discontinuation. 
Details will be provided in the SAP.
10.3.4.
Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of tirzepatide doses, irrespective of adherence to investigational product or initiation of rescue 
therapy. Thus, safety analysis will be conducted using the SAS.  A selected safety analyses
(eg, hypoglycemia) will be conducted after excluding data while on rescue therapy or data after 
starting another permitted antihyperglycemic medication following permanent discontinuation of 
investigational product.
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, SAEs, study 
discontinuation due to AEs, investigational product 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 along with 
assessment of dose-response relationship.  
10.3.4.1. Hypoglycemic Events
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia in each 
category (either total or nocturnal) will be summarized by each treatment which will be repeated 
excluding data following initiation of rescue antihyperglycemic medication.
10.3.4.2. Gastrointestinal Events
Summaries for incidence and severity of nausea, vomiting, and diarrhea will be provided by each 
treatment.  
10.3.4.3. Adjudicated Cardiovascular Events
Listing 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 investigational product, and time from randomization to 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 percentages of patients with treatment-emergent abnormal, high, or low laboratory measures 
at any time will be summarized.  A treatment-emergent abnormal value is defined as a change 
from normal value at baseline to an abnormal value at any time during the follow-up.  
A treatment-emergent high result is defined as a change from a value less than or equal to the 
high limit at baseline to a value greater than the high limit at any time during Periods II and III.  
A treatment-emergent low result is defined as a change from a value greater than or equal to the 

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low limit at baseline to a value less than the low limit at any time during Periods II and III.  
High limit and low limit will be provided in the SAP.
10.3.5. Evaluation of Immunogenicity 
The frequency and percentage of patients with preexisting ADAs, with treatment-emergent
ADAs, and with treatment-emergent neutralizing antibodies 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 ADAs) or those with a 4-fold (2 dilutions) increase in titer, compared to baseline, if 
ADAs were detected at baseline (treatment-boosted ADAs).  For the treatment-emergent ADA 
patients, the distribution of maximum titers will be described by tirzepatide dose. The frequency 
of neutralizing antibodies to tirzepatide and/or cross-reactive and neutralizing antibodies to 
endogenous counterparts will be tabulated in treatment-emergent ADA+ patients.
The relationship between the presence of antibodies and safety and efficacy to tirzepatide may be 
assessed.
10.3.6.
Other Analyses
10.3.6.1. 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.  
10.3.6.2. Subgroup Analyses 
Subgroup analyses of mean change in HbA1c, mean change in body weight, AEs, and 
hypoglycemic events will be provided by age, gender, baseline BMI group (<25 or ≥25 kg/m2), 
duration of diabetes, and baseline HbA1c (≤8.5%, ˃8.5%) for each of the combination therapies.  
Additional details will be provided in the SAP.
10.3.7.
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 
WHO consultation. Diabet Med. 1998;15(7):539-553.
American Diabetes Association. Glycemic Targets. Sec 6. In Standards of Medical Care in 
Diabetes—2017. Diabetes Care. 2017;40(Suppl 1): S48-S56. Available at: 
http://care.diabetesjournals.org/content/40/Supplement_1/S48. Accessed September 26, 2018.
Erratum in: Diabetes Care. 2017;40(7):985. 
Aroda VR, Ratner R. The safety and tolerability of GLP-1 receptor agonists in the treatment of 
type 2 diabetes : a review. Diabetes Metab Res Rev. 2011;27(6):528-542. 
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 
2007;132(6):2131-2157.
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379-2400.
Bradley C. The diabetes treatment satisfaction questionnaire: DTSQ. In: Bradley C, editor. 
Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes 
research and practice. Chur, Switzerland: Harwood Academic Publishers; 1994.
Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
comparing the rate of hypoglycemia – assessed using continuous glucose monitoring – in 125 
preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the 
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601. Erratum in: Pediatr Diabetes. 
2015;16(6):462.
EuroQoL Group. EQ-5D-5L User guide: basic information on how to use the EQ-5D-5L 
instrument. Version 2.1. Available at: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf. Published April 2015. Accessed October 17, 2018.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Millicevic Z, 
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor 
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active 
comparator-controlled phase 2 trial. Lancet.2018;392(10160):2180-2193.
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 
Association and the European Association for the Study of Diabetes. Diabetes Care.
2015;38(1):140-149.
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 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32.

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Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
acute pancreatitis and/or pancreatic cancer: Reassuring data from cardio-vascular outcome
trials. Diabetes Obes Metab. 2017;19(9): 1327-1328.
Neumiller JJ. Incretin-based therapies. Med Clin North Am. 2015;99(1):107-129.
Steinberg WM, Buse JB, Ghorbani ML, Ørsted DD, Nauck MA; LEADER Steering Committee;
LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 
diabetes treated with liraglutide: results from the LEADER Randomized Trial. Diabetes Care.
2017a;40(7):966-972.
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity 
and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from 
the SCALE clinical development program. Diabetes Care. 2017b; 40(7):839-848.
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibodies
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.
a-GI
alpha-glucosidase inhibitor
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CEC
Clinical Events Classification
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease-Epidemiology
COA
clinical outcome assessment
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.
CRF
case report form
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.
CRS
clinical research scientist
CSR
clinical study report
CT
computed tomography
CV
cardiovascular
DNA
deoxyribonucleic acid

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Term
Definition
DPP-4
dipeptidyl-peptidase-4
DTSQc
Diabetes Treatment Satisfaction Questionnaire change
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
EDC 
electronic data capture system 
eGFR
estimated glomerular filtration rate
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.
EQ-5D-5L
European Quality of Life – 5 Dimension – 5 Level Questionnaire
ERB
ethical review board
ET
early termination
FBG
fasting blood glucose
FSG
fasting serum glucose
FSH
follicle-stimulating hormone
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GIPR
gastric inhibitory polypeptide receptor
GLP-1
glucagon like peptide-1 
HbA1c
glycated hemoglobin
HOMA-2
Updated Homeostasis Model Assessment
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on 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.
INR
International Normalized Ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.

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Term
Definition
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
Institutional Review Board
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a 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.
IV
intravenous
IWRS
interactive web-response system
LC/MS
liquid chromatography/mass spectrometry
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia syndrome type 2
MI
myocardial infarction
mITT
modified intention-to-treat (population)
MMRM
mixed-model for repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid cancer
NAFLD
nonalcoholic fatty liver disease
OAM
oral antihyperglycemic medication
OTC
over the counter (medication)
PD
pharmacodynamics
PK
pharmacokinetics
PRO
patient-reported outcome
QW
once weekly administration
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SC
subcutaneous

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Term
Definition
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. 
SD
standard deviation
SGLT-2i
sodium-glucose cotransporter type 2 inhibitor
SMBG
self-monitored blood glucose
SU
sulfonylurea
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TZD
thiazolidinedione
ULN
upper limit of normal

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Appendix 2.
Protocol GPGP Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume (MCV)
Bicarbonate
Mean cell hemoglobin concentration (MCHC)
Total bilirubin
Leukocytes (WBC)
Direct bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT/SGPT)
Monocytes
Aspartate aminotransferase (AST/SGOT)
Eosinophils
Gamma-glutamyl transferase (GGT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatinine
Creatine kinase (creatine phosphokinase)d
Urinalysisa,b
Uric acid
Albumin
Calcium
Creatinine
Albumin
Lipid Panel (fasting)a
Total cholesterol
High-density lipoprotein-cholesterol (HDL-C)
Low-density lipoprotein-cholesterol (LDL-C)e
Nonpharmacogenetic Stored Samplesa
Very-low-density lipoprotein-cholesterol (VLDL-C)
Triglycerides
Serum
EDTA plasma
Pharmacogenetics Samplea
P800 plasma
Pregnancy test (females only)a,f
Follicle-stimulating hormone (FSH)g
Estradiolg
Immunogenicityj
HbA1ca
Anti-tirzepatide antibody 
Glucose, fastinga,h
Hepatitis Testinga,c
Pancreas (exocrine)a
Endocrinea
Pancreatic-amylase
Calcitonin
Lipase
Pharmacokineticsj
Tirzepatide plasma levels
C-peptidea
Insulin, fastingh
eGFR (calculated by CKD-EPI equation)i

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Clinical Laboratory Tests
Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; EDTA = ethylenediaminetetraacetic acid; 
eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; LDL = low-density lipoprotein; 
RBC = red blood cell; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvate 
transaminase; WBC = white blood cell.
a
All tests will be performed or sample stored by the Lilly-designated central laboratory.
b
Urinary albumin and creatinine are measured at a central laboratory and the ratio is calculated.
c
As needed per hepatic monitoring criteria (refer to Appendix 5).
d
Creatine kinase MB (CK-MB) is to be assayed if creatine kinase result >1000 IU/L.
e
LDL is calculated using the Friedwald equation.
f
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only and will be 
analyzed at a central laboratory.  Pregnancy tests may be repeated at any time during the study and analyzed 
locally at the investigator’s discretion.  Urine pregnancy tests will be performed by a local laboratory.
g
Follicle-stimulating hormone (FSH) test performed at Visit 1 for postmenopausal women at least 45 years of age 
with an intact uterus, not on hormone therapy, 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).
h
Fasting serum glucose and insulin values will be used to calculate beta-cell function and insulin sensitivity using
the Updated Homeostasis Model Assessment (HOMA-2).  Fasting serum glucose samples must be obtained after 
8 hours or more without eating, drinking (other than water) or performing any significant physical activity.
i
Estimated glomerular filtration rate will be calculated by the central laboratory at required visits and included in 
laboratory result reports.
j
Assayed by Lilly-designated laboratory.

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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/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that 
his/her 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/patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patients/patient’s legal representative’s willingness to 
continue his/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 
Conference on 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 

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
other relevant documents (eg, curricula vitae, advertisements)
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 
T2DM and clinical research experience in T2DM 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/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 to the best of his/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 their 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.

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
Sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the case report 
forms (CRFs), and study procedures.

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 evaluate CRF data and use standard computer edits to detect errors in 
data collection.

Conduct a quality review of the database.
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 the eCRF 
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 eCRF.
Additionally, clinical outcome assessment (COA) data (questionnaires, scales, self-reported diary 
data, rating scales, etc.) will be collected by the patient (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 system(s) will be stored at third party.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive 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.

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Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
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-JE-GPGP is described in the Letter of Agreement.

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Appendix 4.
Protocol GPGP Oral Antihyperglycemic 
Medication (OAM) Daily Dose
Eligible patients must have been taking monotherapy of sulfonylureas (SUs) (glibenclamide, 
gliclazide, glimepiride, biguanides, thiazolidinedione [TZD], alpha-glucosidase inhibitors [a-
GIs], glinides, or sodium-glucose cotransporter type 2 inhibitor [SGLT-2i’s]) monotherapy for at 
least 3 months before Visit 1 and must have been on the dose for at least 8 weeks before Visit 1 
and have an inadequate glycemic control.
OAM
Generic Name
Minimum Maintenance Dose 
(mg/day)
SUs
glibenclamide
1.25
gliclazide
40
glimepiride
1
Biguanides
buformin
100
metformin
750
a-GIs
acarbose
300
voglibose
0.6
miglitol
150
Glinides
nateglinide
270
mitiglinide
30
repaglinide
1.5
TZD
pioglitazone
15
SGLT-2i’s
ipragliflozin
50
dapagliflozin
5
luseogliflozin
2.5
tofogliflozin
20
canagliflozin
100
empagliflozin
10
Abbreviations; a-GIs = alpha-glucosidase inhibitors; SGLT-2i’s = sodium glucose transporter 2 inhibitors; SUs = 
sulfonylureas; TZD = thiazolidinedione.

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Appendix 5.
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, IgGc
Direct bilirubin
Hepatitis E antibody, IgMc
Alkaline phosphatase
ALT
Anti-nuclear antibody
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation tests may be performed depending on regulatory requirements and/or testing availability.
c
Hepatitis E virus testing in endemic areas only.

I 8 F-J E -G P G P( a) Cli ni c al Pr ot o c ol
P a g e 7 5
L Y 3 2 9 8 1 7 6
A p p e n di x 6.
W orl d H e alt h Or g a ni z ati o n Cl a s sifi c ati o n of 
Di a b et e s a n d Di a g n o sti c Crit eri a
 
 
 
 
 
 
 
 
 
C CI

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Appendix 7.
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 the preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of the preferred and usual lifestyle).  Note:  
periodic abstinence (eg, 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:

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 use 2 forms of effective contraception, where at least 1 form is highly 
effective 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 8.
Management of Patients with Severe, 
Persistent Hyperglycemia during the Treatment Period
Below are 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 the investigator 
in accordance with American Diabetes Association/European Association for the Study of 
Diabetes guidance (Inzucchi et al. 2015). Rescue treatment with antihyperglycemic medications,
including insulins, will be allowed. In this case, GLP-1 receptor agonists and DPP-4 inhibitors
are not allowed as rescue therapies.  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 based on the following criteria: 
1) The patient is fully compliant with the assigned therapeutic regimen
AND
2) has no acute condition that raises blood glucose
AND
a)
Blood glucose concentration measured by weekly 1-point self- monitored BG (SMBG)
before breakfast >270 mg/dL (>15.0 mmol/L) over at least a consecutive 2-week period 
any time during the first 8 weeks postrandomization; 
OR 
b)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>240 mg/dL (>13.3 mmol/L) over at least a consecutive 2-week period at any time 
9-16 weeks postrandomization; 
OR
c)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>200 mg/dL (>11.1 mmol/L) over at least a consecutive 2-week period at any time 
beyond the first 16 weeks postrandomization.
OR 
d)
Glycated hemoglobin (HbA1c) ≥8.5% (69 mmol/mol) 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%.

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Appendix 9.
Protocol Amendment I8F-JE-GPGP(a)
Summary A Phase 3, Long-Term Safety Study of 
Tirzepatide in Combination with Monotherapy of Oral 
Antihyperglycemic Medications in Patients with Type 
2 Diabetes Mellitus (SURPASS J-combo)
Overview
Protocol I8F-JE-GPGP A Phase 3, Long-Term Safety Study of Tirzepatide in Combination with 
Monotherapy of Oral Antihyperglycemic Medications in Patients with Type 2 Diabetes Mellitus 
(SURPASS J-combo) 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 as follows:

A change to section 3.2 to clarify the description of Phase 2 studies

A change to section 5.1 to correct the duration of short-term insulin use 

A change to section 7.4.1.1 to delete the description of the Manual of Operations

Changes to section 7.7 to add the description of prohibited comcomitant therapy

Changes to section 9.2.2.2 for consistency with Appendix 8

A change to section 9.9.1 to correct the number of health states used in EQ-5D-5L

Changes to section 10.3.1 and 10.3.4 for consistency with synopsis

Changes to Appendix 7 for consistency with inclusion criterion [6b]

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
3.2.
Background
…..
Serious AEs (SAEs) were balanced across the treatment groups, and none of the groups in the
either study reported severe hypoglycemia (Frias et al. 2018).
…..
5.1.
Overall Design
…..
Short-term insulin use for up to less than 14 days is allowed for certain clinical situations (eg, 
elective surgery, during hospitalization, hyperosmolar states).
…..
7.4.1.1.
Management of Patients with Gastrointestinal Symptoms
…..
The dose can be de-escalated only once.  After that, the patients will have to discontinue 
tirzepatide if intolerable GI AEs persist. Please see the Manual of Operations for more detailed 
instructions.
…..
7.7.
Concomitant Therapy
…..
Prohibited medications include following; any antihyperglycemic medications, except for 
concomitant OAMs.

Any antihyperglycemic medications, except for concomitant OAMs

Any medications that promote weight loss (eg, Sanorex® [mazindol])

Any chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, 
intra-ocular, intranasal, or inhaled preparations)
…..
9.2.2.2.
Severe, Persistent Hyperglycemia
…..
b)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>240 mg/dL (>13.3 mmol/L) over at least a consecutive 2-week period at any time 9-
16 8 to 16 weeks post-randomization; 
…..

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9.9.1.
European Quality of Life – 5 Demension – 5 Level (EQ-5D-5L)
…..
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 3125 3251 possible health states.
…..
10.3.1.
General Statistical Considerations
…..
A Sselected safety analyses (eg, hypoglycemia) will may be conducted after excluding data 
while on rescue therapy or data after starting another permitted antihyperglycemic medication 
following of data after the permanent discontinuation of investigational product.
…..
10.3.4.
Safety Analyses
…..
A Sselected safety analyses (eg, hypoglycemia) will be conducted after excluding data while on 
rescue therapy or data after starting another permitted antihyperglycemic medication following,
or data after the permanent discontinuation of investigational product.
…..
Appendix 7.
Classification of Contraceptive Methods
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 use 2 forms of effective contraception, where at least 1 form is highly 
effective either remain abstinent (if this is their preferred and usual lifestyle) or use condoms 
plus 1 additional highly effective (<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.

L e o  D o c u m e n t  I D  =  6 5 9 f a 3 d 1 - 7 a 8 f - 4 c 0 b - 8 7 d 7 - c a 1 4 4 2 e 7 0 4 c c
A p p r o v a l  D a t e  &  T i m e :  1 7 - J a n - 2 0 1 9  0 1 : 0 6 : 2 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
A p p r o v a l  D a t e  &  T i m e :  1 7 - J a n - 2 0 1 9  0 3 : 3 2 : 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
P P D
P P D