Conditions: Overweight Obesity Diabetes Mellitus, Type 2
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn more about how tirzepatide affects stomach emptying in overweight/very overweight participants. Participants include those without diabetes and those with type 2 diabetes.

The study will last about 13 weeks for each participant, including screening.

Detailed description:

Arms:
arm 1: Participants received 5mg tirzepatide on Day 1 and Day 8; 10 mg tirzepatide on Day 15, 22 and 29; 15 mg tirzepatide on Day 36 administered subcutaneously (SC) and 160 mg acetaminophen administered orally on Day -1, Day 2 and Day 37.

Interventions: intervention 1: Tirzepatide intervention 2: Acetaminophen
Intervention descriptions: intervention 1: Tirzepatide administered SC. intervention 2: Acetaminophen administered orally.

Protocol document:
Prot_000.pdf: 
Protocol (a): I8F-MC-GPHU 
 
The Impact of Tirzepatide on Gastric Emptying (GE) in Overweight/Obese Non-diabetic 
Subjects and in Overweight/Obese Subjects with Type 2 Diabetes Mellitus 
 NCT04407234 
Approval Date: 23-Jul-2020 


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1
L Y 3 2 9 8 1 7 6
Pr ot o c ol I 8 F-M C -G P H U ( a)
T h e I m p a ct of Tir z e p ati d e o n G a stri c E m pt y i n g ( G E) i n 
O v er w ei g ht/ O b e s e N o n -di a b eti c S u bj e ct s a n d i n 
O v er w ei g ht/ O b e s e S u bj e ct s wit h T y p e 2 Di a b et e s M ellit u s
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 pr ot o c ol 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 o t 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 Y3 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 Y3 2 9 8 1 7 6 )
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Cli ni c al P h ar m a c ol o g y Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 3 0 A pr 
2 0 2 0.
A m e n d m e nt ( a ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y
o n a p pr o v al d at e pr o vi d e d b el o w
A p pr o v al D at e: 2 3- J ul- 2 0 2 0 G M T


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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Table of Contents
The Impact of Tirzepatide on Gastric Emptying (GE) in 
Overweight/Obese Non-diabetic Subjects and in 
Overweight/Obese Subjects with Type 2 Diabetes Mellitus
Section
Page
Protocol I8F-MC-GPHU (a) The Impact of Tirzepatide on Gastric 
Emptying (GE) in Overweight/Obese Non-diabetic Subjects and in 
Overweight/Obese Subjects with Type 2 Diabetes Mellitus.................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................20
6.1.
Inclusion Criteria..........................................................................................................20
6.2.
Exclusion Criteria ........................................................................................................23
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................27
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................27
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................29
7.2.
Method of Treatment Assignment ................................................................................29
7.2.1.
Selection and Timing of Doses.............................................................................29
7.3.
Blinding .......................................................................................................................29


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
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7. 4.
D ose M o dificat i on ........................................................................................................2 9
7. 5.
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...............................................................2 9
7. 6.
Treat me nt C o m plia nce ................................................................................................. 2 9
7. 7.
C o nc o mita nt T hera p y ...................................................................................................2 9
7. 8.
Treat me nt after t he E n d of t he St u d y ............................................................................3 0
8.
Di sc o nti n uatio n Cri t eri a....................................................................................................3 1
8. 1.
Di sc o nti n uatio n f r o m St u d y Treat me nt .........................................................................3 1
8. 1. 1.
P er m a ne nt Disc o nt i n uati on fr o m St u d y Treat me nt ...............................................3 1
8. 1. 2.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d S u bjects ..............................................3 2
8. 2.
Di sc o nti n uatio n f r o m t he St u d y....................................................................................3 2
8. 3.
S u bjects L ost t o F oll o w - u p...........................................................................................3 2
9.
St u d y  Assess me nts a n d Pr oce d ures ...................................................................................3 3
9. 1.
Efficac y Assess me nts ...................................................................................................3 3
9. 2.
A d verse E ve nts ............................................................................................................3 3
9. 2. 1.
S eri o us A d verse E ve nts ........................................................................................3 4
9. 2. 1. 1.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..........................................3 5
9. 2. 2.
A d verse E ve nts of S pecial I nterest .......................................................................3 5
9. 2. 2. 1.
H y p o gl yce mia ................................................................................................3 5
9. 2. 2. 2.
Pa ncreat itis.....................................................................................................3 7
9. 2. 2. 3.
T h y r oid Mali g na ncies a n d C -Cell H y per plasia ................................................3 7
9. 2. 2. 4.
S u pra ve ntric ular Arr h yt h mias a n d Car diac C o n d ucti o n 
Di s or ders ........................................................................................................3 8
9. 2. 2. 5.
H y perse nsi tivi t y E ve nts..................................................................................3 8
9. 2. 2. 6.
I njecti on- Si te Reactio ns.................................................................................. 3 8
9. 2. 2. 7.
He pat o biliar y  Dis or ders..................................................................................3 9
9. 2. 2. 8.
Se vere Gastr oi ntesti nal A d verse E ve nts ..........................................................3 9
9. 2. 2. 9.
Ac ute Re nal E ve nts ........................................................................................3 9
9. 2. 3.
C o m plai nt Ha n dli n g .............................................................................................3 9
9. 3.
Treat me nt of O ver d ose ................................................................................................. 3 9
9. 4.
S af et y ...........................................................................................................................4 0
9. 4. 1.
La b orat or y  Tests..................................................................................................4 0
9. 4. 2.
Vi t al Sig ns........................................................................................................... 4 0
9. 4. 3.
B o d y  We i g ht a n d Waist Circ u mfere nce................................................................4 0
9. 4. 4.
Electr ocar di o gra ms ..............................................................................................4 0
9. 4. 6.
P h ysical E xa mi nat i ons .........................................................................................4 1
9. 4. 7. 
6- p oi nt Pl as ma Gl uc ose Pr ofile ............................................................................4 1
9. 4. 8.
Self -m o nit ori n g o f Pl as ma Gl uc ose ( S M P G) ........................................................4 1
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9.4.9.
Suicidal Ideation Assessment ...............................................................................42
9.4.10.
Safety Monitoring ................................................................................................42
9.4.10.1.
Hepatic Safety................................................................................................42
9.5.
Pharmacokinetics .........................................................................................................44
9.5.1.
Bioanalysis...........................................................................................................45
9.6.
Pharmacodynamics ......................................................................................................45
9.6.1.
Gastric Emptying .................................................................................................45
9.6.2.
Body Weight........................................................................................................45
9.6.3.
Immunogenicity Assessments ..............................................................................45
9.7.
Genetics .......................................................................................................................46
9.8.
Biomarkers...................................................................................................................47
9.9.
Appetite Analysis.........................................................................................................47
9.10. Health Economics ........................................................................................................47
10.
Statistical Considerations and Data Analysis.....................................................................48
10.1. Sample Size Determination ..........................................................................................48
10.2. Populations for Analyses..............................................................................................48
10.2.1.
Study Participant Disposition ...............................................................................48
10.2.2.
Study Participant Characteristics ..........................................................................48
10.3. Statistical Analyses ......................................................................................................48
10.3.1.
Safety Analyses....................................................................................................48
10.3.1.1.
Clinical Evaluation of Safety..........................................................................48
10.3.1.2.
Statistical Evaluation of Safety.......................................................................49
10.3.2.
Pharmacokinetic Analyses....................................................................................49
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................49
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................49
10.3.3.
Pharmacodynamic Analyses.................................................................................49
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................49
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................49
10.3.4.
Evaluation of Immunogenicity .............................................................................50
10.3.5.
Interim Analyses..................................................................................................50
11.
References ........................................................................................................................51
12.
Appendices .......................................................................................................................53


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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List of Tables
Table
Page
Table GPHU.1.
Objectives and Endpoints .......................................................................17
Table GPHU.2.
Treatments Administered........................................................................28


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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List of Figures
Figure
Page
Figure GPHU.1.
Illustration of study design for Protocol I8F-MC-GPHU.........................18


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................54
Appendix 2.
Clinical Laboratory Tests........................................................................58
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................59
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............62
Appendix 5.
Blood Sampling Summary......................................................................64
Appendix 6.
Pancreatic Monitoring ............................................................................65
Appendix 7.
Protocol Amendment I8F-MC-GPHU (a) Summary 
The Impact of Tirzepatide on Gastric Emptying (GE) in 
Overweight/Obese Non-diabetic Subjects and in 
Overweight/Obese Subjects with Type 2 Diabetes Mellitus ....................67


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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1. Protocol Synopsis
Title of Study:
The Impact of Tirzepatide on Gastric Emptying (GE) in Overweight/Obese Non-diabetic Subjects and in 
Overweight/Obese Subjects with Type 2 Diabetes Mellitus
Rationale: 
Tirzepatide (LY3298176) is a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 
(GLP-1) receptor agonist being developed as an adjunct to diet and exercise for chronic weight management in adult 
patients with or without type 2 diabetes mellitus (T2DM) who have an initial body mass index (BMI) of 30 kg/m2 or 
greater (obese) or 27 kg/m2 or greater (overweight).  The impact of tirzepatide on gastric emptying (GE) has been 
assessed in healthy subjects and in patients with T2DM using acetaminophen pharmacokinetics (PK) as a surrogate 
(Study I8F-MC-GPGA).  However, data on the GE effects of tirzepatide in overweight/obese non-diabetic subjects 
are presently lacking.
Study I8F-MC-GPHU (GPHU) will assess the effect of multiple doses of tirzepatide (5 to 15 mg/0.5 mL) on the PK 
of acetaminophen to determine the impact on gastric emptying (GE), and the pharmacodynamics (PD), safety and 
tolerability of tirzepatide in overweight/obese non-diabetic subjects and overweight/obese T2DM subjects when 
administered using a prefilled syringe (PFS).
Objectives/Endpoints:
Objectives
Endpoints
Primary
To assess the effect of tirzepatide on the PK profile of 
acetaminophen, a marker for GE
Acetaminophen area under the concentration versus 
time curve from time zero to time t, where t is the last 
time point with a measurable concentration 
(AUC0-tlast), time of maximum observed drug 
concentration (tmax), maximum observed drug 
concentration (Cmax)
Secondary
To evaluate tirzepatide PK and PD effects following
multiple doses of SC tirzepatide in overweight/obese 
non-diabetic subjects and overweight/obese T2DM 
subjects
To evaluate tirzepatide safety and tolerability following 
multiple doses of SC tirzepatide in overweight/obese 
non-diabetic subjects and overweight/obese T2DM 
subjects
Glycemic control (plasma glucose, HbA1c), and 
tirzepatide area under the concentration versus time 
curve from time zero to infinity (AUC0-∞), AUC0-tlast, 
tmax, Cmax
Adverse events and hypoglycemic events


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 9
L Y 3 2 9 8 1 7 6
S u m m ar y of St u d y Desi g n :
T his is a n o pe n -la bel, fi xe d se q ue nce st u d y i n o ver wei g ht/ o bese n o n-dia betic s u bjects a n d o ver wei g ht/ o bese T 2 D M 
s u bjects.
P ote ntial s u bjects will be scree ne d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys pri or t o Da y 1.  
S u bjects will be a d mitte d t o t he C R U o n Da y -3 a n d will esta blis h baseli ne meas ure me nts d uri n g t he Baseli ne 
Peri o d fr o m Da ys -3 t o -1. 
S u bjects will recei ve s u bc uta ne o us tirze pati de 5 m g o n Da ys 1 a n d 8; 1 0 m g o n Da ys 1 5, 2 2, a n d 2 9 ; a n d 1 5 m g o n 
Da y  3 6, a n d will recei ve or al aceta mi n o p he n o n Da ys -1, 2, a n d 3 7.  D oses will be a d mi nistere d at a p pr o xi matel y 
t he sa me ti me o n eac h d osi n g da y.
S u bjects ma y be per mitte d t o lea ve t he C R U o n Da y 4 of t he Treat me nt Peri o d f oll o wi n g c o m pleti o n of st u d y 
pr oce d ures.  A sec o n d i n patie nt peri o d will ta ke place fr o m Da ys 3 5 t o 3 9.  O ut patie nt visits will ta ke place o n 
Da ys 8 ( ± 1 da y ), 1 5 ( ± 1 da y), 2 2 ( ± 1 da y), 2 9 ( ± 1 da y), a n d 4 3 ( ± 2 da ys).
A fi nal f oll o w -u p visit will occ ur o n Da y 6 4 ± 1 da y (i . e., 2 8 da ys ± 1 da y after t he fi nal tirze p ati de d ose).
Safet y will be assesse d b y vital si g ns, E C Gs, 
, safet y la b orat or y tests, a n d t he 
rec or di n g of A Es.  P h ar mac o ki netic bl o o d sa m ples f or aceta mi n o p he n a n d tirze pati de will be c ollecte d.
Tre at me nt Ar ms a n d Pl a n ne d D ur ati o n f or a n I n di vi d u al S u bject :  
T he st u d y  d urati o n f or i n di vi d ual s u bjects, i ncl usi ve of scree ni n g is e x pecte d t o be a p pr o xi matel y 1 3 wee ks, di vi de d 
as f oll o ws:

Scree ni n g:  u p t o 2 8 da ys pri or t o Da y 1

Treat me nt Peri o d:  Da y 1 t o Da y 4 3 ( ± 2 da ys)

F oll o w -u p:  Da y  6 4 ( ± 1 da y) will be c o nsi dere d as t he fi nal f oll o w-u p visit
N u m ber of S u bjects:
A p pr o xi matel y 1 8 o ver wei g ht or o bese n o n -dia betic s u bjects a n d 1 8 o ver wei g ht or o bese T 2 D M s u bjects will be 
e nr olle d s o t hat a mi ni m u m of 1 2 s u bjects i n eac h gr o u p c o m pletes t he st u d y.  
St atistic al A n al ysis:
T he pri mar y para meters f or a nal ysis will be C m a x , A U C0- ∞, A U C 0-t last, a n d t ma x .
P har mac o ki netic para meters will be e val uate d t o esti mate t he i m pact of tirze pati de o n G E a n d o n t he P K of 
aceta mi n o p he n.  L o g-tra nsf or me d Cm a x a n d A U C will be e val uate d i n a li near mi xe d -effects m o del, wit h da y 
(- 1, 2, 3 7) as a fi xe d effect a n d s u bject as a ra n d o m effect.  T he differe nces i n C m a x a n d A U C bet wee n 
aceta mi n o p he n + tirze pati de ( Test; Da ys 2 a n d 3 7) a n d aceta mi n o p he n al o ne ( Refere nce; Da y -1) will be 
bac k -tra nsf or me d t o prese nt t he rati os of ge o metric least s q uares mea ns a n d t he c orres p o n di n g 9 0 % CI.  Ot her 
para meters ma y be a nal yze d i n t his wa y as nee de d.
T he t ma x will be a nal yze d usi n g a Wilc o x o n si g ne d ra n k test.  Esti mates of t he me dia n differe nce base d o n t he 
o bser ve d me dia ns a n d 9 0 % CIs fr o m t he Wilc o x o n test will be calc ulate d.
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Pla n ne d P K para meters will als o be s u m marize d wit h descri pti ve statistics.
P har mac o d y na mic para meters t hat will be assesse d i ncl u de b o d y wei g ht, a p petite Vis ual A nal o g Scale ( V A S ) sc ores 
a n d H b A 1c.  T he para meters will be liste d a n d s u m marize d usi n g sta n dar d descri pti ve statistics.  A d diti o nal a nal ysis 
will be perf or me d if warra nt e d u p o n re vie w of t he data.  
Safet y para meters t hat will be assesse d i ncl u de safet y la b orat or y para meters, vital si g ns, 
 
 T E A Es (i ncl u di n g T E A Es of s pecial i nterest), a n d S A Es.  T he para meters will be liste d a n d s u m marize d 
usi n g sta n dar d descri pti ve statistics.  A d diti o nal a nal ysis will be perf or me d if warra nte d u p o n re vie w of t he data.  
All A Es relate d t o st u d y or pr ot oc ol pr oce d ure will be liste d, a n d if t he fre q ue nc y of e ve nts all o ws, will be als o 
s u m marize d usi n g descri pti ve met h o d ol o g y.  H y p o gl yce mic e ve nts will be s u m marize d a n d liste d.
P h y sical e xa mi nati o ns a n d E C Gs will be perf or me d f or safet y m o nit ori n g p ur p oses a n d will n ot be prese nte d.  
If warra nte d, a d diti o nal a nal yses will be perf or me d u p o n re vie w of t he data.
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2. Schedule of Activities


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 2
L Y 3 2 9 8 1 7 6
St u d y Sc he d ule Pr ot oc ol I 8 F-M C -G P H U Scree ni n g a n d B aseli ne
Scree ni n g
B aseli ne
C o m me nts
Pr oce d ure
D- 2 8 t o - 4  
D- 3
D- 2  
D- 1
I nf or me d C o nse nt
X
A d missi o n t o C R U
X
E nr oll me nt will occ ur o n Da y -2 after cleari n g me dical assess me nt.
O ut patie nt visits t o C R U
X
Re vie w a n d c o nfir m i ncl usi o n / 
e xcl usi o n criteria
X
Me dical Hist or y
X
P h ysical E xa m / Me dical Assess me nt
X
X
F ull p h ysical e xa mi nati o n at scree ni n g. T hereafter, assess me nts perf or me d t o i ncl u de 
me dical re vie w a n d tar gete d e xa mi nati o n, as a p pr o priate.
Hei g ht , Wei g ht , a n d B MI
X
Refer t o Secti o n 9. 4. 3 o n h o w b o d y wei g ht s h o ul d be meas ure d . B o d y wei g ht at 
scree ni n g m ust be assesse d t o c o nf or m t o I ncl usi o n Criteri o n [ 2].
Waist Circ u mfere nce
X
X
Refer t o Secti o n 9. 4. 3 o n h o w waist circ u mfere nce s h o ul d be meas ure d.
Te m perat ure
X
Distri b uti o n of gl uc ose meters, test 
stri ps, a n d diaries / c o n d uct S M P G a n d 
h y p o gl yce mia trai ni n g
A n y ti me fr o m Da y -3 t o 
Da y - 1
A p plica ble t o T 2 D M s u bjects o nl y, wit h e xce pti o n of h o w t o rec o g nize t he si g ns a n d 
s y m pt o ms of h y p o gl yce mia w hic h is a p plica ble t o all s u bjects.
6 -p oi nt plas ma gl uc ose pr ofile
X
3 0 mi n utes pre -meals, 2 h o urs p ost meals. Meals = brea kfast, l u nc h a n d di n ner.
C- S S R S ( baseli ne / scree ni n g f or m) + 
S H S F + S H F F
X
T he S H F F is o nl y re q uire d o nl y if tri g gere d b y t he S H S F, per i nstr ucti o ns i n t he f or m.
P H Q - 9
X
Safet y 1 2 -lea d E C G 
X
X
Si n gle safet y E C G at site. S u bjects m ust be s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes 
bef ore E C G c ollecti o n a n d re mai n s u pi ne b ut a wa ke d uri n g E C G c ollecti o n.
S u pi ne Vital Si g ns 
X
X
A d diti o n al ti me p oi nts ma y be a d de d at t he i n vesti gat or’s cli nical j u d g me nt .
Cli nical La b orat or y Tests
X
X
See A p pe n di x 2 f or details. Baseli ne ma y be c ollecte d a n yti me fr o m D-3 t o D -1 as l o n g 
as res ults are re vie we d pri or t o first tirze pati de d osi n g o n D 1. Perf or me d b y a l ocal 
la b orat or y.
Meal
-0. 5
A meal will be pr o vi de d a n d s h o ul d be c o m plete d wit hi n 2 0 mi n utes. Aceta mi n o p he n 
d osi n g will occ ur wit hi n 1 5 mi n utes of meal c o m pleti o n. E xact ti me of sa m pli n g m ust 
be rec or de d.   Aceta mi n o p he n P K sa m pli n g ti mes are relati ve t o aceta mi n o p he n d osi n g 
( 0 h o urs).
Aceta mi n o p he n 1 g d ose
0
Aceta mi n o p he n P K sa m pli n g ( h o urs)
- 0. 2 5, 0. 5, 0. 7 5, 1, 
2, 3, 4, 6, 9, 1 2
Pre g na nc y Test
X
X
Fe male s u bjects o nl y.  See A p pe n di x 2 f or details.
Dr u g Scree n
X
A Es/ C o nc o mita nt Me dicati o ns
X  
X  
X  
X
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I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 3
L Y 3 2 9 8 1 7 6
St u d y Sc he d ule Pr ot oc ol I 8 F-M C -G P H U Tre at me nt a n d F oll o w -u p
Tre at me nt a n d F oll o w U p
C o m me nts
Pr oce d ure
D 1  
D 2  
D 3  
D 4  
D 8
± 1
D 1 5
± 1
D 2 2
± 1
D 2 9
± 1
D 3 5
D 3 6  
D 3 7  
D 3 8  
D 4 3
± 2
F U/
E D a
A d missi o n t o C R U
X
Disc har ge fr o m 
C R U
X
D 3 9
C R U sta y ma y be e xte n de d a t t he 
i n vesti gat or’s discreti o n.
O ut patie nt Visit
X  
X  
X  
X
X  
X
Pre g na nc y test
X
Me dical 
Assess me nt
P
P 
P 
P 
P
X
Wei g ht
a n d B MI
P
P 
P 
P 
P
X  
X
Refer t o Secti o n 9. 4. 3 o n h o w b o d y wei g ht 
s h o ul d be meas ure d.
Waist 
circ u mfere nce
X
X  
X
Refer t o Secti o n 9. 4. 3 o n h o w waist 
circ u mfere nce s h o ul d be meas ure d.
Te m perat ure
P
P 
P 
P 
P
X
Safet y 1 2 -lea d 
E C G ( h o urs)
P, 1 2
X  
X  
X 
P 
P 
P 
P
P, 1 2
X  
X  
X  
X
Refer t o scree ni n g a n d baseli ne c o m me nts.
S u pi ne Vital Si g ns 
( h o urs)
P, 1 2
X  
X  
X 
P 
P 
P 
P
P, 1 2
X  
X  
X  
X
A d diti o n al ti me p oi nts ma y be a d de d at 
t he i n vesti gat or’s cli nical j u d g me nt.
Cli nical La b orat or y 
Tests
P 
P
X  
X
Refer t o scree ni n g a n d baseli ne c o m me nts
Plas ma gl uc ose
X 
P 
P 
P 
P 
P
X  
X  
X
6 -p oi nt plas ma 
gl uc ose pr ofile
X
X
Refer t o scree ni n g a n d baseli ne c o m me nts.
S M P G
Perf or me d pre -brea kfast, pre -l u nc h a n d pre-di n ner a n d bef ore be dti me f or at least 3 da ys per wee k a n d 
w he ne ver s u bject e x perie nces h y p o gl yce mic s y m pt o ms . O n wee ks w here s u bjects are a d mitte d t o C R U,
S M P G s h o ul d be perf or me d at least 2 da ys per wee k (as 6 -p oi nt plas ma gl uc ose pr ofile will be perf or me d 
d uri n g i n patie nt visits).
A p plica ble t o T 2 D M s u bjects o nl y.  
Res ults s h o ul d be ca pt ure d i n t he s u bject
diaries.
A Es/ C o n me ds
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A p petite A nal ysis
b y Vis ual A nal o g 
Scale ( V A S)
P  
X  
X
P  
X  
X  
X
Refer t o Secti o n 9. 9 . T o be perf or me d 
pri or t o d osi n g a n d/ or brea kfast.
Meal
-0. 5
-0. 5
Refer t o scree ni n g a n d baseli ne c o m me nts.
Aceta mi n o p he n 1 g 
d ose
0
0
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I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 4
L Y 3 2 9 8 1 7 6
Tre at me nt a n d F oll o w U p
C o m me nts
Pr oce d ure
D 1  
D 2  
D 3  
D 4  
D 8
± 1
D 1 5
± 1
D 2 2
± 1
D 2 9
± 1
D 3 5
D 3 6  
D 3 7  
D 3 8  
D 4 3
± 2
F U/
E D a
Aceta mi n o p he n
P K sa m pli n g 
( h o urs)
2 4 
- 0. 2 5, 0. 5, 
0. 7 5, 1, 2, 3, 
4, 6, 9, 1 2
2 4, 3 6
- 0. 2 5, 0. 5, 
0. 7 5, 1, 2, 3, 
4, 6, 9, 1 2
2 4, 3 6
E xact ti me of sa m pli n g m ust be rec or de d.  
Aceta mi n o p he n P K sa m pli n g ti mes are 
relati ve t o aceta mi n o p he n d osi n g 
( 0 h o urs).  2 4 -hr aceta mi n o p he n P K o n 
D a y 1 m ust be ta ke n pri or t o tirze pati de 
d osi n g.
Tirze pati de d osi n g
X
X  
X  
X  
X  
X
D a ys 1 a n d 8 = 5 m g; D a ys 1 5, 2 2, a n d 
2 9 = 1 0 m g; Da y 3 6 = 1 5 m g. All 
tirze pati de d oses will be a d mi nistere d 
s u bc uta ne o usl y as detaile d i n Secti o n 7. 1 .
Tirze pati de P K 
Sa m pli n g ( h o urs )
P, 8, 
1 2
2 4, 3 6 
4 8 
7 2 
P 
P 
P 
P
P, 8, 
1 2
2 4, 3 6 
4 8  
X  
X 
E xact ti me of sa m pli n g m ust be rec or de d.
P K sa m pli n g ti mes are relati ve t o 
tirze pati de d osi n g.  
I m m u n o ge nicit y 
Sa m ples 
P
P
P
X
P har mac o ge netics
P
A b bre viati o ns:  C R U = cli nical researc h u nit; C- S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; E C G = electr ocar di o gra m; E D = earl y disc o nti n uati o n; 
P = pr e d ose; P H Q -9 = Patie nt Healt h Q uesti o n naire -9; P D = p har mac o d y na mics; P K = p har mac o ki netics ; S H F F = Self -Har m F oll o w -U p F or m; 
S H S F = Self -Har m S u p ple me ntar y F or m ; S M P G = self-m o nit ori n g of plas ma gl uc ose . 
N ote:  Site s h o ul d sc he d ule pr oce d ures per as a p pr o priate.  H o we ver, if m ulti ple pr oce d ures ta ke place at t he sa me ti me p oi nt, t he f oll o wi n g or der of t he 
pr oce d ure s h o ul d be use: E C G, vital si g ns, P K / P D sa m ples, gl uc ose sa m ples, i m m u n o ge nicit y, cli nical la b orat or y sa m ples a n d st ora ge sa m ples. U nless 
ot her wise s pecifie d, pre d ose sa m ples a n d pr oce d ure ma y be c ollecte d or perf or me d a n y ti me o n t he sa me da y pri or t o d osi n g. A 1 0 % ti me all o wa nce varia nce 
will be c o nsi dere d acce pta ble f or aceta mi n o p he n a n d tirze pati de P K sa m pli n g.
a Fi nal f oll o w -u p will occ ur o n Da y 6 4 ±
1 da y (i.e. 2 8 da ys ±
1 da y after fi nal tirze pati de d ose ). Earl y disc o nti n uati o n visit s h o ul d ta ke place wit hi n 1 4 da ys 
u p o n c o nfir mati o n of earl y disc o nti n uati o n. Tirze pati de P K a n d i m m u n o ge nicit y sa m ples nee d n ot be dra w n if t he s u bject disc o nti n ues pri or t o recei vi n g a 
d ose of tirze pati de.


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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LY3298176
3. Introduction
3.1.
Study Rationale
Tirzepatide (LY3298176) is a dual glucose-dependent insulinotropic peptide (GIP) and 
glucagon-like peptide 1 (GLP-1) receptor agonist being developed as an adjunct to diet and 
exercise for chronic weight management in adult patients with or without type 2 diabetes 
mellitus (T2DM) who have an initial body mass index (BMI) of 30 kg/m2 or greater (obese) or
27 kg/m2 or greater (overweight).  The impact of tirzepatide on gastric emptying (GE) has been 
assessed in healthy subjects and in patients with T2DM using acetaminophen pharmacokinetics 
(PK) as a surrogate (Study I8F-MC-GPGA).  However, data on the GE effects of tirzepatide in 
overweight/obese non-diabetic subjects are presently lacking.
Study I8F-MC-GPHU (GPHU) will assess the effect of multiple doses of tirzepatide (5 to 15 mg) 
on the PK of acetaminophen to determine the impact on gastric emptying, and the 
pharmacodynamics (PD), safety and tolerability of tirzepatide in overweight/obese non-diabetic
subjects and overweight/obese T2DM subjects when administered using a prefilled syringe 
(PFS).
3.2.
Background
The available preclinical and clinical data indicate that co-stimulation of GIP and GLP-1 
receptors may enhance insulin secretion, improve insulin sensitivity, and reduce body weight 
beyond the effect of selective GLP-1 receptor stimulation (Frias et al. 2018; Coskun et al. 2018).
Tirzepatide, a dual agonist of GIP and GLP-1, is a 39-amino acid synthetic peptide.  It is 
administered once weekly by subcutaneous (SC) injection.  Its structure is based on the GIP 
sequence and includes a C20 fatty di-acid moiety that prolongs the duration of action.  It has a 
chemical structure and pharmacologic profile that is distinct from the GLP-1 receptor agonists 
due to the addition of GIP, which is unique among the marketed incretin mimetics.
In a Phase I study (Coskun et al. 2018) that included single and multiple ascending dose (SAD, 
MAD) parts, tirzepatide has been administered as single SC doses up to 8 mg in healthy subjects.  
In the MAD part, higher doses up to 10 mg were attained in healthy subjects via dose escalation.  
Doses up to 15 mg were achieved in patients with T2DM via dose escalation.  In this study, 
gastrointestinal (GI) adverse events (AEs) (nausea, vomiting, diarrhea, abdominal distension) 
and decreased appetite were the most frequently reported events by both healthy subjects and 
also by patients with T2DM and were dose related.  Most AEs were mild in severity, a few were 
moderate, and none were reported as severe.  During the single ascending dose study, the high 
incidence of GI AEs, notably vomiting, were considered to be dose limiting at the 8-mg dose; 
therefore, the 5-mg dose was considered the maximum tolerated dose.  A dose-dependent 
increase in heart rate was detected for both healthy subjects and patients with T2DM who 
received tirzepatide, similar to what was observed with selective GLP-1 receptor agonists. 
Immunogenicity assessments in Phase I showed low treatment-emergent antidrug antibody 
(TE-ADA) rate in tirzepatide-treated subjects (2.6%).  Highest ADA titers in TE-ADA+ subjects 
ranged from 1:40 to 1:160 and showed no impact on tolerability or PK profile of tirzepatide.  A 


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 1 6
L Y 3 2 9 8 1 7 6
fe w s u bjects e x perie nce d tra nsie nt ele vati ons i n li pase a n d/ or a m ylase le vels, b ut t hese e pis o des 
were n ot ass ociate d wit h a n y  rele va nt o utc o mes.  O nce-wee kl y d oses of 1, 5, 1 0, a n d 1 5 m g wi t h 
titr atio n ha ve bee n f urt her i n vesti gate d i n a P hase 2 st u d y  ( Frias et al, 2 0 1 8).  A n a d diti onal d ose 
le vel of 1 2 m g a n d alter nate d ose escalat i on sc he mes were i n vest i gate d i n a 1 2-wee k P hase 2 
st u d y.  T he P hase 1 a n d 2 cli nical data ha ve n ot s h o w n A Es differe nt fr om t hat of a vaila ble G L P 
rece pt or a g o nists c urre ntl y mar kete d.
Base d o n t he pr o perties of tirze pat i de
 
t is e x pecte d t o be meta b olize d via pr ote ol ytic clea va ge of pe pti d e c o m p o ne nts a n d is 
n ot a ntici pate d t o be meta b o lize d b y a n y si n gle or ga n or b y a n y c yt o c hr o me P 4 5 0 e nz y mes 
c o ntri b uti n g si g nifica nt l y t o its meta b olis m.  He nce, t he ris k of dr u g-dr u g i nteracti o ns ( D DIs) 
t hat ma y be n ote d c o uld be lar gel y attri b ute d t o t he i nfl ue nce of tirze pat i de o n G E w hic h i n t ur n 
c o uld al ter t he a bs or ptio n of  c o m m onl y  c o-a d mi nistere d me dicat i ons a d mi nistere d via oral r o ute. 
I n healt h y s u bjects a n d patie nts wit h T 2 D M, c ha n ges i n t he mea n c o nce ntrati o n-ti me pr ofiles of 
aceta mi n o p he n s u g geste d a d ose- de pe n de nt dela y i n G E f o ll owi n g a si n gle d ose of tirze pat i de. 
T he dela y i n G E res ulte d i n a 5 0 % decrease i n C m a x a n d a p pr o xi mately a 1- h o ur dela y i n tm a x . 
T he o verall A U C was n ot affecte d.
T he dela y i n G E was greatest f o ll owi n g t he first d ose of 
tirze pati de (at d ose le vel ≥1. 5 m g) a n d a p peare d t o s h o w tac h y p h yla xis after re p eate d d osi n g.
F urt her details ca n be f o u n d i n t he I n vesti gat or’s Br oc h ure (I B).
T he i m pact of  tirze pati de o n G E dela y a n d tac h y p h yla xis after re peate d d osi n g was si milar 
bet wee n healt h y v o l unt eers a n d patie nts wit h T 2 D M (i ncl u di n g s ome w h o were o ver wei g ht)
base d o n P hase 1 st u d y . H o we ver, t he i m pact of  tirze pati de o n G E dela y i n n o n -dia bet ic s u bjects 
w h o are o bese/ o ver wei g ht ha s n ot bee n deter mi ne d. 
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
Ris ks of t irze pat i de ha ve bee n c o nsiste nt wit h ris ks ass ociate d wit h ot her G L P-1 rece pt or
a g o nists c urre ntl y mar kete d.  P ote ntial ris ks i nclu de, b ut are n ot li mite d t o, GI effects, ac ute 
pa ncreat itis ( ver y rare), i ncreases i n heart rate, a n d h yp o gl yce mic e ve nts ( G L P -1 rece pt or a g o nist 
class effect).
N o cli nicall y  sig nifica nt safety or t ol era bilit y c o ncer ns ha ve bee n ide ntifie d d uri n g cli nical 
i n vesti gati on of t irze pat i de u p t o t he si n gle d ose le vel of 5 m g or m ult i ple wee kl y d oses, w he n 
escalate d u p t o 1 5 m g.  Base d o n t his i nf or mati o n, t he 6 wee kl y d oses of 5 t o 1 5 m g/ 0. 5 m L 
tirze pati de ( 5/ 5/ 1 0/ 1 0/ 1 0/ 1 5 m g ) t o be a d mi nistere d in t his st u d y  are reas o na bl y a ntici pate d t o be 
t olera ble i n t his gr o u p of s u bjects.
Base d o n t he k n o w n p har mac o l og y  of tirze pati de, o ver wei g ht/ o bese n o n- dia bet ic s u bjects ma y 
be nefit fr o m wei g ht re d ucti o n .  I n a d diti on, t he refere nce s u bjects wit h T 2 D M are als o e x pecte d 
t o e x perie nce be nefits of t he st u d y treat me nts, i ncl u di n g i m pr o ve d gl yce mic c o ntr ol a n d re d uce d 
b o d y  wei g ht.  
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, seri o us a d verse e ve nts ( S A Es) 
a n d reas o na bl y a nt ici pate d A Es of  tir ze pat i de are t o be f o u n d i n t he I n vestigat or’s Br oc h ure I B .
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I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
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4. O bj e cti v e s a n d E n d p oi nt s
Ta ble G P H U . 1 s h o ws t he o bjecti ves a n d e n d p oi nts of t he st u d y.
T a bl e G P H U . 1.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
Pri m ar y
T o assess t he effect of tirze pati de o n t he P K 
pr ofile of aceta mi n o p he n, a mar ker f or G E
Aceta mi n o p he n area u n der t he c o nce ntrati o n 
vers us ti me c ur ve fr o m t i me zer o t o ti me t, 
w here t i s t he last ti me p oi nt wit h a 
meas ura ble c o nce ntrati o n (A U C 0-t last), ti me 
of  ma xi m u m o bser ve d dr u g c o nce ntratio n 
(tma x ), ma xi m u m o bser ve d dr u g c o nce ntrati o n 
( Cma x )
Sec o n d ar y
T o e val uate tirze pati de P K a n d P D effects
f oll owi n g m ult i ple d oses of S C tirze pati de in 
o ver wei g ht/ o bese n o n- dia bet ic s u bjects a n d 
o ver wei g ht/ o bese T 2 D M s u bjects
T o e val uate tirze pati de safety a n d t olera bilit y 
f oll owi n g m ult i ple d oses of S C ti rze pati de i n
o ver wei g ht/ o bese n o n- dia bet ic s u bjects a n d 
o ver wei g ht/ o bese T 2 D M s u bjects
Gl yce mic c o ntr ol ( plas ma gl uc ose , H b A 1c), 
a n d tirze pati de area u n der t he c o nce ntrati o n 
vers us ti me c ur ve fr o m t i me zer o t o i nfi nity 
(A U C 0- ∞) A U C 0 -tlast, tma x , Cma x
A d verse e ve nts a n d h y p o gl yce mic e ve nts
E x pl or at o r y
T o e val uate t he P D effects of tirze pat i de o n 
a p petite a n d wei g ht
B o d y  wei g ht, waist circ u mfere nce, a p petit e 
V A S sc ores
A b br e viati o ns:  A U C 0- ∞= area u n der t he dr u g c o nce ntrati o n-ti me c ur ve fr o m zer o t o i nfi nit y; 
C ma x = ma xi m u m o bser ve d dr u g c o nce ntrati o n; P K = p har mac o ki netics; S C = s u bc uta ne o us d ose; 
tma x = ti me t o ma xi m u m c o nce ntrati o n; V A S = Vis ual A nal o g Scale.
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I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
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5. St u d y  D e si g n
5. 1.
O v er all D e si g n
T his is a n o pe n -la bel, fi xe d se q ue nce st u d y i n o ver wei g ht/ o bese n o n- dia bet ic s u bjects a n d 
o ver wei g ht/ o bese T 2 D M s u bjects.
P ote nti al s u bjects will be scree ne d t o assess t heir eli gi bilit y t o e nter t he st u d y wit hi n 2 8 da ys 
pri or t o Da y  1.  S u bjects will be a d mitte d t o t he C R U o n Da y - 3 a n d will esta blis h baseli ne 
meas ure me nts d uri n g t he Baseli ne Peri o d fr o m Da ys -3 t o - 1.
S u bjects m a y be per mitt e d t o lea ve t he C R U o n Da y 4 of t he Treat me nt Perio d f ol l owi n g 
c o mplet i on of st u d y  pr oce d ures.  A sec o n d i n patient  perio d will ta ke pl ace fr o m Da y s 3 5 t o 3 9 .  
O ut pati e nt visits will ta ke place o n Da ys 8 ( ± 1 da y), 1 5 ( ± 1 da y), 2 2 ( ± 1 da y), 2 9 ( ± 1 d a y ), a n d 
4 3 ( ± 2 da ys).
A fi nal f oll ow- u p visi t will occ ur o n Da y 6 4 ± 1 da y (i.e. 2 8 da ys ± 1 da y  aft er t he fi nal 
tirze pati de d ose).
St u d y  g over na nce c o nsi derati o ns are descri be d i n detail i n A p pe n di x 3 .
Fi g ure G P H U .1 ill ustrates t he st u d y desi g n.
A b bre viat i ons:   G E = gastric e m pt yi n g; P K = p har mac o ki net ics.
Fi g ur e G P H U . 1.
Ill u str ati o n of st u d y d e si g n f or Pr ot o c ol I 8 F-M C -G P H U .
S af et y will be assesse d b y vital si g ns, E C G s, 
, safety la b orat or y 
tests, a n d t he rec or di n g of A Es acc or di n g t o t he sc he d ule of acti vities ( Secti o n 2 ).
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LY3298176
The PK blood samples for acetaminophen and tirzepatide will be collected according to the 
schedule of activities (Section 2).
5.2.
Number of Participants
Approximately 18 overweight or obese non-diabetic subjects and 18 overweight or obese T2DM
subjects will be enrolled so that a minimum of 12 subjects in each group completes the study. 
For purposes of this study, a patient completes the study when all scheduled procedures shown in 
the Schedule of Activities have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject/patient.
5.4.
Scientific Rationale for Study Design
This study will be open-label as the study primary endpoint PK measures are objective rather 
than subjective.  This study is designed to assess the effect of multiple doses of tirzepatide (5 to 
15 mg/0.5 mL) on gastric emptying and the PD, safety and tolerability of tirzepatide in both 
overweight/obese nondiabetic subjects and overweight/obese T2DM subjects.  Acetaminophen is 
selected as the study probe drug as it is a well-established marker for the rate and extent of 
gastric emptying (Young 2005).  A delay in gastric emptying is reflected in the alterations to the 
concentration-time profile of acetaminophen
The dose justification for tirzepatide is provided in Section 5.5 (Justification of Dose).
The rationale for the sample size is provided in Section 10.1 (Sample Size Determination).
5.5.
Justification for Dose
The tirzepatide doses of 5 to 15 mg administered SC QW have been selected based on current 
preclinical pharmacology, toxicology, and clinical data; 15 mg SC QW is the highest 
maintenance dose planned for evaluation in the Phase 3 programs.
Tirzepatide dosing will start at a low dose of 5 mg followed by 5-mg, 10-mg, 10-mg, 10-mg 
every week to finally achieve the target dose of 15-mg.  The stepwise increments are expected to
permit adequate time for development of tolerance to GI events and are expected to minimize GI 
tolerability concerns. As shown in previous studies, the delay in GE is greatest following the 
first tirzepatide dose and appeared to show tachyphylaxis, and hence, the acetaminophen tests are 
planned after first dose (5 mg on Day 1) and after the first maximum dose (15 mg on Day 36) of 
tirzepatide.  The highest dose of 15 mg tirzepatide is predicted to maintain 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, respectively.  Additional information can be found in the IB.


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6. Study Population
Eligibility of subjects for the study will be largely based on the results of medical history, 
physical examination, vital signs, clinical laboratory tests and 12-lead electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to Day 1.  If the investigator decides not to administer 
the dose to a subject or not to enroll a subject on a particular day, the subject’s visit may be 
rescheduled, and any assessments or procedures performed up to that point may be repeated to 
confirm their eligibility.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
Subject Characteristics
[1]
Are overweight or obese (body mass index [BMI] of 27 kg/m2 to 45 kg/m2, 
inclusive)
[1a] nondiabetic male or female subjects, as determined by medical history,
physical examination, and safety laboratory assessments at screening
[1b] diabetic male or female subjects as determined by medical history

Have a diagnosis of T2DM for at least 1 year

Have T2DM controlled with diet and exercise alone or are on a stable 
dose of metformin for at least 3 months

Have a hemoglobin A1c value at screening of ≥7.0% and ≤10.0 %

Have a self-reported change in body weight of not more than ±5 kg 
within 3 months prior to screening
[2]
Have safety laboratory test results within normal reference range or with 
abnormalities deemed clinically insignificant by the investigator
[3]
Have venous access sufficient to allow for blood sampling as per the protocol
[4]
Male or female subjects between the ages of 18 to 65 years, inclusive;
[4a] Male subjects:


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
men, regardless of their fertility status, with nonpregnant woman of 
childbearing potential (WOCBP) partners must agree to either remain 
abstinent (if this is their preferred and usual lifestyle) or use condoms 
plus 1 additional highly effective (less than 1% failure rate) method of 
contraception (such as combination oral contraceptives, implanted 
contraceptives, or intrauterine device) or effective method of 
contraception, (such as diaphragms with spermicide or cervical sponge) 
for the duration of the study and for 5 half-lives of study drug plus 
90 days, corresponding to 4 months after the last injection .  
o
men and their partners may choose to use a double-barrier method 
of contraception.  (Barrier protection methods without concomitant 
use of a spermicide are not an effective or acceptable method of 
contraception.  Thus, each barrier method must include use of a 
spermicide.  It should be noted however that the use of male and 
female condoms as a double-barrier method is not considered 
acceptable due to the high failure rate when these barrier methods 
are combined.)
o
periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the 
duration of a study, and withdrawal are not acceptable methods of 
contraception.

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 WOCBP, which corresponds to 4 months following last 
injection.  

men must agree to refrain from sperm donation for the duration of the 
study and until their plasma concentrations are below the level that could 
result in a relevant potential exposure to a possible fetus, predicted to be 
4 months following last injection.

men who are in exclusively same-sex relationships (as their preferred 
and usual lifestyle) are not required to use contraception.
[4b] Female subjects:

women of childbearing potential (WOCBP) who are abstinent (if this is 
complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must 
agree to either remain abstinent or stay in a same-sex relationship 
without sexual relationships with males.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence just for the duration of a study, and withdrawal 
are not acceptable methods of contraception.


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
otherwise, WOCBP participating must agree to use effective 
contraception, where at least 1 form is highly effective (less than 1% 
failure rate), for the entirety of the study.  Contraception must continue 
following completion of IP administration for 30 days.
o
women of childbearing potential participating must test negative 
for pregnancy prior to initiation of treatment as indicated by a 
negative serum pregnancy test at the screening visit followed by a 
negative urine pregnancy test within 24 hours prior to exposure 
o
two forms of effective contraception, where at least 1 form is 
highly effective (less than 1% failure rate, such as combination 
oral contraceptives, implanted contraceptives or intrauterine 
devices) will be used.  Effective contraception (such as male or 
female condoms with spermicide, diaphragms with spermicide or 
cervical sponges) may be used as the second therapy.  Barrier 
protection methods without concomitant use of a spermicide are 
not an effective or acceptable method.  Thus, each barrier method 
must include use of a spermicide (that is, condom with spermicide, 
diaphragm with spermicide, female condom with spermicide).  It 
should be noted that the use of male and female condoms as a 
double barrier method is not considered acceptable due to the high 
failure rate when these methods are combined.
o
Must not be breastfeeding

women who are not of childbearing potential may participate and 
include those who are:
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis, or
o
postmenopausal – defined as either
i.
a woman at least 40 years of age with an intact uterus, not 
on hormone therapy, who has cessation of menses for at 
least 1 year without an alternative medical cause, AND a 
follicle-stimulating hormone (FSH) >40 mIU/mL; women 
in this category must test negative in pregnancy test prior to 
study entry
ii.
a woman 55 years or older not on hormone therapy, who 
has had at least 12 months of spontaneous amenorrhea; or
iii.
a woman 55 years or older with a diagnosis of menopause 
prior to starting hormone replacement therapy.


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Informed Consent
[5]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[6]
Are willing and able to participate in the dietary intervention part of the study, 
in the opinion of the investigator
[7]
Have given written informed consent approved by Eli Lilly and Company 
(Lilly) and the institutional review board (IRB) governing the site
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions – General
[8]
Have a history or current CV (for example, acute myocardial infarction, 
congestive heart failure, unstable angina, uncontrolled hypertension [systolic 
blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg], 
cerebrovascular accident [including transient ischemic attack], venous 
thromboembolis, etc), respiratory, hepatic, renal, GI, endocrine, hematological 
(including history of thrombocytopenia), or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; or
constituting a risk when taking the IP; or may interfere with the interpretation 
of data
[9]
Have obesity induced by other endocrinologic disorders (for example, 
Cushing Syndrome) or diagnosed monogenetic or syndromic forms of obesity 
(for example, Melanocortin 4 Receptor deficiency or Prader Willi Syndrome)
[10] Have acute or chronic pancreatitis or a history of acute idiopathic pancreatitis; 
or have other GI disorders (for example, relevant esophageal reflux or gall 
bladder disease) that could be aggravated by GLP-1 analogs; subjects who had 
cholecystolithiasis (gall stones) and/or cholecystectomy (removal of gall 
bladder) in the past, with no long-term complications, are eligible for 
participation
[11] Have a known clinically significant gastric emptying abnormality (e.g., gastric 
outlet obstruction), have undergone weight loss surgery such as gastric bypass 
(bariatric) surgery or restrictive bariatric surgery (e.g., Lap-Band®), or have 
endoscopic and/or device-based therapy for obesity or have had device 
removal within the last 6 months (for example, mucosal ablation, gastric 
artery embolization, intragastric balloon and duodenal-jejunal bypass sleeve)
[12] Have a personal or family history of medullary thyroid carcinoma (MTC), 
have multiple endocrine neoplasia syndrome type 2 (MEN 2), or calcitonin 
≥20 pg/mL at screening


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[13] Have confirmed type 1 diabetes mellitus, or a history of ketoacidosis, or 
hyperosmolar state/coma
[14] Have findings in the 12-lead ECG at screening that, in the opinion of the 
investigator, may increase the risks of potentially clinically relevant 
worsening associated with participation in the study
[15] Have an active or untreated malignancy or have been 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 <5 years 
prior to screening
[16] Have evidence of human immunodeficiency virus (HIV) and/or positive HIV 
antibodies at screening
[17] Have evidence of hepatitis B or positive hepatitis B surface antigen and/or 
evidence of hepatitis C virus (HCV) or hepatitis C antibody with confirmed 
presence of hepatitis C virus ribonucleic acid (RNA) at screening (a positive 
HCV antibody at screening will need an additional HCV RNA 
assay – detectable HCV RNA means a subject will meet exclusion criteria)  

Subjects with a previous diagnosis of HCV who have been treated with 
antiviral therapy and achieved a sustained virological response may be 
eligible for inclusion in the study, provided they have no detectable HCV 
RNA on the screening HCV polymerase chain reaction test.  A sustained 
virological response is defined as an undetectable HCV RNA level 24 
weeks after completion of a full, documented course of an approved 
antiviral therapy for HCV.

Subjects who have spontaneously cleared HCV infection, defined as (1):  a 
positive HCV antibody test and (2):  a negative HCV RNA test, with no 
history of anti-HCV treatment, may be eligible for inclusion in the study, 
provided they have no detectable HCV RNA on screening for this study.
[18] Have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2.0 × the upper limit of normal (ULN) or total bilirubin (TBL) 
>1.5 × ULN; (except for subjects with Gilbert’s syndrome, which can be 
enrolled with TBL <2.0× ULN), or alkaline phosphatase (ALP) >1.5× ULN;

subjects with nonalcoholic fatty liver disease are allowed to participate
[19] Have had a blood donation of 450 mL or more in the last 3 months or any 
blood donation within the last month prior to screening
[20] Have a history of drug or alcohol abuse or a positive drug screen (unless the 
positive testing is due to a drug prescribed to the subject by a health care 
professional); and/or smoke >10 cigarettes per day or the equivalent; or are 
unable or unwilling to refrain from nicotine use during CRU admission


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[21] Have had a blood transfusion or severe blood loss within the last 3 months or 
have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have 
a hemoglobin value <11 g/dL (males) or <10 g/dL (females), or any other 
condition known to interfere with hemoglobin A1c measurement
[22] Have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females) (1 unit = 12 oz or 360 mL of beer; 5 oz or 
150 mL of wine; 1.5 oz or 45 mL of distilled spirits), or are unwilling to stop 
alcohol consumption from admission to the CRU and until discharge from the 
study or completion of all study procedures
[23] Have a history of atopy or clinically significant multiple or severe drug 
allergies, or severe posttreatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear immunoglobulin A dermatosis, 
toxic epidermal necrolysis, or exfoliative dermatitis)
[24] Impaired renal estimated glomerular filtration rate <60 mL/min/1.73 m2
calculated by Chronic Kidney Disease-Epidemiology.  One retest may be 
performed in case of an initial borderline result <60 mL/min/1.73 m2.  The 
highest value from the 2 tests will be accepted
Prior/Concomitant Therapy – General
[25] Have been treated with prescription drugs that promote weight loss (e.g., 
sibutramine, mazindol, phentermine, naltrexone/bupropion, liraglutide) or 
similar other BW loss medications, including over-the-counter medications 
(e.g., Alli®) within 6 months prior to screening or between screening and 
enrollment
[26] Have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-articular, and inhaled preparations) within 
1 month before screening, or between screening and enrollment
[27] Have been treated with:
[27a] Non-diabetic subjects: any glucose-lowering agent during the last 
3 months prior to screening or between screening and enrollment
[27b] T2DM subjects: have taken any glucose-lowering medications other 
than metformin any time during the last 3 months before screening or during 
the screening/lead-in period; short-term use of insulin (<14 days) for treatment 
of acute conditions is allowed in the 3-month period prior to entry and after 
enrollment
[28] Have received treatment with a drug that has not received regulatory approval 
for any indication within 30 days or 5 half-lives (whichever is longer) of 
screening
Prior/Concurrent Clinical Trial Experience
[29] Are persons who have previously completed or withdrawn from this study


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[30] Have previous exposure or known allergies to tirzepatide or related 
compounds
[31] Are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study.
Exclusions Applicable Only to T2DM Subjects
[32] Have had more than 1 episode of severe hypoglycemia, as defined by the 
American Diabetes Association criteria, within 6 months before screening or 
has a history of hypoglycemia unawareness or poor recognition of 
hypoglycemic symptoms; any patient that cannot communicate an 
understanding of hypoglycemic symptoms and the appropriate treatment of 
hypoglycemia prior to the first dose of study drug should also be excluded
[33] Have a history of proliferative retinopathy or maculopathy as determined by 
the investigator based on a recent (<6 months) ophthalmologic examination
Other Exclusions
[34] Have any lifetime history of a suicide attempt
[35] Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at 
screening
[36] On the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening:

a “yes” answer to either Question 4 (Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan) or

a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan 
and Intent) on the “Suicidal Ideation” portion of the C-SSRS, or

a “yes” answer to any of the suicide-related behaviors (Actual Attempt, 
Interrupted Attempt, Aborted Attempt, Preparatory Act or Behavior) on 
the "Suicidal Behavior" portion of the C-SSRS, and

the ideation or behavior occurred within the past month
[37] Are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted;
[38] Are Eli Lilly and Company employees;
[39] Are deemed unsuitable by the investigator for any other reason.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.


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6.3.1. Meals and Dietary Restrictions
Subjects will be required to fast overnight for at least 8 hours before tirzepatide and when 
undergoing specific procedures, and also when clinical laboratory test samples are taken (see 
Schedule of Activities [Section 2]). A meal will be offered to study subjects after about 2 hours 
post tirzepatide dose.  On the day of gastric emptying evaluation, a meal will be given about half 
an hour before the scheduled acetaminophen dose in order to assess gastric emptying (see 
Schedule of Activities [Section 2]).  The macronutrient composition (i.e. number of grams of 
carbohydrate, fat and protein) of this meal for each subject should be consistent on all gastric 
emptying procedure days and the amount consumed must be recorded in the subject’s CRF.  For 
T2DM patients, the morning dose of metformin may be taken together with this meal if 
applicable.  During inpatient stays, subjects may not consume any food other than that provided 
by the CRU, although water may be consumed freely.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol and nicotine use will be permitted while the subject is resident in the CRU. While 
not resident in the CRU, subjects must consume no more than 10 cigarettes or the equivalent per 
day and alcohol consumption should be limited to approximately 3 units daily for males and 
2 units daily for females, as defined in Exclusion Criteria [22].
Subjects will be allowed to maintain their regular caffeine consumption throughout the study 
period (except during specific fasting time periods).
6.3.3. Activity
No strenuous physical activity will be allowed for 48 hours prior to tirzepatide dosing on Day 1 
until completion of all study procedures.
6.4. Screen Failures
Screening tests such as clinical laboratory tests and vital signs/ECGs may be repeated at the 
discretion of the investigator.  Individuals who do not meet the criteria for participation in this 
study (screen failure) may not be re-screened.  Subject numbers/enrollment numbers are assigned 
on Day -2 of the Baseline Period to ensure only eligible subjects enter the study.
LY3298176


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7. Treatment
7.1.
Treatment Administered
Subjects will receive tirzepatide SC QW alone for 6 weeks on Days 1, 8, 15, 22, 29, and 36, and 
will receive oral acetaminophen on Days -1, 2, and 37.  Acetaminophen may be administered 
with water and dosing cups or syringes should be flushed with water to ensure the complete dose 
is delivered.
Table GPHU.2 shows the treatments administered.
Table GPHU.2.
Treatments Administered
Treatment Name
Tirzepatide
Acetaminophen
Dosage 
Formulation
Prefilled syringe
Liquid
Dosage strength
and volume
5 mg / 0.5 ml; 10 mg/0.5 ml; 15 mg/0.5 ml
160 mg/5 mL
Route of 
Administration
SC
Oral
Dosing 
instructions
SC QW into abdominal quadrant
Single dose of 31.3 mL to be taken orally
Abbreviations:  QW = once weekly; SC = subcutaneous.
The investigator or designee is responsible for:

explaining the correct use of the investigational product (IP) to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
Site staff will administer all injections.  Detailed instructions for will be provided by the sponsor. 
All injections will be administered into the SC tissue of the abdominal wall, with injection sites 
alternated weekly between 4 sites, that is, right and left upper quadrants and right and left lower 
quadrants. Only a limited number of individuals will perform SC administration for consistency
reasons. Dosing will ideally occur at approximately the same time of day in all dose 
cohorts. The actual time of dosing will be recorded in the patient’s electronic case report form 
(eCRF).


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7.1.1. Packaging and Labeling
Tirzepatide will be supplied by Lilly.  Tirzepatide will be provided as prefilled syringes
containing 0.5 mL solution and provided in individual cartons to be dispensed.  
The IP will be labeled according to the country’s regulatory requirements.
Commercially available liquid acetaminophen will be site sourced.
7.2.
Method of Treatment Assignment
All subjects will receive the same treatment
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same time on each dosing day.  The actual 
time of all dose administrations will be recorded in the subject’s eCRF.
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
Dose modification is not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by Sponsor, during transit for all IP received and any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply or administer IP. All IP should be stored in an environmentally controlled 
and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
Tirzepatide and acetaminophen will be administered at the study site and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided.  If the need for concomitant medication 
arises (for example, to treat an AE), inclusion or continuation of the subject may be at the 
discretion of the investigator, preferably after consultation with a Lilly Clinical Pharmacologist 
(CP) or CRP or designee.  Any medication used during the course of the study must be 
documented.


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All subjects on stable concomitant medication at the time of study entry, other than those that are 
prohibited, should continue their regular, unchanged dose throughout the study.  
Subjects with T2DM may be on a stable dose of metformin at screening should continue to 
receive metformin for the duration of the study.  In addition, T2DM subjects may have received 
or be permitted to receive short-term (<14 days) insulin within 3 months prior to study entry 
and/or after enrollment.
The tirzepatide dose escalation schemes have been designed to reduce the development of 
intolerable GI symptoms.  During the dose escalation period, every effort should be made by the 
investigator to be able to escalate and maintain subjects on the tirzepatide dosage.
To mitigate GI symptoms and manage subjects with poorly tolerated GI AEs, the investigator 
should:

Advise subjects to eat smaller meals, for example, splitting 3 daily meals into 4 or more 
smaller meals, and to stop eating when they feel full.

Prescribe symptomatic medication (for example, approved anti-emetic or anti-diarrheal 
medication)
7.8.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the treatment or study prematurely for any reason should complete 
adverse event and other follow-up procedures per Section 2 (Schedule of Activities).
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of IP:

The subject/patient requests to discontinue IP

If a subject/patient is inadvertently enrolled and it is determined that continued treatment
with study drug would not be medically appropriate (Section 8.1.2 Discontinuation of 
Inadvertently Enrolled Subjects)

If a subject is diagnosed with acute or chronic pancreatitis after enrollment

If a subject is confirmed to have developed T1DM after enrollment

If a subject is diagnosed with MTC after enrollment

If a subject 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 enrollment

If the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study drug 
administration, the participant should be permanently discontinued from the 
investigational drug. 

If a subject is diagnosed with any other TEAE, SAE, or clinically significant laboratory
value for which the investigator believes that permanent IP discontinuation is the 
appropriate measure to be taken

If female subject becomes pregnant
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a patient meets 1 of the following conditions after consultation with the Lilly designated medical 
monitor:

ALT or AST >8× ULN 

ALT or AST >5× ULN sustained for more than 2 weeks

ALT or AST >3× ULN and (TBL >2× ULN or international normalized ratio >1.5)

ALT or AST >3× ULN, with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).Drug-related vomiting 
requiring intravenous (IV) hydration treatment or causing severe distress (prevents daily 


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activities and results in no appetite, or requires an emergency department visit, or 
hospitalization), that cannot be resolved by temporary interruption of IP.
Subjects who discontinue IP early will be also discontinued from the study after performing the 
ED visit and safety follow-up visit procedures, as specified in Section 2 (Schedule of Activities).
8.1.2. Discontinuation of Inadvertently Enrolled Subjects
If the Sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP
and the investigator to determine if the subject may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist/CRP to allow the inadvertently enrolled subject to continue in the 
study with or without continued treatment with IP.  
8.2.
Discontinuation from the Study
In addition to the situations that result in IP discontinuation described in Section 8.1.1
(Permanent Discontinuation from Study Treatment), subjects will be discontinued in the 
following circumstances:

Enrollment in any other clinical study involving an IP 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

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the eCRF.  Failure or delays 
(i.e., outside stipulated time allowances) in performing procedures or obtaining samples, 
including those due to legitimate clinical issues (e.g., equipment technical problems, venous 
access difficulty, or subject defaulting or turning up late on an agreed scheduled procedure) must
be documented in writing via a file note but will not be considered as a protocol deviation.
Unless otherwise stated in 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
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects 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 subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject 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.
The investigator will record all relevant AE and SAE information in the eCRF.  After the ICF is 
signed, study site personnel will record, via eCRF, the occurrence and nature of each subject’s
preexisting conditions, including clinically significant signs and symptoms of the disease under 


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treatment in the study.  Additionally, site personnel will record any change in the condition(s) 
and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.

when a condition related to the PFS necessitates medical or surgical intervention to 
preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned.
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, 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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the patient summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 


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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. 
Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an adverse event.  
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.
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 reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the 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
Tirzepatide is an incretin which acts on the pancreatic β cell as a non-secretagogue; therefore, the 
risk of hypoglycemia is very low.
If hypoglycemia occurs, each episode should be treated according to the standards of care by the 
investigator and additional monitoring of glucose levels may be requested at the investigator’s 
discretion. As a general safety precaution, subjects will be trained during the baseline period 
about signs and symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect 
appropriate information for each episode of hypoglycemia.
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood/plasma glucose 
samples collected during study visits.
Subjects with T2DM will be given glucometers (plus consumables such as test strips, lancets, 
alcohol swabs etc) by the site staff to assist in the evaluation of reported symptoms consistent 
with hypoglycemia.  Subjects receiving glucometers will record relevant information (for 
example, glucose values, symptoms) in a site developed diary. Subjects without T2DM may, at 
the investigator’s discretion, be given glucometers to assist in the evaluation of reported 
symptoms consistent with hypoglycemia.  Subjects receiving glucometers will record relevant 
information (for example, glucose values, symptoms) in a diary.
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the PG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine plasma-equivalent glucose meters and strips) (American Diabetes Association 2019):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a subject feels 
that he or she is experiencing symptoms and/or signs associated with 
hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L).


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
Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a subject feels 
that he/she is experiencing symptoms and/or signs associated with hypoglycemia, 
and has a PG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).
Severe Hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions.  These episodes may be associated with 
sufficient neuroglycopenia to induce seizure or coma.  Blood glucose 
measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of BG to normal is considered sufficient 
evidence that the event was induced by a low BG concentration.  
Other Hypoglycemia Categories:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE pages of the eCRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive plasma glucose values ≤70 mg/dL (3.9 mmol/L) 
occurring within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg 
et al. 2010; Danne et al. 2013).
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated.  The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established.  The subject should receive additional 
education, if deemed appropriate.


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9.2.2.2.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all studies with tirzepatide including this 
study.  Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases [Banks and 
Freeman 2006; Koizumi et al. 2006]; the pain is often associated with nausea 
and vomiting);

serum amylase (total and/or pancreatic) and/or lipase ≥3 × ULN

characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the local laboratory.  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 subject must discontinue IP, and will be discontinued from the study after 
completing all ED and follow-up procedures.  The most appropriate diabetes therapeutic regimen 
will be decided by the investigator, based on the subject’s clinical status.  A review of the 
subject’s medical data, including concomitant medications, should be conducted to assess 
potential causes of pancreatitis.
Each case of AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE.  For a potential case that 
does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to IP.
Each subject will have measurements of amylase and lipase, part of safety laboratory tests as 
shown in Section 2 (Schedule of Activities) to assess the effects of study treatment on pancreatic 
enzyme levels.  Serial measures of pancreatic enzymes have limited clinical value for predicting 
episodes of acute pancreatitis in asymptomatic subjects (Nauck et al. 2017; Steinberg et al. 
2017a; Steinberg et al. 2017b).  Thus, further diagnostic follow-up of cases of asymptomatic 
pancreatic hyperenzymemia (lipase and/or pancreatic amylase ≥3 × ULN) is not mandated but 
may be performed based on the investigator’s clinical judgment and assessment of the subject’s 
overall clinical condition.  If further diagnostic assessment due to asymptomatic 
hyperenzymemia will be warranted, it should follow Lilly standard algorithm for the monitoring 
of pancreatic enzymes (refer to Appendix 6).
9.2.2.3.
Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or MEN 2 will be excluded from the 
study, as well as those with calcitonin ≥20 pg/mL at screening.  Subjects who are diagnosed with 


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MTC and/or MEN-2 during the study will have study drug stopped and should continue 
follow-up with an endocrinologist.
9.2.2.4.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders should be further evaluated.  Subjects who 
develop any event from this group of disorders should undergo an ECG. Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed. The specific diagnosis will 
be recorded as an AE in the eCRF. Events that meet criteria for serious conditions as described 
in Section 9.2.1 (Serious Adverse Events) must be reported as SAEs.
9.2.2.5.
Hypersensitivity Events
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided 
to the sponsor in the eCRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study subjects are receiving study drug. It is recommended that subjects who 
experience a systemic hypersensitivity reaction be treated per the local standard of care.
In the case of generalized urticaria or anaphylaxis, additional blood samples should be collected 
as described in Section 9.6.3 (Immunogenicity Assessments).  Laboratory results are provided to 
the sponsor via the central or a referral laboratory.
9.2.2.6.
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

itching

pain
Injection-site reactions will be collected on the eCRF created for these events.  At the time of AE 
occurrence, unscheduled samples may be collected for measurement of tirzepatide ADA and 
tirzepatide PK if the event is suspected to be immune related by the investigator.
All injection-site reactions reported as AEs will be closely monitored until resolution.  The report 
of a clinically significant AE of injection-site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation and consideration of a skin biopsy 


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and laboratory evaluations (ALT, AST, complete blood count with percent eosinophils, and 
additional immunogenicity testing).
Site staff will be provided with separate instructions/training on how to evaluate injection-site 
reactions and their severity in a consistent manner.  Photographs of injection-site reactions may 
be taken if deemed necessary by the investigator for subject monitoring and record-keeping 
purposes; however, the photographs will not be used to evaluate the severity of injection-site 
reaction.
9.2.2.7.
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 9.4.10.1 (Hepatic Safety) and Appendix 4.
9.2.2.8.
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 AE form of 
the eCRF.
9.2.2.9.
Acute Renal Events
Renal safety will be assessed based on routine laboratory renal functional assessment as well as 
assessment of AEs suggestive of acute renal failure or worsening of chronic renal failure.  
Subjects with GI AEs, including nausea, diarrhea, and vomiting are at increased risk of 
developing dehydration.  Dehydration may cause a deterioration in renal function, including 
acute renal failure.  Subjects should be advised to notify investigators in case of severe nausea, 
frequent vomiting, or symptoms of dehydration.
9.2.3. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP or PFS so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
protocol-specified dose.  There is no specific antidote.  The subject should be watched for GI 
symptoms and hypoglycemia.  Treatment is supportive, depending on the subject’s symptoms.  
For detailed information, refer to the IB for tirzepatide.


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9.4.
Safety
9.4.1. Laboratory Tests
For each subject, 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 subject receives the first dose of the IP should be reported to Lilly, or its designee, as an 
AE via eCRF.
9.4.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 5 minutes in the supine position.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.3. Body Weight and Waist Circumference
Weight and waist circumference will be measured according to the schedule provided in the 
Schedule of Activities (Section 2).  
Subjects will be weighed at approximately the same time in the morning, before dosing and after 
an overnight fast and evacuation of the bowel and bladder, if possible.  Weight will be measured 
twice on each scheduled occasion, with the subject stepping off the scale between measurements.  
A third measurement will be made if the first 2 measurements are >0.5 kg apart.  The 2 closest 
measurements will be recorded.  Wherever possible, the same scale will be used for all weight 
measurements throughout the study, and every effort will be made to ensure the scale will not be 
moved or need to be recalibrated.  Subjects will be weighed in light clothing.  The mean weight 
will be captured in the eCRF.
Waist circumference will be measured at the midpoint between the inferior border of the rib cage 
and the superior aspect of the iliac crest.  The subject will stand in a straight, upright position 
with feet together and arms at the side.  The area measured will be cleared of all clothing other 
than undergarments.  The measurement should be taken at the end of normal expiration.  Two 
separate measures will be taken and steps are repeated until 2 measurements are obtained within 
0.5 cm of each other.  The mean waist circumference will be captured in the eCRF.
9.4.4. Electrocardiograms
For each subject, a single 12-lead ECG should be collected according to the Schedule of 
Activities (Section 2). 
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 4 1
L Y 3 2 9 8 1 7 6
d uri n g E C G c ollect i on.  El ectr ocar dio gra ms ma y be o btai ne d at a d dit i onal t i mes, w he n dee me d 
cli nicall y necessar y.  All E C Gs rec or de d s h o ul d be st ore d at t he i n vest i gati onal sit e.
Electr ocar di o gra ms will  be i nter prete d b y a q ualifie d i n vesti gat or (a p h ysicia n or q ualifie d 
desi g nee) at t he site as s o o n after t he ti me of E C G c ollect i on as p ossi ble, a n d i deall y w hile t he 
s u bject is still prese nt, t o deter mi ne w het her t he s u bject meets e ntr y criteria at t he rele va nt 
visit(s) a n d f or i m me diate s u bject ma na ge me nt, s h o ul d a n y cli nicall y rele va nt fi n di n gs be 
i de ntifie d.  
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges i n Q T/ Q Tc 
i nter val fr o m baseli ne) after e nr oll me nt, t he i n vesti gat or will deter mi ne if t he s u bject ca n 
c o nti n ue i n t he st u d y.  T he i n vesti gat or, or q ualifie d desi g nee, is res p o nsi ble f or deter mi ni n g if 
a n y c ha n ge i n s u bject ma na ge me nt is nee de d a n d m ust d oc u me nt his/ her re vie w of t he E C G 
pri nte d at t he ti me of c o llecti on.  A n y ne w cli nicall y  rele va nt fi n di n g s h o uld be re p orte d as a n 
a d verse e ve nt . A n y cli nicall y si g nifica nt fi n di n gs fr o m E C Gs t hat res ult i n a dia g n osis a n d t hat 
occ ur after t he s u bject recei ves t he first d ose of t he I P, s h o ul d be re p orte d t o Lill y, or i ts 
desi g n ee, as a n A E via e C R F.
9. 4. 6.
P h y si c al E x a mi n ati o n s
P h ysical e xa mi nat i ons a n d r o uti ne me dical assess me nts will be c o n d ucte d as s pecifie d i n 
Secti o n 2 ( Sc he d ule of Acti vities) a n d as cli nicall y i n dicate d.
9. 4. 7.
6- p oi nt Pl a s m a Gl u c o s e Pr ofil e
Pl as ma s a mples will be ta ke n f or t he pr ofili n g of plas ma gl uc ose bef or e a n d after meals, as 
s pecifie d i n Secti o n 2 .  A n y plas ma gl uc ose res ults t hat f ulfil t he criteria of h y p o gl yce mia will be 
ca pt ure d in t he eC R F as s pecifie d i n Sect i on 9. 2. 2. 1 .
9. 4. 8.
S elf -m o nit ori n g of Pl a s m a Gl u c o s e ( S M P G)
S u bjects wi t h T 2 D M will be e d ucate d o n t he s y m pt o ms of h y p o gl yce mia a n d i nstr ucte d o n h o w 
t o use t he gl uc omet er pr o vide d b y  t he site t o perfor m  S M P G.  T he site will pr ovi de a s u bject
di ar y car d a n d i nstr uct T 2 D M s u bjects t o perf or m a n d rec or d S M P G res ults d uri n g t he d osi n g 
p hase of t he st u d y  a n d w he ne ver t he s u bject e x perie nces s y m pt o ms of h y p o gl yce mia as s pecifie d 
C CI


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in the Schedule of Activities (Section 2).  Results of the SMPG need not be databased, but 
investigator review of glucose results clinically indicative of hypoglycemia or symptomatic 
hyperglycemia is required.
All hypoglycemic events will be captured in the eCRF as specified in Section 9.2.2.1.  Clinically 
significant hyperglycemic events should be reported as AEs. 
9.4.9. Suicidal Ideation Assessment
Overweight and obese subjects are at an increased risk of depression (Luppino et al. 2010).  
Depression can increase the risk of suicidal ideation and behavior.  Therefore, study subjects will 
be screened at trial entry for depression, suicidal ideation and behavior using the C-SSRS and 
PHQ-9 as specified in the Schedule of Activities (Section 2), and excluded from the study if they 
meet thresholds defined by Exclusion Criteria [35] and [36].
The C-SSRS (Columbia Lighthouse Project [WWW]) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and/or behavior during the assessment period.  The 
scale includes suggested questions to solicit the type of information needed to determine if 
suicidal ideation and/or behavior occurred.  The tool was developed by the National Institute of 
Mental Health trial group for the purpose of being a counterpart to the Columbia Classification 
Algorithm of Suicide Assessment categorization of suicidal events.  For this study, the C-SSRS 
is adapted for the assessment of the ideation and behavior categories only.  The Intensity of 
Ideation and Lethality of Behavior sections are removed.
The PHQ-9 is a validated self-report screening tool that assesses the presence and intensity of 
depressive symptoms.  The PHQ-9, which incorporates the 9 Diagnostic and Statistical Manual-
IV depression criteria as “0” (not at all) to “3” (nearly every day), was developed for use in 
primary care settings (Kroenke et al. 2001).
9.4.10. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes including glucose, amylase, and lipase

serious and nonserious AEs, including AEs of interest (see Section 9.2.2 for full list) 
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
9.4.10.1. Hepatic Safety
Close hepatic monitoring


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Laboratory tests (Appendix 4), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 
72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if 1 or 
more of these conditions occur:
If a participant with baseline results of ... 
develops the following elevations:
ALT or AST <1.5× upper limit of normal (ULN)
ALT or AST ≥3× ULN
ALP <1.5× ULN
ALP ≥2× ULN
TBL <1.5× ULN
TBL ≥2× ULN (except for subjects with Gilbert’s syndrome)
ALT or AST ≥1.5× ULN
ALT or AST ≥2× baseline
ALP ≥1.5× ULN
ALP ≥2× baseline
TBL ≥1.5× ULN
TBL ≥2× baseline (except for subjects with Gilbert’s 
syndrome)
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated CP/CRP.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize.  Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:
If a participant with baseline results of...  
develops the following elevations:
ALT or AST <1.5× ULN
ALT or AST ≥3× ULN with hepatic signs/symptoms*, or
ALT or AST ≥5× ULN
ALP <1.5× ULN
ALP ≥3× ULN
TBL <1.5× ULN
TBL ≥2× ULN (except for subjects with Gilbert’s syndrome)
ALT or AST ≥1.5× ULN
ALT or AST ≥2× baseline with hepatic signs/symptoms*, or
ALT or AST ≥3× baseline
ALP ≥1.5× ULN
ALP ≥2× baseline
TBL ≥1.5× ULN
TBL ≥1.5× baseline (except for subjects with Gilbert’s syndrome) 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalized ratio 


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(PT-INR); tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an 
abdominal imaging study (for example, ultrasound or CT scan).  
Based on the subject’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and serum phosphatidylethanol.  Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.  
Additional safety data collection in hepatic safety eCRF should be performed in study 
participants who meet 1 or more of the following conditions: 

Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5 × ULN)
o
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT 
≥3 × baseline on 2 or more consecutive tests

Elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)
o
In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL 
≥2 × baseline

Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 
o
In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × baseline 
on 2 or more consecutive blood tests

Hepatic event considered to be a SAE

Discontinuation of study drug due to a hepatic event
Note: the interval between the 2 consecutive blood tests should be at least 2 days.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
tirzepatide.  A maximum of 3 unscheduled samples may be collected at additional time points 
during the study if warranted and agreed upon between both the investigator and sponsor.  
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.
Failure or being late (i.e., outside stipulated time allowances) to perform obtain samples due to 
legitimate clinical issues (e.g., equipment technical problems, venous access difficulty, or subject 


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defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will have to notify the sponsor in writing via a file note.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of tirzepatide and acetaminophen will be assayed using a validated liquid 
chromatography tandem mass spectrometry method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism, protein binding, or 
bioanalytical method cross-validation.
9.6.
Pharmacodynamics
9.6.1. Gastric Emptying
Acetaminophen is a well-established marker for the rate and extent of gastric emptying. It is 
rapidly absorbed from the duodenum upon release from the stomach. A delay in gastric 
emptying is reflected in the alterations to the concentration-time profile of acetaminophen, 
specifically, decreasing its Cmax and tmax without altering the extent (total drug amount) of 
absorption. A dose of approximately 1 g acetaminophen is considered to be sufficient for 
bioanalytical detection and will be administered on Day -1 and about 24 hours after first and 
sixth tirzepatide doses (Schedule of Activities [Section 2]). 
Venous blood samples of approximately 2 mL each will be collected to determine the plasma
concentrations of acetaminophen (Schedule of Activities [Section 2]).  Up to 3 additional 
samples may be taken if required.
9.6.2. Body Weight
Weight will be measured according to the schedule provided in Section 2 (Schedule of 
Activities).  Refer to Section 9.4.3 for details. 
9.6.3. Immunogenicity Assessments 
For immunogenicity testing, venous blood samples of approximately 10 mL will be collected 
from each subject according to the Schedule of Activities (Section 2), to determine antibody 
production against tirzepatide.  Up to 3 additional samples may be collected if there is a 
possibility that an AE is immunologically mediated (see Section 9.2.2.5).  All samples for 
immunogenicity testing should have a time-matched sample for PK analysis where relevant.  
Detailed instructions for the sample collections and handling will be provided by the sponsor.  
The actual date and 24-hour clock time of each sampling will be recorded. 
Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies 
(ADA) in the presence of tirzepatide at a laboratory approved by the sponsor.  Antibodies may 


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be further evaluated for their ability to neutralize the activity of tirzepatide on GIP and GLP-1 
receptors.  Positive tirzepatide ADA samples may also be tested for cross-reactivity against 
native GIP and GLP-1, and, if positive, may then be tested for neutralizing antibodies against 
native GIP and/or GLP-1. 
All subjects will have an ADA sample measured at early discontinuation or at Day 64 ± 1 day.  
A risk-based approach will be used to monitor subjects who develop treatment-emergent ADA 
(TE ADA), defined in Section 10.3.4 (Evaluation of Immunogenicity). 
Clinically significant TE ADA will be defined as any TE ADA at the last visit with: 

a high titer (≥1280) or an increasing titer from last measured value 

an association with a moderate-to-severe injection-site reaction 
Subjects who have clinically significant TE ADA at early discontinuation or at the safety 
follow-up should be followed with ADA testing every 3 months until the ADA titers have 
returned to the baseline ADA titer (defined as ADA titer within 2-fold of baseline) or for up to 
1 year, whichever is less. A PK sample may be collected at the follow-up immunogenicity 
assessment(s), if warranted and agreed upon by the investigator and sponsor. 
Every effort should be made to contact subjects for the follow-up immunogenicity assessment; 
however, if subjects are unwilling or unable to return for the visit, this is not considered a 
protocol deviation. 
Subjects followed for at least 1 year after dosing who have not returned to baseline, as defined 
above, will be assessed for safety concerns and, if no clinical sequelae are recognized by the 
clinical team, no further follow-up will be required.  Subjects who have clinical sequelae that are 
considered potentially related to the presence of TE ADA may also be asked to return for 
additional follow-up testing.
Samples will be retained for a maximum of 15 years after the last subject 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 the tirzepatide.  Any 
samples remaining after 15 years will be destroyed.
9.7.
Genetics
A 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 exposure or response to 
tirzepatide and to 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 subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  


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Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  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 is 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, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers
Not applicable.  
9.9.
Appetite Analysis
To explore the effects of tirzepatide on meal intake and appetite sensation, subjects will be asked 
to rate their appetite sensations using a 100-mm visual analog scale (VAS) for parameters of 
hunger, fullness, satiety, and prospective food consumption prior to dosing on Day 1, and in the 
fasted state while inpatient as well as on scheduled outpatient visits.  These measurements shall 
be performed according to the Schedule of Activities (Section 2).
The VAS is a validated tool to assess appetite sensation parameters (Flint et al. 2000).  The VAS 
is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually “extremely” and 
“not at all”.  Subjects are required to rate their subjective sensations on four 100-mm scales 
combined with questions similar to the following:
1. “How hungry do you feel?”
2. “How satisfied do you feel?”
3. “How full do you feel?”
4. “How much do you think you could eat?”
A staff member will use a caliper to measure the distance from 0 to the mark that the subject 
placed on the VAS and record the measurement in the source document.  Overall appetite score 
is calculated as the average of the 4 individual scores: satiety + fullness + (100-prospective food 
consumption) + (100-hunger) / 4 (van Can et al. 2014).  The higher overall appetite score 
indicates less appetite, and the lower score indicates more appetite.
9.10. Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 18 overweight or obese non-diabetic subjects and 18 overweight or obese T2DM
subjects will be enrolled so that a minimum of 12 subjects in each group completes the study.  In 
total, approximately 36 subjects will be enrolled so that a minimum of 24 subjects complete the 
study.
For acetaminophen AUC and Cmax, the intra-subject variability (coefficient of variation [CV]) 
was estimated to be 15.7% and 21.9%, respectively (derived from study I8F-MC-GPGA). Based 
on this assumption, 24 subjects will provide a precision of 0.09 and 0.13 on a log-scale for AUC 
and Cmax, respectively. This would result in a 90% probability that the half-width of the 90% 
confidence interval (CI) of the ratio of the geometric least square means for AUC and Cmax is no 
larger than 8.8% and 12.0%, respectively.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. All 
subjects who discontinue from the study will be identified, and the extent of their participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, height, BMI, or other demographic characteristics will be 
recorded and may be used in the PK and safety analyses as quantitative of classification 
variables.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic and PD analyses will be conducted on data from all subjects who receive at 
least one dose of the IP and have evaluable data.  
Safety analyses will be conducted for all subjects who receive at least one dose of the IP, 
whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP, protocol procedure AEs, and complaints will be listed, and if the frequency of events 
allows, data will be summarized using descriptive methodology.


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The incidence of adverse events will be presented by severity and by association with IP as 
perceived by the investigator.  Adverse events reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, 
 TEAEs (including TEAEs of special interest), and SAEs.  The 
parameters will be listed and summarized using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data. All AEs related to study or
protocol procedure will be listed, and if the frequency of events allows, will be also summarized 
using descriptive methodology.
Hypoglycemic events, as defined in Section 9.2.2.1, will be summarized and listed.
Physical examinations and ECGs will be performed for safety monitoring purposes and will not 
be presented.  If warranted, additional analyses will be performed upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for tirzepatide will be calculated by standard 
noncompartmental methods of analysis. The primary parameters for analysis will be Cmax, 
AUC0-∞, AUC0-tlast, and tmax.  Other noncompartmental parameters, such as half-life, apparent 
clearance, and apparent volume of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Planned PK parameters will be summarized with descriptive statistics.
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
Acetaminophen PK parameters will be estimated to assess the effect of tirzepatide on gastric 
emptying delay. The PK parameter estimates for acetaminophen will be calculated by standard 
noncompartmental methods of analysis. The primary parameters for analysis will be the Cmax, 
the AUC0-tlast, and the tmax of acetaminophen. Other parameters, such as half-life, apparent 
clearance, and apparent volume of distribution, may be reported.
A comparison of acetaminophen parameters on Day -1 (prior to study drug) and following first 
and sixth dose of study drug will be summarized.
10.3.3.2. Pharmacodynamic Statistical Inference
Pharmacokinetic parameters will be evaluated to estimate the impact of tirzepatide on gastric 
emptying and on the PK of acetaminophen.  Log-transformed Cmax and AUC will be evaluated 
in a linear mixed-effects model, with day (-1, 2, 37) as a fixed effect and subject as a random 


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effect.  The differences in Cmax and AUC between acetaminophen + tirzepatide (Test; Days 2 
and 37) and acetaminophen alone (Reference; Day -1) will be back-transformed to present the
ratios of geometric least squares means and the corresponding 90% CI.  Other parameters may be 
analyzed in this way as needed.
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians and 90% CIs from the Wilcoxon test will be calculated.
Planned PK parameters will also be summarized with descriptive statistics.
Pharmacodynamic parameters that will be assessed include body weight, appetite VAS scores 
and HbA1c.  The parameters will be listed and summarized using standard descriptive statistics.  
Additional analysis will be performed if warranted upon review of the data.
10.3.4. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TE ADA+ to 
tirzepatide will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA). The minimum required 
dilution of the ADA assay is 1:10. For the TE ADA+ subjects the distribution of maximum titers 
will be described.  If cross-reactivity with native GLP-1 and GIP or neutralizing antibodies
against native GLP-1 and GIP assays are performed, the frequency of each will be reported.
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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11.
References
[ADA] American Diabetes Association.  Glycemic targets.  Standards of medical care in 
diabetes-2019.  Diabetes Care.  2019;42(Suppl.  1):S61-S70.
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.  
2006;101(10):2379-2400.
Columbia Lighthouse Project. Columbia-Suicide Severity Rating Scale (C-SSRS) website. 
Available at: http://www.cssrs.columbia.edu. Accessed 21 February 2020.
Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, 
Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D’ Alessio DA, 
Haupt A.  LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of 
type 2 diabetes mellitus:  From discovery to clinical proof of concept.  Molecular metabolism.  
2018;18:3-14.
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
LY3298176 125 preschool children with type 1 diabetes treated with insulin glargine or NPH 
insulin (the PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601.
Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue 
scales in assessment of appetite sensations in single test meal studies. Int J Obes. 2000; 
24(1):38-48.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic 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 randomized, placebo-controlled and active 
comparator-controlled phase 2 trial.  The Lancet.  2018;392(10160):  2180-2193.
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.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med. 2001;16(9):606-613.
Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, Zitman FG. 
Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal 
studies. Arch Gen Psychiatry. 2010;67(3):220-229.
Nauck MA, Frossard J-L, Barkin JS, Anglin G, Hensley IE, Harper KD, Milicevic Z. 
Assessment of pancreas safety in the development program of once-weekly GLP-1 receptor 
agonist dulaglutide. Diabetes Care. 2017;40(5):647-654.
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people 


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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.
van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 
analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism 
in obese, non-diabetic adults. Int J Obes (Lond). 2014;38(6):784-793.
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.
Young A. Inhibition of gastric emptying. Adv Pharmacol. 2005;52:99-121.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE 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.
ALP
alkaline phosphatase
ALT
alkaline phosphatase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-∞
area under the concentration versus time curve from time zero to infinity
AUC0-tlast
area under the concentration versus time curve from time zero to time t, where t is the last 
time point with a measurable concentration
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
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 the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
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.


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C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FSH
follicle-stimulating hormone
GCP
good clinical practice
GE
gastric emptying
GI
gastrointestinal
GIP
glucose-dependent insulinotropic peptide
GLP-1
glucagon-like peptide 1
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
informed consent
A process by which a subject 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 subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, 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.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.


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MAD
multiple ascending dose
MEN 2
multiple endocrine neoplasia syndrome type 2
MTC
medullary thyroid carcinoma
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PD
pharmacodynamics
PFS
pre-filled syringe
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetics
PK/PD
pharmacokinetic/pharmacodynamic
PG
plasma glucose
QW
once-weekly
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets the minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SHSF
Self-Harm Supplementary Form
SMPG
self-monitoring of plasma glucose
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
TE-ADA
treatment-emergent antidrug antibody
TEAE
treatment-emergent adverse event:  Any 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 
tmax
time of maximum observed drug concentration
T2DM
type 2 diabetes mellitus


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ULN
upper limit of normal
VAS
visual analog scale
WOCBP
woman of childbearing potential


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistry (fasting)a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucose
Leukocytes (WBC)
Blood urea nitrogen
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes
Aspartate aminotransferase
Eosinophils
Alanine aminotransferase
Basophils
Creatinine
Platelets
Amylase
Lipase
Hemoglobin A1ca,b
Urinalysisa
Uric acid
Phosphorous
Calcitoninc
Follicle-stimulating hormonec
Specific gravity
Hepatitis B surface antigenc,d
pH
Hepatitis C antibody, hepatitis C RNAc,d
Protein
HIVc,d
Glucose
Pregnancy teste
Ketones
Bilirubin
Lipid Panel (Fasting)a,b
Urobilinogen
Triglycerides
Blood
Total Cholesterol
Nitrite
LDL
Microscopic examination of sedimentf
HDL
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
a
Performed by local laboratory.  Results will be validated by the laboratory at the time of initial testing.
b
Performed at Screening, Day -2, Day 29, and FU/ED.
c
Performed by local laboratory at screening only.
d
Tests may be waived if they have been performed within 6 months before screening with reports available for review.
e
Serum pregnancy test will be performed at screening and urine pregnancy tests at subsequent visits.
f    Test only if dipstick result is abnormal (i.e., positive for blood, protein, or nitrites).


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject.  This includes obtaining the 
appropriate signatures and dates on the ICF prior to the performance of any protocol 
procedures and prior to the administration of IP.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.  Study specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by 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 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF 

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) 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 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, 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 eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


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In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly 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 the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the Sponsor.
Study and Site Closure
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.
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.


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
Page 62
LY3298176
Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Evaluation of subjects with treatment-emergent abnormal hepatic biochemical tests during a 
clinical trial.  Extent and type of work-up may vary by subject’s history, severity of liver injury, 
underlying disease, and geography.  Laboratory assays should preferably be performed locally 
for faster turnaround. 
Recommended Evaluation
Competing Causes of Abnormal Liver Tests
1st Line Testing
ALT, AST, ALP, TBL, direct bilirubin, GGT, CK
Routine follow up 
Thorough history of symptoms, co-existing medical 
conditions, concomitant medications, dietary and 
nutritional supplements, excessive exercise or muscle 
injury, alcohol consumption, illicit substances.  
Systemic infection/ sepsis; ischemic/ congestive 
hepatic injury; gallstone disease; alcoholic liver 
disease; muscle injury/ rhabdomyolysis; 
acetaminophen toxicity; DILI due to another drug, 
herbal or dietary supplement.  
Serum CK
Muscle injury/rhabdomyolysisa
Anti-HAV (IgM)
Acute HAV infection
HBsAg
Anti-HBc IgG, IgM
Acute hepatitis B; exacerbation of chronic hepatitis B
Anti-HCV 
HCV RNA (PCR)b
Acute hepatitis Cc; exacerbation of chronic hepatitis C
Anti-HEV (IgG, IgM), HEV RNAd
Acute hepatitis E
ANA, ASMA, quantitative immunoglobulins 
(IgG, IgM, IgA)
Autoimmune hepatitise
Hepatobiliary imaging 
(ultrasonography, CT scan, MRI, MRCP)f
Biliary obstruction; pancreatitis; gallstones; 
portal-vein/ hepatic vein thrombosis; hepatic 
metastasis 
2nd Line Testing
PT-INR
For subjects with elevated TBL or suspected liver 
failure 
Serological tests for EBV, CMV, HSV 
May need to obtain acute and convalescent serological 
tests
Hepatic injury caused by CMV, EBV, HSV
EBV-DNA, CMV- DNA, HSV-DNA by PCR.  
Liver biopsy needed to confirm HSV
Hepatic injury caused by CMV, EBV, HSV
Additional Testsg
Bone specific ALP (ALP fractionation)
Differentiate bone from liver origin 
LKM-1 antibody
Autoimmune hepatitis
Urinary ethylglucuronideh, 
serum phosphatidylethanoli
Alcoholic liver disease
Serum acetaminophen level; 
acetaminophen protein adducts
Acetaminophen toxicity
Review of blood pressure, pulse, electrocardiogram, 
echocardiogram, cardiology consult
Ischemic or congestive hepatic injury 


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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LY3298176
Urine toxicology screen
Hepatotoxicity due to cocaine, opiates and other illicit 
substances
Anti-HDV
Hepatitis D 
Blood or urine cultures 
Systemic infection, sepsis
Serum ceruloplasmin, serum copper Slit lamp eyes 
examination for Kayser-Fleischer rings, genetic testing
Wilson’s disease
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANA = antinuclear antibody; 
anti- = antibody; ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; CK = creatinine 
kinase; CMV = cytomegalovirus; CT = computed tomography; DILI = drug-induced liver injury; EBV = Epstein 
Bar Virus; GGT = gamma-glutamyl transferase; HAV = hepatitis A virus; HBc = hepatitis B core; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E 
virus; HSV = herpes simplex virus; Ig = immunoglobulin; INR = international normalized ratio; LKM-1 = liver 
kidney microsomal type 1; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance 
imaging; PCR = polymerase chain reaction; PT-INR = prothrombin time-international normalized ratio; 
RNA = ribonucleic acid; TBL = total bilirubin.
a
Serum AST typically (although not always) is higher than ALT
b
If anti-HCV positive, HCV RNA is required to confirm HCV infection
c
Acute hepatitis C may be anti-HCV negative but HCV RNA positive 
d
If anti-HEV IgM positive, consider confirmation with HEV RNA by nested PCR
e
A liver biopsy is needed to confirm a diagnosis of autoimmune hepatitis 
f
If cholestatic injury, MRCP may be recommended
g
Based on medical history and clinical judgment
h
Alcohol consumption in past 3 to 5 days 
i
Alcohol consumption in past 3 weeks


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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LY3298176
Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPHU Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa,b
25
1
25
Safety laboratory testsa,b
12.5
5
62.5
Hemoglobin A1cb
4
4
16
Tirzepatide pharmacokineticsc
3
19 (+3)
66
Immunogenicityc
10
4 (+3)
70
Acetaminophen pharmacodynamicsc
3
35 (+3)
114
6-point plasma glucosec
2
6 × 3 occasions
36
Plasma glucosec
2
9
18
Pharmacogeneticsc
10
1
10
Total
417.5
Total for clinical purposes
420
a
Additional samples may be drawn if needed for safety purposes. Safety laboratory tests will be inclusive of lipid 
panels on days when they are performed (refer to Appendix 2)
b Performed on site or in a local laboratory. 
c    Performed at a central or referral laboratory approved by the sponsor, including for storage


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
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Appendix 6.
Pancreatic Monitoring
Abbreviations:  CT = computed tomography; MRI = magnetic resonance imaging; ULN = upper limit of normal.


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
Page 66
LY3298176
Subjects diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate healthcare option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as SAEs.  For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to study 
drug.


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 6 7
L Y 3 2 9 8 1 7 6
A p p e n di x 7.
Pr ot o c ol A m e n d m e nt I 8 F -M C -G P H U ( a) 
S u m m ar y  
T h e I m p a ct of Tir z e p ati d e o n G a stri c E m pt y i n g ( G E) i n 
O v er w ei g ht/ O b e s e N o n -di a b eti c S u bj e ct s a n d i n 
O v er w ei g ht/ O b e s e S u bj e ct s wit h T y p e 2 Di a b et e s 
M e llit us
O v er vi e w
Pr ot oc ol  I 8 F-M C -G P H U ‘T he I mpact of  Tirze pati de o n Gastric E m ptyi n g ( G E) i n 
O ver wei g ht/ O bese N o n -di a bet ic S u bjects a n d i n O ver wei g ht/ O bese S u bjects wi t h T ype 2 
Di a betes Mellit us ’ has bee n a me n de d.  T he ne w pr ot oc ol is i n dicate d b y A me n d me nt (a) a n d will 
be use d t o c o n d uct t he st u d y  in pl ace of a n y prece di n g versi o n of t he pr ot oc ol.  T his a me n d me nt 
is c o nsi dere d t o be n o n- s u bsta ntial si nce it d oes n ot alter t he s u bject safety a n d t he pri mar y a n d 
sec o n dar y o bjecti ves of t he st u d y.
T he o verall c ha n ges a n d rati o nale f or t he c ha n ges ma de t o t h is pr ot oc ol are as f oll ows:

Li pi d pa nel c ollect i on ti me has bee n r e mo ve d fr om t he sc he d ule of act i vities ( Secti o n 2)
t o a v oi d i nf or mati on d u plicati o n wi t h A p pe n di x 2 . 

F o ot n ote attri b ut i ons f or he m o gl o bi n A 1c a n d li pi d pa nel o f A p pe n di x 2 ha ve bee n 
c o rrecte d.

Bl o o d sa m pli n g v ol u me liste d i n  A p pe n di x 6 has bee n c orrecte d t o reflect u p dates i n 
act ual la b orat or y sa m pli n g re q uire me nt.

Mi n or e di t orial c ha n ges a n d f or matti n g c orrectio ns were m a de b ut are n ot necessaril y 
d oc u m e nte d i n t he re visi o n bel o w.
C CI


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 6 8
L Y 3 2 9 8 1 7 6
R e vi s e d Pr ot o c ol S e cti o n s
N ote:
All deleti o ns ha ve bee n i de nt ifie d b y striket hr o u g hs .
All a d ditio ns ha ve bee n i de nt ifie d b y t he use of u n dersc ore .
2.
S c h e d ul e of A cti viti e s
St u d y Sc he d ule Pr ot oc ol I 8 F -M C -G P H U Scree ni n g a n d B aseli ne
Scree ni n g 
B aseli ne
C o m me nts
Pr oce d ure
D- 2 8 t o - 4  
D- 3  
D- 2  
D- 1
…
…  
…  
…  
…  
…
Cli nical La b orat or y Tests
X
X
Se e A p pe n di x 2 f or details. Baseli ne ma y be c ollecte d a n yti me 
fro m D -3 t o D- 1 as l o n g as res ults are re vie we d pri o r t o first 
tirze pati de d osi n g o n D 1. Perf or me d b y a l ocal la b o rat or y.
…
…  
…  
…  
…  
… .
Li pi d Pa nel
X
St u d y Sc he d ule Pr ot oc ol I 8 F-M C -G P H U Tre at me nt a n d F oll o w -u p
Tre at me nt a n d F oll o w U p
C o m m e nts
Pr oce d ure
D 1  
D 2  
D 3  
D 4  
D 8
± 1
D 1 5
± 1
D 2 2
± 1
D 2 9
± 1
D 3 5
D 3 6  
D 3 7
D 3 8
D 4 3
± 2
F U/
E D a
…
…  
…  
…  
…  
…  
…  
…  
…
…  
…  
…  
…  
…  
…  
…
Cli nical 
La b orat or y 
Tests
P
P
X  
X
Refer t o scree ni n g a n d 
baseli ne c o m me nts
…
…  
…  
…  
…  
…  
…  
…  
…  
…  
…  
…  
…  
…  
…  
…
C CI
C CI


I 8 F-M C -G P H U Cli ni c al P h ar m a c ol o g y Pr ot o c ol ( a)
P a g e 6 9
L Y 3 2 9 8 1 7 6
4.
O bj e cti v e s a n d E n d p oi nt s
T a bl e G P H U . 3.
O bj e cti v e s a n d E n d p oi nt s
O bjecti ves
E n d p oi nts
E x pl or at o r y
T o e val uate t he P D effects of tirze pat i de o n 
a p petite a n d wei g ht
B o d y  wei g ht, waist circ u mfere nce, a p petite 
V A S sc ores
C CI
C CI


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
Page 70
LY3298176
Appendix 2
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistry (fasting)a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucose
Leukocytes (WBC)
Blood urea nitrogen
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes
Aspartate aminotransferase
Eosinophils
Alanine aminotransferase
Basophils
Creatinine
Platelets
Amylase
Lipase
Hemoglobin A1ca,b
Urinalysisa
Uric acid
Phosphorous
Calcitoninc
Follicle-stimulating hormonec
Specific gravity
Hepatitis B surface antigenc,d
pH
Hepatitis C antibody, hepatitis C RNAc,d
Protein
HIVc,d
Glucose
Pregnancy teste
Ketones
Bilirubin
Lipid Panel (Fasting)a,cb
Urobilinogen
Triglycerides
Blood
Total Cholesterol
Nitrite
LDL
Microscopic examination of sedimentf
HDL
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
a
Performed by local laboratory.  Results will be validated by the laboratory at the time of initial testing.
b
Performed at Screening, Day -2, Day 29, and FU/ED.
c
Performed by local laboratory at screening only.
d
Tests may be waived if they have been performed within 6 months before screening with reports available for review.
e
Serum pregnancy test will be performed at screening and urine pregnancy tests at subsequent visits.
f    Test only if dipstick result is abnormal (i.e., positive for blood, protein, or nitrites).
Appendix 5
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  


I8F-MC-GPHU Clinical Pharmacology Protocol (a)
Page 71
LY3298176
Protocol I8F-MC-GPHU Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa,b
2125
1
2125
Safety laboratory testsa,b
1712.5
5
8562.5
Hemoglobin A1cb
4
4
16
Calcitoninb
2
1
2
Tirzepatide pharmacokineticsc
3
19 (+3)
66
Immunogenicityc
10
74 (+3)
10070
Acetaminophen pharmacodynamicsc
23
35 (+3)
76114
6-point plasma glucosec
2
6 × 3 occasions
36
Plasma glucosec
2
9
18
Pharmacogeneticsc
10
1
10
Total
424417.5
Total for clinical purposes
423.5420
a
Additional samples may be drawn if needed for safety purposes. Triglycerides and total cholesterol will be 
excluded on study days where a lipid panel pharmacodynamics sample is collected. Safety laboratory tests will 
be inclusive of lipid panels on days when they are performed (refer to Appendix 2)
b Performed on site or in a local laboratory. 
c    Performed at a central or referral laboratory approved by the sponsor, including for storage


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

SAP_001.pdf: 
Statistical Analysis Plan: I8F-MC-GPHU 
 
The Impact of Tirzepatide on Gastric Emptying (GE) in Overweight/Obese Non-diabetic 
Subjects and in Overweight/Obese Subjects with Type 2 Diabetes Mellitus 
 NCT04407234 
Approval Date: 11-Sep-2020 


Fi nal, 1 0 Se p 2 0 2 0
             Pa ge 1 of 2 2
S T A TI S TI C A L A N A L Y SI S P L A N
T he I m p act of Tirze p ati de o n G astric E m pt yi n g ( G E) i n O ver wei g ht/ O bese N o n -di a betic 
S u bjects a n d i n O ver wei g ht/ O bese S u bjects wit h T y pe 2 Di a betes Mellit us
Stati stical A nal ysis Pla n Stat us : Fi nal
Stati stical A nal ysis Pla n Date : 1 0- Se pte m ber - 2 0 2 0
St u d y  Dr u g: L Y 3 2 9 8 1 7 6
S p o ns or Refere nce : I 8 F-M C -G P H U
C o va nce C R U St u d y : 1 0 0 0 0 7 1- 8 4 1 6 6 5 7
Cli nical P hase I
A p pr o v al D at e: 1 1- S e p- 2 0 2 0 G M T


Fi nal, 1 0 Se p 2 0 2 0
             Pa ge 2 of 2 2
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 4 1 6 6 5 7
S p o ns or Refere nce I 8 F-M C -G P H U
1. T A B L E O F C O N T E N T S
1.
T A B L E O F C O N T E N T S .....................................................................................................2
2.
A B B R E VI A TI O N S ..............................................................................................................4
3.
I N T R O D U C TI O N ...............................................................................................................6
4.
S T U D Y O BJ E C TI V E S ........................................................................................................6
4. 1
Pri mar y O bject i ve..........................................................................................................6
4. 2
Sec o n dar y  O bjecti ves ....................................................................................................6
4. 3
E x pl or at or y O bjecti ves..................................................................................................6
5.
S T U D Y D E SI G N .................................................................................................................7
6.
T R E A T M E N T S ...................................................................................................................8
7.
S A M P L E SI Z E J U S TI FI C A TI O N .......................................................................................8
8.
D E FI NI TI O N O F A N A L Y S I S P O P U L A TI O N S..................................................................8
9.
S T A TI S TI C A L M E T H O D O L O G Y .....................................................................................9
9. 1
Ge ne r al..........................................................................................................................9
9. 2
D e m o gra p hics a n d S u bject Dis p osit i on ..........................................................................9
9. 3
P har mac o ki net ic a n d P har mac o d y na mic Assess me nt...................................................1 0
9. 3. 1
P har mac o ki net ic A nal ysis ...................................................................................1 0
9. 3. 2
P har mac o ki net ic Statistical Met h o d ol o g y ...........................................................1 4
9. 3. 3
P har mac o d y na mic Statistical Met h o d ol o g y ........................................................1 5
9. 4
S af et y a n d T olera bilit y Assess me nts ............................................................................1 6
9. 4. 1
A d verse e ve nts ...................................................................................................1 6
9. 4. 2
Gl uc ose M o ni t ori n g a n d H yp o gl yce mia ..............................................................1 7
9. 4. 3
6- p oi nt Pl as ma Gl uc ose Pr ofile ...........................................................................1 8
9. 4. 4
C o nc o mita nt me dicat i on .....................................................................................1 8
9. 4. 5
Cli nical la b orat or y  para meters............................................................................1 8
9. 4. 6
Vi t al si g ns ..........................................................................................................1 8
9. 4. 7
Electr ocar di o gra m ( E C G) ...................................................................................1 8
9. 4. 8
B o d y  wei g ht a n d Waist Circ u mfere nce...............................................................1 8
9. 4. 1 0
Assess me nt of A p pet ite ......................................................................................1 8
9. 4. 1 1
He pati c M o nit orin g ............................................................................................1 9
9. 4. 1 2
H y perse nsit i vity reacti ons ...................................................................................2 0
9. 4. 1 3
I njecti on -Si te Reactio ns...................................................................................... 2 1
9. 4. 1 4
I mm u n o ge nicit y Assess me nts .............................................................................2 1
9. 4. 1 5
Ot her assess me nts ...............................................................................................2 1
9. 4. 1 6
S afet y a n d T olera bilit y Statisti c al Met h o d olo g y.................................................. 2 1
C CI


Final, 10 Sep 2020
             Page 3 of 22
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
10. INTERIM ANALYSES .....................................................................................................21
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............21
12. REFERENCES ..................................................................................................................22
13. DATA PRESENTATION ..................................................................................................22
13.1 Derived Parameters .....................................................................................................22
13.2 Missing Data ...............................................................................................................22
13.3 Insufficient Data for Presentation ................................................................................22


Final, 10 Sep 2020
             Page 4 of 22
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
Percentage of AUC that is due to extrapolation from the last 
measureable concentration to 
ADA
Anti-drug antibody
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-168h)
Area under the concentration versus time curve from time zero to 168 
hours postdose
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BG
Blood glucose
BQL
Below the lower limit of quantitation
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Coefficient of variation
ECG
Electrocardiogram
GE
Gastric emptying
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic
PG
Plasma glucose
PK
Pharmacokinetic


Final, 10 Sep 2020
             Page 5 of 22
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
QW
Once weekly
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
SOP
Standard Operating Procedure
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
T2DM
Type 2 Diabetes Mellitus
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Fi nal, 1 0 Se p 2 0 2 0
             Pa ge 6 of 2 2
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 4 1 6 6 5 7
S p o ns or Refere nce I 8 F-M C -G P H U
3. I N T R O D U C TI O N
T his S A P has bee n de vel o pe d after re vie w of t he Cli nical St u d y  Pr ot oc ol (fi nal versio n date d 
3 0 A pril 2 0 2 0 ) a n d Pr ot oc ol A me n d me nt (a) (fi nal versi o n date d 2 3 J ul y 2 0 2 0).
T his S A P descri bes t he pla n ne d a nal y sis of t he safet y, t olera bilit y, p har m ac o ki netic (P K ) a n d 
p har mac o d y na mic ( P D) data fr o m t his st u d y. A detaile d descri pt i on of t he pla n ne d T F Ls t o be 
prese nte d i n t he cli nical st u d y  re p ort ( C S R) is pr o vi de d i n t he acc om pa n yi n g T F L s hell 
d oc u m e nt.
T he i nte nt of t his d oc u me nt is t o pr o vi de g ui da nce f or t he statist ical, P D a n d P K a nal yses of data . 
I n ge neral , t he a nal yses are base d o n i nf or mati on fr o m t he pr ot oc ol, u nless t he y ha ve bee n 
m o difie d b y  a gree me nt wit h El i Lill y  a n d C o mpa n y . A li mite d a m o u nt of i nf or mati o n 
c o ncer ni n g t his st u d y (e. g., o bject i ves, st u d y desi g n) is gi ve n t o help t he rea der’s i nter pretati o n . 
F or o pe n -label st u dies, t his S A P m ust be sig ne d off pri or t o first s u bject visit f or t his st u d y. 
W he n t he S A P a n d T F L s hells are a gree d u p o n a n d fi nalize d, t he y  will ser ve as t he te mplate f or 
t his st u d y’s C S R.
T his S A P s u perse des t he statist ical c o nsi derati ons i de ntifie d i n t he pr ot oc ol; w here 
c o nsi derati o ns are s u bsta nt iall y differe nt, t he y will be s o ide nt ifie d. If a d diti on al  a nal yses are 
re q uire d t o s u p ple me nt t he pla n ne d a nal yses descri be d i n t his S A P, t he y ma y be perf or me d a n d 
will be i de nt ifie d i n t he C S R. A n y s u bsta ntial de viati o ns fr o m t his S A P will be a gree d u p o n wi t h
Eli Lill y a n d C o m pa n y a n d i de nt ifie d i n t he C S R. A n y mi n or de viat i ons fr om t he T F Ls ma y not 
be d oc u m e nte d i n t he C S R.
T his S A P is writte n wit h c o nsi derati o n of t he rec o m me n dat i ons o utli ne d i n t he I nte r nati o nal 
C o nfere nce o n H ar m o nis at i on (I C H) E 9 G ui deli ne e ntit le d G ui da nce f or I n d ustr y: Stati stical 
Pri nci ples f or Cli nical Trials 1 a n d t he I C H E 3 G ui deli ne e nt itle d G ui da nce f or I n d ustr y: 
Str uct ure a n d C o nte nt of Cli nical St u d y  Re p orts2.
4. S T U D Y O B J E C TI V E S
4. 1
Pri m ar y O bjecti ve
T o assess t he effect of tirze pati de o n t he P K pr ofile of aceta mi n o p he n, a mar ker f or G E .
4. 2
Sec o n d ar y O bjecti ve s

T o e val uate tirze pat i de P K a n d P D effects f oll owi n g m ul tiple d oses of su bc uta ne o us (S C )
tirze pati de i n o ver wei g ht/ o bese n o n-dia bet ic s u bjects a n d o ver weig ht/ o bese t ype 2 
di a betes mellit us ( T 2 D M) s u bjects.

T o e val uate tirze pat i de safety a n d t olera bilit y f oll owi n g m ult i ple d oses of S C tirze pati de 
i n o ver wei g ht/ o bese n o n -dia bet ic s u bjects a n d o ver wei g ht/ o bese T 2 D M s u bjects .
4. 3
E x pl or at or y O bjecti ve s
C CI


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU

To evaluate the PD effects of tirzepatide on appetite and weight.
5. STUDY DESIGN
This is an open-label, fixed sequence study in overweight/obese non-diabetic subjects and
overweight/obese T2DM subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days
prior to Day 1. Subjects will be admitted to the clinical research unit (CRU) on Day -3 and will 
establish baseline measurements during the Baseline Period from Days -3 to -1.
Subjects may be permitted to leave the CRU on Day 4 of the Treatment Period following
completion of study procedures. A second inpatient period will take place from Days 35 to 39. 
Outpatient visits will take place on Days 8 (±1 day), 15 (±1 day), 22 (±1 day), 29 (±1 day), and
43 (±2 days).
A final follow-up visit will occur on Day 64 ± 1 day (i.e. 28 days ± 1 day after the final
tirzepatide dose).
Figure 1: Study design


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
6. TREATMENTS
The following is a list of the study treatment labels that will be used in the Safety TFLs.
Study Treatment Name
Treatment order in TFL
1 g acetaminophen oral (Day -1)
1
5 mg tirzepatide SC (Day 1/Week 1)
2
1 g acetaminophen oral (Day 2)
3
5-15 mg tirzepatide SC QW (Days 8-36/Weeks 2-6)
4
1 g acetaminophen oral (Day 37)
5
Abbreviations: QW = once weekly; SC = subcutaneous.
The following is a list of the study treatment labels that will be used in the PD and PK TFLs
(where a full profile is collected):
Analyte
Profile 
Day
Study Treatment Name
Treatment 
order in TFL
Acetaminophen
-1
1 g acetaminophen oral
1
2
5 mg tirzepatide SC + 1 g acetaminophen oral
2
37
15 mg tirzepatide SC + 1 g acetaminophen oral
3
Tirzepatide
1
5 mg tirzepatide SC
4
36
15 mg tirzepatide SC
5
Abbreviations: SC = subcutaneous.
7. SAMPLE SIZE JUSTIFICATION
Approximately 18 overweight or obese non-diabetic subjects and 18 overweight or obese T2DM
subjects will be enrolled so that a minimum of 12 subjects in each group completes the study. In
total, approximately 36 subjects will be enrolled so that a minimum of 24 subjects complete the
study.
For acetaminophen area under the concentration versus time curve (AUC) and maximum 
observed drug concentration (Cmax), the intra-subject variability (coefficient of variation [CV])
was estimated to be 15.7% and 21.9%, respectively (derived from study I8F-MC-GPGA). Based
on this assumption, 24 subjects will provide a precision of 0.09 and 0.13 on a log-scale for AUC
and Cmax, respectively. This would result in a 90% probability that the half-width of the 90%
confidence interval (CI) of the ratio of the geometric least square means for AUC and Cmax is no
larger than 8.8% and 12.0%, respectively.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of 
acetaminophen or tirzepatide, whether or not they completed all protocol requirements.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
The “Primary Pharmacokinetic” population will consist of all subjects who received at least one 
dose of acetaminophen and have evaluable acetaminophen PK data. Subjects may be excluded 
from the PK summary statistics if a subject has an adverse event (AE) of vomiting that occurs at 
or before 2 times median time of maximum observed drug concentration tmax. 
The “Secondary Pharmacokinetic” population will consist of all subjects who received at least 
one dose of acetaminophen and tirzepatide and have evaluable tirzepatide PK data. Subjects may 
be excluded from the PK summary statistics if a subject has an adverse event (AE) of vomiting 
that occurs at or before 2 times median time of maximum observed drug concentration tmax.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be summarized and listed.
The demographic variables age, sex, race, ethnicity, body weight, height, body mass index,
hemoglobin A1c, T2DM diagnosis (yes/no) and duration of diabetes will be summarized by 
treatment and listed. All other demographic variables will be listed only.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
9.3
Pharmacokinetic and Pharmacodynamic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined using non-compartmental methods in validated 
software program, Phoenix WinNonlin (Certara, Version 8.1 or later):
Plasma concentrations of acetaminophen will be used to determine the following PK parameters, 
when possible:  
Parameter
Units
Definition
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Plasma concentrations of tirzepatide (LY3298176) will be used to determine the following PK 
parameters, when possible:  


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
Parameter
Units
Definition
AUC(0-∞)
ng.h/mL area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-168h)
ng.h/mL
area under the concentration versus time curve from time zero to 
168 hours postdose
%AUC(tlast-∞)
%
percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis (Day 36 only)
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (Day 36 only)
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration (Day 36 only)
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (Day 36 only)
Additional PK parameters may be calculated where appropriate.
The software and version used for the final analysis will be specified in the CSR. Any exceptions 
or special handling of data will be clearly documented within the final study report.
PK analysis will, where possible, be carried out using actual postdose times recorded in the raw 
data. 
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool:  
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed. 
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one time
point, tmax will be assigned to the first occurrence of Cmax.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU

Where concentration data are supplied in ng equiv/g a matrix density of 1g/mL will be 
used for PK calculation.

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification, with at least 
one of these concentrations following Cmax.  

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table. If AUC(0-∞) cannot be determined for all subjects an 
alternative AUC measure, such as AUC to a fixed time point, may be used in the 
assessment exposure between dose groups.

Half-life (t1/2) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t1/2 is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t1/2 value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on the last predicted quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero
when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent dose 
period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not 
an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
No formal statistical analysis will be performed on the PK parameters of tirzepatide.
The PK parameters of tirzepatide will be summarized using descriptive statistics by treatment. 
Plasma concentrations of tirzepatide will be graphically represented with an arithmetic mean plot 
and a concentration-time profile by subject. Trough concentrations will also be presented by 
timepoint.


 
Final, 10 Sep 2020 
 
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Statistical Analysis Plan  
 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657 
Sponsor Reference I8F-MC-GPHU
All analyses of the PK parameters of tirzepatide will be based upon the Secondary PK 
population. 
9.3.3 
Pharmacodynamic Statistical Methodology 
Acetaminophen PK parameters will be evaluated to estimate the impact of tirzepatide on GE 
using acetaminophen PK as probe. Log-transformed Cmax and AUC(0-tlast) will be evaluated in a 
linear mixed-effects model3, with day (-1, 2, 37) as a fixed effect and subject as a random effect. 
The differences in Cmax and AUC(0-tlast) between acetaminophen + tirzepatide (Test; Days 2 and 
37) and acetaminophen alone (Reference; Day -1) will be back-transformed to present the ratios 
of geometric least squares means and the corresponding 90% CI. All available data will be 
included in the analysis. 
Example SAS code: 
proc mixed data=XXXX; 
  class subject day; 
  model logpk = day / residual cl ddfm=kr; 
  random subject; 
  lsmeans day / pdiff cl alpha=0.1; 
  ods output lsmeans=lsm; 
  ods output diffs=diff; 
run; 
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the median difference 
based on the observed medians and 90% CIs from the Wilcoxon test will be calculated.  
For the secondary objective, population (non-diabetic/T2DM subjects) and the 
population-by-day interaction term will be added to the above model. Subject nested within 
population will be fitted as a random effect. The following comparisons will be assessed for Cmax 
and AUC(0-tlast): 
 Day 2 (Test) versus Day -1 (Reference) for non-diabetic subjects 
 Day 2 (Test) versus Day -1 (Reference) for T2DM subjects 
 Day 37 (Test) versus Day -1 (Reference) for non-diabetic subjects 
 Day 37 (Test) versus Day -1 (Reference) for T2DM subjects 
In addition, the impact of tirzepatide on GE will be compared between populations. I.e., the 
following ratios will be derived: 
  Day 2୬୭୬ିୢ୧ୟୠୣ୲୧ୡ
Day -1୬୭୬ିୢ୧ୟୠୣ୲୧ୡ
/ Day 2୘ଶୈ୑
Day -1୘ଶୈ୑
  Day 37୬୭୬ିୢ୧ୟୠୣ୲୧ୡ
Day -1୬୭୬ିୢ୧ୟୠୣ୲୧ୡ
/ Day 37୘ଶୈ୑
Day -1୘ଶୈ୑


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
Example SAS code:
proc mixed data=XXXX;
  class subject day population;
  model logpk = day population population*day / residual cl ddfm=kr;
  random subject(population);
  lsmeans population*day / pdiff cl alpha=0.1;
  estimate ‘Day 2 ratio, non-diabetic versus T2DM’ population*day
      -1 1 0
1 -1 0 / alpha=0.1 cl;
  estimate ‘Day 37 ratio, non-diabetic versus T2DM’ population*day
      -1 0 1
1 0 -1 / alpha=0.1 cl;
  ods output lsmeans=lsm;
  ods output diffs=diff;
  ods output estimates=est;
run;
The tmax will be analyzed using a Wilcoxon signed rank test for comparisons within each 
population. Estimates of the median difference based on the observed medians and 90% CIs 
from the Wilcoxon test will be calculated. For comparisons between populations, the Wilcoxon 
rank-sum test will be used.
The PK parameters of acetaminophen will be summarized using descriptive statistics by 
treatment. Plasma concentrations of acetaminophen will be graphically represented with an 
arithmetic mean plot and a concentration-time profile by subject.
All analyses of the PK parameters of acetaminophen will be based upon the Primary PK 
population.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to the first dose of acetaminophen. A 
treatment-emergent AE is defined as an AE which occurs postdose or which is present prior to 
dosing and becomes more severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.0 system organ class (SOC) and preferred term (PT). The summary and frequency AE
tables will be presented for all causalities and those considered related to the study drug by the 
investigator. Any serious AEs will be listed. AEs by week of onset for tirzepatide will be 
presented. 
Discontinuations due to AEs will be listed.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
9.4.2
Glucose Monitoring and Hypoglycemia
During the study, blood glucose (BG) concentrations will be monitored for safety assessments.
Glucose data will be listed and summarized by treatment together with changes from baseline, 
where baseline is defined as Day 1 predose.
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual BG value, if measured, will be recorded in the CRF, together with any 
treatments administered. Each category of hypoglycemic events (defined below) will be listed 
and summarized by treatment. Hypoglycemia is defined as follows:

Glucose Alert Level (Level 1):
o
Documented symptomatic hypoglycemia is defined as any time a patient feels 
that he or she is experiencing symptoms and/or signs associated with 
hypoglycemia and has a plasma glucose (PG) level of ≤70 mg/dL (≤3.9 mmol/L).
o
Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured 
PG ≤70 mg/dL (≤3.9 mmol/L).
o
Documented unspecified hypoglycemia is defined as any event with no
information about symptoms of hypoglycemia available, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).

Clinically Significant Hypoglycemia (Level 2):
o
Documented symptomatic hypoglycemia is defined as any time a patient feels
that he or she is experiencing symptoms and/or signs associated with
hypoglycemia and has a PG level of <54 mg/dL (<3.0 mmol/L).
o
Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG <54 
mg/dL (<3.0 mmol/L).
o
Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).

Severe hypoglycemia (Level 3):
o
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. BG measurements may not 
be available during such an event, but neurological recovery attributable to the 
restoration of BG to normal is considered sufficient evidence that the event was 
induced by a low BG concentration.

Other hypoglycemia categories:
o
Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.
Investigator review of glucose results clinically indicative of hypoglycemia will be required.


Fi nal, 1 0 Se p 2 0 2 0
             Pa ge 1 8 of 2 2
Stati stical A nal ysis Pla n 
C O N FI D E N TI A L
C o va nce Cli nical St u d y  N o. 1 0 0 0 0 7 1- 8 4 1 6 6 5 7
S p o ns or Refere nce I 8 F-M C -G P H U
9. 4. 3
6 -p oi nt Pl as m a Gl uc ose Pr ofile
Data fr o m t he 6 -p oi nt plas ma gl uc ose pr ofile will be s u m mar ise d b y treat me nt a n d ti me p oi nt, 
a n d liste d.
9. 4. 4
C o nc o mit a nt me dic ati o n
C o nc o mita nt me dicat i on will be c o de d usi n g t he W H O dr u g dict i onar y  ( Versio n  Marc h
2 0 2 0
B 3 ). C o nc o mita nt me dicat i on will be liste d.
9. 4. 5
Cli nic al l a b or at or y p ar a meters
All cli nical c he mistr y a n d he mat ol o g y data w ill be s u m marize d b y para meter, treat me nt a n d 
ti me p oi nt t o get her wit h c ha n ges fr o m baseli ne, w here baseli ne is defi ne d as t he Da y  - 2
assess me nt . All cli nical c he mistr y, he mat ol o g y a n d uri nal ysis data will be liste d.
A d dit i onall y , cli nical c he mistr y, he mat ol og y a n d uri nal ysis data o utsi de t he refere nce ra n ges will 
be liste d a n d fla g ge d o n i n di vi d ual s u bject data listi n gs.
9. 4. 6
Vit al si g ns
Vi t al si g ns data will be s u m marize d b y treat me nt t o get her wit h c ha n ges fr o m baseli ne, w here 
baseli ne is defi ne d as t he D a y  - 2 assess me nt . Fi g ures of m ea n vit al si g ns a n d mea n c ha n ges fr o m 
baseli ne pr ofiles will be prese nte d b y  tr e at me nt. 
V alu es f or i n di vi d ual s u bjects will be liste d.
9. 4. 7
Electr oc ar di o gr a m ( E C G)
E C Gs will be perf or me d f or safet y m o nit ori n g p ur p oses o nl y a n d will n ot be prese nte d . A n y 
cli nicall y si g nifica nt fi n di n gs fr o m E C Gs will be re p orte d as a n A E.
9. 4. 8
B o d y wei g ht a n d W aist Circ u mfere nce
B o d y  wei g ht a n d waist circ u mfere nce data will be s u m marize d b y  tr e at me nt t o get her wit h 
c ha n ges fr o m baseli ne , w here baseli ne f or b o d y wei g ht is defi ne d as t he Da y 1 pre d ose 
assess me nt a n d f or waist circ u mfere nce is defi ne d as t he Da y  -2 assess me nt.
9. 4. 1 0
Assess me nt of A p petite
T o e x p l ore the effects of tirze pat i de o n meal i nta ke a n d a p petite se nsati on , s u bjects will be as ke d 
t o rate t heir a p petite se nsat i ons usi n g a 1 0 0 -m m vali date d vis ual a nal o g scale ( V A S) f or 
para m eters of h u n ger, f ull ness, sat iety,  a n d pr os pecti ve f o o d c o ns u m pti on . 
C CI


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
Overall appetite score is calculated as the average of the 4 individual scores – satiety + fullness + 
(100-prospective food consumption) + (100-hunger) / 4. The higher overall appetite score 
indicates less appetite, and the lower score indicates more appetite.
Each parameter and overall appetite score will be listed and summarized, along with change
from baseline (defined as Day 1 predose), by treatment and timepoint.
9.4.11
Hepatic Monitoring
Close hepatic monitoring
If a subject who had normal or near normal baseline alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBL) (i.e., <1.5× upper 
limit of normal [ULN]), experiences elevated ALT≥3× ULN, AST≥3× ULN, ALP≥2× ULN, or
TBL≥2× ULN, laboratory tests should be repeated within 48 to 72 hours, including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyltransferase, and creatinine phosphokinase to
confirm the abnormality and to determine if it is increasing or decreasing.
In subjects enrolled with elevated baseline ALT, AST, ALP or TBL (≥1.5× ULN), the thresholds
for close monitoring are ALT≥2× baseline, AST≥2× baseline, ALP≥2× baseline, or TBL≥2×
baseline.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, including symptoms, recent illnesses, (for example, heart failure, systemic infection, 
hypotension, or seizures), recent travel, history of concomitant medications (including over-the-
counter), herbal and dietary supplements, history of alcohol drinking and other substance abuse
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.
Comprehensive hepatic evaluation
If a study subject, who had baseline ALT, AST, ALP, TBL<1.5× ULN, experiences elevated
ALT≥5× ULN, AST≥5× ULN, ALP ≥3× ULN, TBL ≥2× ULN, or elevated ALT, AST ≥3× ULN
with hepatic signs/symptoms (severe fatigue, nausea, vomiting, right upper quadrant abdominal
pain, fever, rash, and/or eosinophilia>5%), a comprehensive evaluation should be performed to
search for possible causes of liver injury.
In subjects who had elevated baseline ALT, AST, ALP, or TBL (≥1.5× ULN), the thresholds for
performing this evaluation are ALT≥3× baseline, AST≥3× baseline, ALP≥2× baseline, 
TBL≥1.5× baseline, or ALT, AST ≥2× baseline with hepatic signs/symptoms.
At a minimum, this evaluation should include physical examination and a thorough medical
history, as outlined above, as well as tests for prothrombin time-international normalized ratio,
viral hepatitis A, B, C, E, tests for autoimmune hepatitis, and an abdominal imaging study (for
example, ultrasound or computed tomography [CT] scan).


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
Additional hepatic data collection in subjects who have abnormal liver tests during the 
study
Additional hepatic safety data collection should be performed in subjects who meet 1 or more of 
the following 5 conditions:
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline
ALT<1.5x ULN)
In subjects with baseline ALT≥1.5× ULN, the threshold is ALT≥3x baseline on 2 
or more consecutive tests
2. Elevated TBL to ≥2× ULN (if baseline TBL <1.5× ULN)
In subjects with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2x
baseline
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline
ALP <1.5× ULN)
In subjects with baseline ALP≥1.5× ULN, the threshold is ALP ≥2× baseline on 2
or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of the investigational produce due to a hepatic event
Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medications that have potential for hepatotoxicity, including acetaminophen 
will be listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography (MRE) scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.12
Hypersensitivity reactions
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.
For moderate-to-severe hypersensitivity reactions that occur, additional follow-up data will be 
collected to assess the subject’s medical history, alternative causes, and symptoms. These data 
will be listed.
Additionally, unscheduled PK, immunogenicity, and laboratory data may be collected. All data 
will be included in the relevant listings.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
9.4.13
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Injection site assessment data (erythema, induration, categorical pain, pruritus, and edema) will
be summarized and listed.
9.4.14
Immunogenicity Assessments
Immunogenicity data will be listed and frequency tables will be presented if analysed. The 
frequency and percentage of subjects with pre-existing ADA and with treatment-emergent ADAs 
(TE ADAs) will be presented. TE ADAs are those that are boosted or induced by exposure to 
study drug, with a 4-fold increase in titer compared to baseline if ADAs were detected at 
baseline or a titer 2-fold greater than the minimum required dilution (1:10) if no ADAs were 
detected at baseline, where baseline is defined as Day 1 predose.
If cross-reactivity with native glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP) or a neutralization assay is performed, the frequency of each 
will be determined. 
The relationship between the presence of antibodies and PK parameters of tirzepatide may be 
assessed if deemed appropriate.
9.4.15
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.16
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
Additional statistical analyses were added for the secondary objective, evaluating the impact of 
tirzepatide on GE within each population (non-diabetic subjects and T2DM subjects) and 
between populations.


Final, 10 Sep 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8416657
Sponsor Reference I8F-MC-GPHU
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & Sons, 
1999
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


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A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 0 - S e p - 2 0 2 0  1 3 : 5 3 : 0 8  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 0 - S e p - 2 0 2 0  1 4 : 0 2 : 0 8  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 0 - S e p - 2 0 2 0  1 4 : 0 5 : 2 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 1 - S e p - 2 0 2 0  0 9 : 1 7 : 3 5  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
P P D
P P D