A Randomized, Phase 3, Open-Label Trial Comparing the Effect of LY3298176 Versus Titrated Insulin Degludec on Glycemic Control in Patients With Type 2 Diabetes
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Protocol I8F-MC-GPGH (c) 
 
A Randomized, Phase 3, Open-Label Trial Comparing the Effect of LY3298176 versus Titrated 
Insulin Degludec on Glycemic Control in Patients with Type 2 Diabetes (SURPASS-3) 
 
NCT03882970 
 
Approval Date: 30-Jul-2020 

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

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Table of Contents
Section
Page
Protocol I8F-MC-GPGH(c) A Randomized, Phase 3, Open-Label Trial 
Comparing the Effect of LY3298176 versus Titrated Insulin 
Degludec on Glycemic Control in Patients with Type 2 Diabetes 
(SURPASS-3).....................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................14
3.
Introduction ......................................................................................................................22
3.1.
Study Rationale............................................................................................................22
3.2.
Background..................................................................................................................23
3.3.
Benefit/Risk Assessment..............................................................................................24
4.
Objectives and Endpoints..................................................................................................25
5.
Study Design.....................................................................................................................27
5.1.
Overall Design .............................................................................................................27
5.2.
Number of Participants.................................................................................................32
5.3.
End of Study Definition ...............................................................................................32
5.4.
Scientific Rationale for Study Design...........................................................................32
5.5.
Justification for Dose ...................................................................................................33
6.
Study Population...............................................................................................................34
6.1.
Inclusion Criteria..........................................................................................................34
6.2.
Exclusion Criteria ........................................................................................................35
6.3.
Lifestyle Restrictions....................................................................................................38
6.4.
Screen Failures.............................................................................................................38
7.
Treatments........................................................................................................................39
7.1.
Treatments Administered .............................................................................................39
7.1.1.
Packaging and Labeling .......................................................................................40
7.1.2.
Medical Devices...................................................................................................40
7.2.
Method of Treatment Assignment ................................................................................40
7.2.1.
Selection and Timing of Doses.............................................................................40
7.2.1.1.
LY3298176 ....................................................................................................40
7.2.1.2.
Insulin Degludec.............................................................................................41
7.3.
Blinding .......................................................................................................................42
7.4.
Dosage Modification....................................................................................................42
7.4.1.
Study Drugs .........................................................................................................42

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7.4.2.
Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications...........................................................................42
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................44
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................45
7.8.
Treatment after the End of the Study............................................................................46
7.8.1.
Treatment after Study Completion........................................................................46
7.8.2.
Special Treatment Considerations ........................................................................46
8.
Discontinuation Criteria ....................................................................................................47
8.1.
Discontinuation from Study Treatment.........................................................................47
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................47
8.1.2.
Temporary Discontinuation from Study Treatment...............................................48
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................48
8.2.
Discontinuation from the Study....................................................................................49
8.3.
Lost to Follow-up.........................................................................................................49
9.
Study Assessments and Procedures ...................................................................................51
9.1.
Efficacy Assessments...................................................................................................51
9.1.1.
Primary Efficacy Assessments and Procedures.....................................................51
9.1.2.
Secondary Efficacy Assessments and Procedures.................................................51
9.1.3.
Exploratory Efficacy Assessments and Procedures...............................................51
9.1.4.
Appropriateness of Assessments ..........................................................................52
9.2.
Adverse Events ............................................................................................................52
9.2.1.
Serious Adverse Events........................................................................................53
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................54
9.2.2.
Adverse Events of Special Interest .......................................................................54
9.2.2.1.
Hypoglycemia ................................................................................................54
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................55
9.2.2.3.
Pancreatitis.....................................................................................................56
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia................................................57
9.2.2.5.
Major Adverse Cardiovascular Events............................................................58
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................58
9.2.2.7.
Hypersensitivity Events..................................................................................58
9.2.2.7.1.
Injection Site Reactions ............................................................................58
9.2.2.7.2.
Anti-Drug Antibodies ...............................................................................58
9.2.2.8.
Diabetic Retinopathy Complications...............................................................59
9.2.2.9.
Hepatobiliary Disorders..................................................................................59

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9.2.2.10.
Severe Gastrointestinal Adverse Events..........................................................59
9.2.2.11.
Acute Renal Events ........................................................................................59
9.2.2.12.
Metabolic Acidosis, Including Diabetic Ketoacidosis .....................................59
9.2.2.13.
Amputation/Peripheral Revascularization .......................................................59
9.2.2.14.
Major Depressive Disorder/Suicidal Ideation..................................................60
9.2.3.
Complaint Handling.............................................................................................60
9.3.
Treatment of Overdose.................................................................................................60
9.4.
Safety...........................................................................................................................60
9.4.1.
Electrocardiograms ..............................................................................................60
9.4.2.
Vital Signs ...........................................................................................................60
9.4.3.
Laboratory Tests ..................................................................................................61
9.4.4.
Immunogenicity Assessments ..............................................................................61
9.4.5.
Safety Monitoring ................................................................................................62
9.4.5.1.
Hepatic Safety Monitoring..............................................................................62
9.5.
Pharmacokinetics .........................................................................................................62
9.6.
Pharmacodynamics ......................................................................................................62
9.7.
Pharmacogenomics ......................................................................................................62
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................62
9.8.
Biomarkers...................................................................................................................63
9.9.
Health Economics ........................................................................................................63
9.9.1.
Diabetes Treatment Satisfaction Questionnaire.....................................................64
9.9.2.
Impact of Weight on Self-Perception Questionnaire .............................................64
9.9.3.
Ability to Perform Physical Activities of Daily Living .........................................64
9.9.4.
European Quality of Life......................................................................................64
10.
Statistical Considerations ..................................................................................................66
10.1. Sample Size Determination ..........................................................................................66
10.2. Populations for Analyses..............................................................................................66
10.3. Statistical Analyses ......................................................................................................67
10.3.1.
General Statistical Considerations ........................................................................67
10.3.2.
Treatment Group Comparability...........................................................................68
10.3.2.1.
Patient Disposition..........................................................................................68
10.3.2.2.
Patient Characteristics ....................................................................................68
10.3.2.3.
Concomitant Therapy .....................................................................................68
10.3.2.4.
Treatment Compliance....................................................................................68
10.3.3.
Efficacy Analyses ................................................................................................68
10.3.3.1.
Primary Analyses ...........................................................................................68
10.3.3.2.
Secondary Analyses........................................................................................69
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................70

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10.3.4.
Safety Analyses....................................................................................................70
10.3.4.1.
Hypoglycemic Events.....................................................................................70
10.3.4.2.
Gastrointestinal Events...................................................................................70
10.3.4.3.
Adjudicated Cardiovascular Events ................................................................71
10.3.4.4.
Central Laboratory Measures, Vital Signs, and 
Electrocardiograms.........................................................................................71
10.3.5.
Evaluation of Immunogenicity .............................................................................71
10.3.6.
Other Analyses.....................................................................................................71
10.3.6.1.
Health Economics...........................................................................................71
10.3.6.2.
Subgroup Analyses.........................................................................................71
10.3.7.
Interim Analyses..................................................................................................72
11.
References ........................................................................................................................73
12.
Appendices .......................................................................................................................76

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List of Tables
Table
Page
Table GPGH.1.
Schedule of Activities....................................................................................15
Table GPGH.2.
Objectives and Endpoints...............................................................................25
Table GPGH.3.
Study Treatments...........................................................................................39
Table GPGH.4.
Titration of Insulin Degludec .........................................................................41
Table GPGH.5.
Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments in Study GPGH..........................................45
Table GPGH.6.
Description of Analysis Sets ..........................................................................66

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List of Figures
Figure
Page
Figure GPGH.1. Illustration of study design for Clinical Protocol I8F-MC-GPGH...................28

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................77
Appendix 2.
Clinical Laboratory Tests...............................................................................82
Appendix 3.
Study Governance Considerations..................................................................84
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................88
Appendix 5.
World Health Organization Classification of Diabetes and Diagnostic 
Criteria ..........................................................................................................89
Appendix 6.
Classification of Contraceptive Methods........................................................90
Appendix 7.
Changes to Study Procedures due to the COVID-19 Pandemic ......................91
Appendix 8.
Protocol Amendment I8F-MC-GPGH(c)
A Randomized, Phase 3, Open-Label Trial Comparing the Effect of 
LY3298176 versus Titrated Insulin Degludec on Glycemic Control in 
Patients with Type 2 Diabetes (SURPASS-3) ................................................92

I 8 F-M C -G P G H( c) Cli ni c al Pr ot o c ol
P a g e 9
L Y 3 2 9 8 1 7 6
1. S y n o p si s
Title of St u d y:
A Ra n d o mize d, P hase 3, O pe n -La bel Tri al C o mpari n g t he Effect of L Y 3 2 9 8 1 7 6 vers us Ti trate d 
I ns uli n De gl u dec o n Gl yce mic C o ntr ol i n Pati e nts wi t h T ype 2 Di a betes ( S U R P A S S- 3)
R ati o n ale: 
T y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c haracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y increase d i ns uli n resista nce a n d pr o gressi ve beta -cell fail ure a n d c o nse q ue nt l y 
i na de q uate i ns uli n secreti on. As t he disease pr o gresses, treat me nt wit h m ult i ple dr u gs will be 
nee de d t o ac hie ve gl yce mic c o ntr o l ( A merica n Dia betes Ass ociati on [A D A ] 2 0 1 7). W he n oral 
a nt i h y per gl yce mic me dicat i ons ( O A M s) are i ns ufficie nt t o reac h tar get gl yce mia, i njecta ble 
t hera pies are a d de d (I nz ucc hi et al. 2 0 1 5).  Basal i ns uli ns, s uc h as de gl u dec, are c o m m o nl y  use d 
as t he first i njecta ble aft er fail ure of oral t hera p y. A de q uatel y t itrate d i ns uli n de gl u dec t hera p y , 
i n c o m bi nat i on wi t h O A Ms , ma y ac hie ve t he tar get gl yce mic le vel; h o we ver, t he t w o mai n 
li mitati o ns of i ns uli n treat me nt are wei g ht gai n a n d h yp o gl yce mia ( Zi n ma n et al. 2 0 1 2, Pa n et al. 
2 0 1 6).
I njecta ble i ncreti n- base d treat me nts (f or e xa mple , G L P -1 [ gl uca g o n -li ke pe pti de-1] rece pt or 
a g o nists) are als o c o m m o nl y use d i n c o m bi nat i on wi t h O A Ms t o ac hie ve a n d mai ntai n gl uc ose 
c o ntr ol ( A D A 2 0 1 7, I nz ucc hi et al. 2 0 1 5). W hile ass ociate d wit h l o wer ris k f or h y p o gl yce mia 
a n d eit her wei g ht ne utral o r weig ht l oss effects, c urre nt pre parati o ns are directe d at a si n gle 
m o lec ular tar get ( G L P- 1 rece pt ors) a n d pr o vi de d ose-de pe n de nt gl uc ose -l oweri n g effects , w hic h 
ca n be li mite d b y gastr oi ntest i nal t olera bility ( Na uc k 2 0 1 6).
L Y 3 2 9 8 1 7 6 is a 3 9-a mi n o aci d s y nthet ic pe pti de with a g o nist acti vit y at b ot h t he GI P 
( gluc ose -de pe n de nt i ns uli n otr o pic p ol y pe pt i de) a n d G L P-1 rece pt ors. Its str uct ure is base d o n 
t he GI P se q ue nce a n d i ncl u des a C 2 0 fatt y di-aci d moi et y t hat 
 It is a d mi nistere d o nce-wee kl y  ( Q W) b y s u bc uta ne o us ( S C) i njecti on . 
St u d y  I 8 F-M C -G P G H ( G P G H) is a P hase 3, m ult ice nter, ra n d o mize d, o pe n-label, parallel -gr o u p 
st u d y t hat will i n vesti gate t he effects of treat me nt wit h L Y 3 2 9 8 1 7 6, 5 m g, 1 0 m g, a n d 1 5 m g 
Q W, c o m pare d wi t h titrate d i ns uli n de gl u dec i n patie nts wit h T 2 D M nai ve of  ins uli n treat m e nt 
w h o ha ve i na de q uate gl yce mic c o ntr ol o n sta ble d oses of metf or mi n wit h or wi t ho ut a 
s o diu m -gl uc ose c o -tra ns p orter- 2 i n hi bit or ( S G L T-2i ).
C CI

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Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To demonstrate that QW LY3298176 10 mg 
and/or 15 mg is noninferior to insulin 
degludec for change from baseline in HbA1c 
at 52 weeks

Mean change in HbA1c 
Key Secondary (controlled for type 1 error)
Efficacy

To demonstrate that QW LY3298176 5 mg is 
noninferior to insulin degludec for change in 
baseline in HbA1c at 52 weeks

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
degludec for change from baseline in weight 
at 52 weeks 

Mean change in HbA1c 

Mean change in body weight 

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
degludec for change from baseline in HbA1c 
at 52 weeks 

Mean change in HbA1c 

To demonstrate QW LY3298176 5 mg, 10 
mg, and /or 15 mg is superior to insulin 
degludec for the proportion of patients with
HbA1c target value of <7.0% (53 mmol/mol) 
at 52 weeks

HbA1c
Additional Secondary (not controlled for type 1
error)

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
degludec at 52 weeks

To compare LY3298176 5 mg, 10 mg, and 
15 mg to insulin degludec at 52 weeks for:

Mean change in fasting serum glucose
(central lab) from baseline

Proportion of patients achieving an HbA1c 
target values of ≤6.5% (48 mmol/mol) and
<5.7% (39 mmol/mol)

Mean change in 7-point self-monitored blood 
glucose (SMBG) profiles from baseline

Proportion of patients who achieved weight
loss ≥5%, ≥10%, and ≥15% from baseline

Patient-reported outcomes:
o
Diabetes Treatment Satisfaction 
Questionnaire status/ Diabetes
Treatment Satisfaction Questionnaire 
change 
o
Impact of Weight on Self-Perception
o
Ability to Perform Physical 

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Objectives
Endpoints
Activities of Daily Living
Safety

To compare LY3298176 5 mg, 10 mg, and 
15 mg to insulin degludec for:

Treatment-emergent adverse events (TEAEs)

Early discontinuation of study drug due to 
adverse events (AEs)

Adjudicated pancreatic AEs

Serum calcitonin

Incidence of allergic and hypersensitivity 
reactions 

Incidence of treatment-emergent anti-drug 
antibodies to LY3298176

Mean change in systolic and diastolic blood 
pressure and heart rate from baseline 

Occurrence of hypoglycemic episodes

Incidence of initiation of rescue therapy for 
severe, persistent hyperglycemia
Abbreviations:  HbA1c = hemoglobin A1c; HDL=high density lipoprotein; QW = once weekly; T2DM = type 2 
diabetes mellitus; TG = triglycerides; VLDL = very low density lipoprotein
Summary of Study Design:  
Study GPGH is a Phase 3, multicenter, randomized, open-label, parallel-arm study that will 
investigate the effects of treatment with LY3298176 5 mg, 10 mg, and 15 mg QW compared 
with titrated insulin degludec in patients with T2DM who have inadequate glycemic control on 
stable doses of metformin with or without an SGLT-2i.
Treatment Groups and Duration:  
Study GPGH will consist of 3 periods:  an approximately 3-week screening/lead-in period, 
followed by a 52-week treatment period, and a 4-week safety follow-up period.  Patients will be 
randomized in a 1:1:1:1 ratio to receive LY3298176 doses:  5 mg QW, 10 mg QW, 15 mg QW, 
or insulin degludec once daily (QD).  Patients will be stratified at randomization based on 
HbA1c (≤8.5%, >8.5% [69 mmol/mol]), country, and use of concomitant oral antidiabetic 
treatments (metformin alone, metformin plus an SGLT-2i).
Number of Patients:
A total of approximately 1420 patients will be randomized in a 1:1:1:1 ratio to receive 
LY3298176 doses:  5 mg QW (355 patients), 10 mg QW (355 patients), 15 mg QW (355 
patients), or insulin degludec QD (355 patients).
Statistical Analysis:
Efficacy Analyses:

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Efficacy and safety will be assessed using the modified intention-to-treat (mITT) population, 
which consists of all randomly assigned participants who are exposed to at least 1 dose of study 
drug.  There will be 2 estimands of interest in comparing efficacy of LY3298176 doses with 
insulin degludec relative to the primary endpoint of mean change in HbA1c from baseline to the 
52-week visit. The “efficacy” estimand represents efficacy prior to discontinuation of study drug 
without confounding effects of rescue therapy for persistent severe hyperglycemia.  The 
“treatment-regimen” estimand represents the efficacy irrespective of adherence to investigational 
product or introduction of rescue therapy for persistent severe hyperglycemia.
For the FDA, the primary efficacy assessment will be guided by the “treatment-regimen” 
estimand.  This assessment will analyze change from baseline in HbA1c to the 52-week visit 
using an analysis of covariance (ANCOVA) with terms:  treatment, country, baseline 
concomitant oral antidiabetic treatment (metformin alone, metformin plus SGLT-2i), and 
baseline HbA1c as a covariate.  The ANCOVA analysis will be conducted using Full Analysis 
Set at 52-week visit, which consists of all available changes from baseline in HbA1c data at the 
52-week visit, irrespective of whether they were obtained while the participants had discontinued 
the study drug or whether the participant had been given rescue medication.  Additionally, data 
for subjects with missing change from baseline in HbA1c values will be imputed based on 
observed data in the same treatment group from subjects who had their efficacy measure at the 
Week 52 visit assessed after early discontinuation of study drug and/or initiation of rescue 
medication (retrieved dropouts).  If there are not sufficient numbers of retrieved dropouts, 
baseline data may be used to develop an imputation model.  Analysis will be conducted with 
multiple imputations, and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987).
For all other purposes, the primary efficacy assessment will be guided by the “efficacy” 
estimand.  This assessment will use efficacy analysis set which consists of data obtained before 
the initiation of any rescue therapy and before premature treatment discontinuation.  The analysis 
model for change from baseline in HbA1c assessed over time will be a mixed model for repeated 
measures (MMRM), with terms:  treatment, visit, and treatment-by-visit interaction, country, 
baseline concomitant oral antidiabetic treatment (metformin alone, metformin plus SGLT-2i) as 
fixed effects, and baseline HbA1c as a covariate.  An unstructured covariance structure will 
model relationship of within-patient errors.  
A 0.3% boundary will be used for noninferiority evaluations between LY3298176 and insulin 
degludec relative to mean change in HbA1c from baseline.
Since the estimands are different, each of the 2 primary efficacy assessments will be conducted 
at a family-wise type 1 error rate of 0.05.  Additional details, including analysis methods for key
secondary endpoints and a strategy for controlling overall family-wise type 1 error rate at an
alpha of 0.05 of primary and key secondary endpoint evaluation, will be provided in the 
statistical analysis plan (SAP).

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Safety Analysis:
Unless specified otherwise, safety assessments will be based on all available data, irrespective of 
whether they were obtained while the participants had discontinued the study drug or whether the 
participant had been given rescue medication. Summary statistics will be provided for incidence 
of TEAEs, serious AEs, and study discontinuation due to AEs or death from the time of first 
dose through end of safety follow-up.  Counts and proportions of subjects experiencing AEs will 
be reported for each treatment group, and Fisher’s exact test will be used to compare the 
treatment groups.  For continuous laboratory analytes, summary statistics will be provided by 
visit, with statistical comparisons among treatment at each visit conducted using an MMRM 
analysis.  Selected safety analyses may be conducted excluding data after the introduction of
another anti-hyperglycemic therapy (for example, rescue therapy). Additional details, including 
analysis of AEs of special interest, will be provided in the Statistical Analysis Plan (SAP).

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2. Schedule of Activities
The Schedule of Activities described below should be followed for all patients enrolled in 
Study GPGH.  However, for those patients whose participation in this study is affected by severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel 
Coronavirus Disease 2019 (COVID-19), please refer to Appendix 7 for additional instructions.

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Table GPGH.1.
Schedule of Activities
Study Period I
Study Period 
II
Study Period III
Screening Lead 
in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
ET
b
801
Week of Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
46
52
4 weeks Post 
End of Tx
Allowable Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Informed consent
X
Randomization
X
Clinical Assessments
Medical historye
X
Physical
X
X
X
X
Height
X
Weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
X
X
X
Vital signs (2 sitting 
BP and HR)g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dilated Fundoscopic 
Examinationh
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review hypoglycemic 
events collected in 
diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGH(c) Clinical Protocol
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LY3298176
Study Period I
Study Period 
II
Study Period III
Screening Lead 
in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
ETb
801
Week of Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
46
52
4 weeks Post 
End of Tx
Allowable Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Patient Education
Diabetes educationi,j
X
BG meter, SMBG 
trainingj
X
Dispense BG 
meter/supplies, as 
needed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug injection 
trainingj
X
Hand out diary, 
instruct in usej
X
X
X
X
X
Remind patients 
about 7-point SMBGk
X
X
X
X
Review 7-point 
SMBG values 
collected in diary
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
X
Observe patient 
administer 
LY3298176l
X
Patient returns study 
drugs and injection 
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGH(c) Clinical Protocol
Page 17
LY3298176
supplies
Study Period I
Study Period 
II
Study Period III
Screening Lead 
in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
ETb
801
Week of Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
46
52
4 weeks Post 
End of Tx
Allowable Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Assess study drug 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review insulin dose 
and adjustment per 
TTT algorithmm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess compliance 
with insulin dose 
adjustment TTT 
algorithmn
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGH(c) Clinical Protocol
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LY3298176
Study Period 
I
Study Period II
Study Period 
III
Screening 
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
ETb
801
Week of Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
46
52
4 weeks Post 
End of Tx
Allowable Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Laboratory Tests
Serum pregnancy testo
X
Urine pregnancy testp
X
X
X
X
X
Follicle-stimulating 
hormone testq
X
Chemistry panel
Xr
X
X
X
X
X
X
Fasting serum glucose
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
Urinary albumin/
creatinine ratio
Xr
X
X
X
X
Serum creatinine, eGFR 
(CKD-EPI)s
Xr
X
X
X
X
X
Calcitonin
Xr
X
X
X
X
X
X
Hematology
Xr
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
Pancreatic amylase, 
lipase
Xr
X
X
X
X
X
X
Immunogenicityt
X
X
X
X
X
X
X
X
PK sample for 
Immunogenicityu
X
X
X
X
X
X
X
X
Anti-GAD antibody
X
Stored samples

I8F-MC-GPGH(c) Clinical Protocol
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LY3298176
Study Period 
I
Study Period II
Study Period 
III
Screening 
Lead in
Treatment Period
Safety F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
ETb
801
Week of Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
32
40
46
52
4 weeks Post 
End of Tx
Allowable Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
Pharmacogenetic stored 
sample
X
Nonpharmacogenetic 
stored samples:
EDTA plasma, Serum,
P800 plasma-2.0 ml
X
X
X
X
X
X
Patient Reported Outcomesv
APPADL
X
X
X
EQ-5D-5L
X
X
X
IW-SP
X
X
X
DTSQs
X
DTSQc
X
X
Abbreviations:  ADA = anti-drug antibodies; APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BP = blood pressure; 
CKD-EPI = Chronic Kidney Disease-Epidemiology; DTSQc = Diabetes Treatment Satisfaction Questionnaire change; DTSQs = Diabetes Treatment 
Satisfaction Questionnaire status; ECG = electrocardiogram; eCRF =electronic case report form; EDTA = ethylenediaminetetraacetic acid; eGFR = estimated 
glomerular filtration rate; EQ-5D-5L = European Quality of Life- dimensions; ET = early termination; F/U = follow-up; GAD = glutamic acid decarboxylase; 
HbA1c = hemoglobin A1c; HR = heart rate; IW-SP = Impact of Weight on Self-Perception; PK = pharmacokinetics; PRO = patient-reported outcome;
SGLT-2 = sodium-glucose co-transporter-2; SMBG = self-monitored blood glucose; TTT = treat to target; Tx = treatment.

I8F-MC-GPGH(c) Clinical Protocol
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LY3298176
a
Baseline assessments must be completed before processing in the interactive web-response system.
b
Patients who are unable or unwilling to continue in the study for any reason will perform an ET visit.  If the patient is discontinuing during an unscheduled 
visit, that visit should be performed as the ET visit.  If the patient is discontinuing during a scheduled visit, that visit should be performed as an ET visit.  
Visit 801 (safety follow-up visit) should be performed 4 weeks after the ET visit as the final study visit.
c
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window).
d
On visits 3, 5, 7, 11, 13, 15, 16, 17, 19, 21, ET, and at follow-up, patients should be reminded to report to the site in a fasting condition, after a period of 
approximately 8 hours without eating, drinking (except water), or any significant physical activity and before taking study drug(s), metformin and SGLT-2i (if 
used).
e
Medical history includes assessment of preexisting conditions (including history of gallbladder disease, cardiovascular disease, diabetic retinopathy, and 
medullary thyroid carcinoma) and substance usage (such as, alcohol and tobacco).
f
Weight measurements must be in kilograms.
g
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, at visits where 
required.  The participant should sit quietly for 5 minutes before vital sign measurements are taken.  For each parameter, 2 measurements will be taken using 
the same arm; the recordings should be taken at least 1 minute apart.  BP must be taken with an automated blood pressure machine.
h
Dilated fundoscopic examination will be performed by an eye care professional (ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 to 
exclude patients with proliferative diabetic retinopathy and/or diabetic maculopathy or nonproliferative diabetic retinopathy that requires acute treatment.  The 
results from this examination will be recorded on a specific retinopathy eCRF as a baseline measure of retinopathy.  Follow up dilated fundoscopic
examination should be performed when clinically indicated, and, the results recorded on the retinopathy eCRF.
i
Includes counseling on diet and exercise, symptoms and management of hypoglycemia, etc.
j
All training should be repeated as needed to ensure patient compliance. 
k
Patient is required to collect two 7-point SMBGs on nonconsecutive days prior to the next visit.  A 7-point SMBG consists of measurements before and 2 
hours after each of 3 main meals within the same day and at bedtime.  These SMBG profiles will be collected by the patient within 2 weeks prior to the 
assigned visits.  If 7-point SMBG is not performed, then data from the most recent nonconsecutive 4-point SMBG profiles can be used.  If more than two (2)
7-point SMBG profiles are available, the 2 most recent profiles on nonconsecutive days should be used.
l
Patients should administer their first dose of LY3298176 at the end of this visit, after other study procedures and randomization.
m During the first 8 weeks, the dose adjustment will be determined by the investigator in discussion with the patient by following a TTT algorithm.  After 
Week 8, the dose adjustment will be determined by the patient in a weekly manner and will be reviewed by the investigator at each office visit.  Patients will 
have weekly visits (clinic or phone) in the first 8 weeks and then biweekly visits (clinic or phone) until Week 16 in order to improve compliance with the TTT 
algorithm.
n
Assessment of the patient’s compliance to the TTT algorithm will be collected in the eCRF at Visits 7, 9, 11, 13, 15 and 21 for the period since the previous 
clinic visit.
o
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
p
A urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first injection of study drug(s) for women of 
childbearing potential only.  Additional pregnancy tests will be performed at Visits 13, 17, 19 and 21. Pregnancy tests may also be performed at the 
investigator’s discretion during the study.  If required per local regulations and/or institutional guidelines, pregnancy testing can also occur at other times 
during the study treatment period.

I8F-MC-GPGH(c) Clinical Protocol
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LY3298176
q
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 45 years of age with an intact uterus, not on hormone therapy, and 
who have had spontaneous amenorrhea for more than 6 months and less than 12 months and estradiol levels consistent with a postmenopausal state (FSH ≥40 
mIU/mL and estradiol <30 pg/mL).
r
Screening visit assessment will serve as baseline.
s
The CKD-EPI equation will be used by the central lab to estimate and report eGFR. 
t
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples will be collected including ADA, PK, and an 
exploratory immune safety sample.
u
PK samples for immunogenicity must be taken prior to drug administration.
v
All PROs should be completed before any other study procedures if the patient is not adversely affected by the fasting condition or completed after the patient 
has sufficiently recovered from the preceding visit procedures.
Note: Patients will be encouraged to collect a daily fasting BG and a weekly 4-point SMBG.  Missing a fasting BG measurement will not be considered 
a protocol deviation.

I 8 F-M C -G P G H ( c) Cli ni c al Pr ot o c ol
P a g e 2 2
L Y 3 2 9 8 1 7 6
3. I ntr o d u cti o n
3. 1.
St u d y R ati o n al e
T y pe 2 di a betes mellit us ( T 2 D M) is a meta b o lic c o n diti on c haracterize d b y i m paire d gl yce mic 
c o ntr ol ca use d b y increase d i ns uli n resista nce a n d pr o gressi ve beta -cell fail ure a n d c o nse q ue nt l y 
i na de q uate i ns uli n secreti on. T y pe 2 di a betes mellit us is ass ocia te d wit h c o mor bi di ties s uc h as 
i ncrease d wei g ht or o besity,  h y perte nsi on, i ncrease d bl o o d li p o pr otei n c o nce ntrati o ns, a n d a 
hi g her ri s k f or macr o- a n d micr o vasc ular c o m plicati o ns.  T o pre ve nt t hese c o m plicati o ns, ti g ht 
gl yce mic c o ntr ol is rec o m me n de d ( A mer ica n Dia betes Ass ociati on ( AD A) 2 0 1 7).
T he treat me nt f or T 2 D M us uall y starts wit h lifest yle a n d diet c ha n ges f o ll owe d b y ste p wise 
a d ditio n of  or al a nti h y per gl yce mic me dicati o ns ( O A Ms) t o mai ntai n a de q uate gl uc ose c o ntr ol 
(I nz ucc hi et al. 2 0 1 5).  Wit h f urt her pr o gressio n of t he di sease, O A M will be i ns ufficie nt t o reac h 
a n d mai ntai n t he t hera p y g o al of tar get gl yce mia, a n d ma n y patient s will e ve nt uall y re q uir e 
i njecta ble t hera pies. Cli nical g ui deli nes ( A D A 2 0 1 7, I nz ucc hi et al. 2 0 1 5) c urre ntl y  rec o m me n d 
i nitiat i n g basal i ns uli n i n patient s wit h T 2 D M eit her directl y aft er met f or mi n or after ma xi mizi n g 
a c o m bi nat i on of or al  a ntidia betic dr u gs ( O A Ds ), wi t h or wit ho ut gl uca g o n -li ke pe pti de- 1 
( G L P-1) rece pt or a g o nists. A de q uatel y t itrate d de glu dec t hera p y , i n c om bi nat i on wi t h or al 
treat me nt, fre q ue ntl y ac hie ves t he tar get gl yce mic le vel alth o u g h it is fre q ue nt l y ass ociate d wit h 
w ei g ht i ncrease a n d e ve nt ual h y p o gl yce mia ( Zi n ma n et al. 2 0 1 2 , Pa n et al. 2 0 1 6 ). 
I njecta ble i ncreti n-base d treat me nts (f or e xa m ple , G L P -1 rece pt or a g o nists) are als o c o m m o nl y 
use d i n c o m bi nati o n wit h O A Ms t o ac hie ve a n d mai ntai n gl uc ose c o ntr ol ( A D A 2 0 1 7, I nz ucc hi 
2 0 1 5).  W hile ass ociate d wit h l o wer ris k f or h y p o gl yce mia a n d eit her wei g ht ne utral or wei g ht 
l oss effects, c urre nt pre parati o ns are directe d at a si n gle m olec ular tar get ( G L P -1 rece pt ors) a n d 
pr o vi de d ose -de pe n de nt gl uc ose -l oweri n g effects , w hic h ca n be li mite d b y gastr oi ntesti nal ( GI) 
t olera bilit y ( Na uc k 2 0 1 6).
T he m eta b o lic effects of G L P-1 rece pt or a g o nists ca n be e n ha nce d b y c o m bi ni n g t he m wit h t he 
actio ns of  ot her e nter o pa ncreatic h or m o nes. Gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pti de 
( GI P) sti m ulates i ns uli n secreti on i n a gl uc ose-de pe n de nt m a n ner, a n d ma y e xert s o me ot her 
actio ns be y o n d i ts r ole as a n i ncreti n t hat c o ul d p ote nt iall y i m pr o ve t hera pe utic efficac y i n 
c o m bi nat i on wi t h G L P-1 rece pt or a g o ni sts alo ne ( f or e xa m ple, i m pr o ve d li pi d h ome o stasis a n d 
w h o le b o d y  e ner g y meta b o lis m) ( Na uc k a n d Meier 2 0 1 8, As mar et al. 2 0 1 6).
L Y 3 2 9 8 1 7 6 is a 3 9-a mi n o aci d s y nt het ic pe pti de with a g o nist acti vit y at b ot h t he GI P a n d G L P - 1 
rece pt ors. Its str uct ure is base d o n t he GI P se q ue nce a n d i ncl u des a C 2 0 fatt y di-aci d moi et y t hat 
It is a d mi nistere d as o nce -wee kl y  ( Q W) s u bc uta ne o us ( S C) 
i njecti on ( C os k u n et al. 2 0 1 8).
St u d y  I 8 F-M C -G P G H ( G P G H) is a P hase 3, m ult ice nter, ra n d o mize d, o pe n-label, parallel -gr o u p 
st u d y t hat will i n vesti gate t he effects of treat me nt wit h L Y 3 2 9 8 1 7 6 5 m g, 1 0 m g, a n d 1 5 m g 
Q W, c o mpare d wi t h titrate d i ns uli n de gl udec i n pati e nts wit h T 2 D M naive of i ns uli n treat me nt 
w h o ha ve i na de q uate gl yce mic c o ntr ol o n sta ble d oses of metf or mi n wit h or wi t ho ut a 
s o diu m -gl uc ose c o -tra ns p orter-2 i n hi bit or ( S G L T- 2i).
C CI

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

I8F-MC-GPGH(c) Clinical Protocol
Page 24
LY3298176
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of LY3298176 are to be found in the Investigator’s Brochure (IB).
In addition, detailed information about the known and expected benefits and risks of insulin 
degludec may be found in the insulin degludec package insert (Tresiba USPI, 2015 [WWW]).

I8F-MC-GPGH(c) Clinical Protocol
Page 25
LY3298176
4.
Objectives and Endpoints
Table GPGH.2 shows the objectives and endpoints of the study.
Table GPGH.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To demonstrate that QW LY3298176 10 mg 
and/or 15 mg are noninferior to insulin 
degludec for change from baseline in HbA1c 
at 52 weeks 

Mean change in HbA1c 
Key Secondary (controlled for type 1 error)
Efficacy

To demonstrate that QW LY3298176 5 mg is 
noninferior to insulin degludec for change in 
baseline in HbA1c at 52 weeks

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
degludec for change from baseline in weight 
at 52 weeks 

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
degludec for change from baseline in HbA1c 
at 52 weeks 

Mean change in HbA1c 

Mean change in body weight 

Mean change in HbA1c 

To demonstrate QW LY3298176 5 mg, 10 
mg, and/or 15 mg is superior to insulin 
degludec for the proportion of patients with
HbA1c target value of <7.0% (53 mmol/mol) 
at 52 weeks

HbA1c 
Additional Secondary (not controlled for type 1 
error)

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
degludec at 52 weeks for:

Mean change in fasting serum glucose (central 
lab) from baseline

Proportion of patients achieving an HbA1c 
target value of ≤6.5% (48 mmol/mol), <5.7% 
(39 mmol/mol)

Mean change in 7-point self-monitored blood 
glucose (SMBG) profiles from baseline

Proportion of patients who achieved weight 
loss ≥5%, ≥10%, and ≥15% from baseline

To compare LY3298176 5 mg, 10 mg, and 
15 mg to insulin degludec at 52 weeks for:

Patient-reported outcomes:
o
Diabetes Treatment Satisfaction 
Questionnaire status/ Diabetes
Treatment Satisfaction Questionnaire 
change 
o
Impact of Weight on Self-Perception
o
Ability to Perform Physical 

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Objectives
Endpoints
Activities of Daily Living
Safety

To compare the safety of LY3298176 5 mg, 
10 mg, and 15 mg to insulin degludec for:

Treatment-emergent adverse events (TEAEs)

Early discontinuation of study drug due to 
adverse events (AEs)

Adjudicated pancreatic AEs

Serum calcitonin

Incidence of allergic and hypersensitivity 
reactions

Incidence of treatment-emergent anti-drug 
antibodies to LY3298176

Mean change in systolic and diastolic blood 
pressure and heart rate from baseline 

Occurrence of hypoglycemic episodes

Incidence of initiation of rescue therapy for 
severe persistent hyperglycemia
Tertiary/Exploratory

To compare LY3298176 5 mg, 10 mg, and 15 
mg with insulin degludec with respect for the 
following:

Change in lipids (total cholesterol, HDL, 
VLDL, and TG)

Changes from baseline in mean body mass 
index

Mean change in waist circumference

Biomarkers

European Quality of Life- dimensions 
(EQ-5D-5L) scores
Abbreviations:  HbA1c = hemoglobin A1c; HDL=high density lipoprotein; QW = once weekly; T2DM = type 2 
diabetes mellitus; TG = triglycerides; VLDL = very low density lipoprotein

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5. Study Design
5.1.
Overall Design
Study GPGH is a Phase 3, multicenter, randomized, open-label, parallel-group study that will 
investigate the effects of treatment with LY3298176 5 mg, 10 mg, and 15 mg QW compared 
with titrated insulin degludec in patients with T2DM who have inadequate glycemic control on 
stable doses of metformin, with or without an SGLT-2i.  The primary endpoint will be the mean 
change in HbA1c from baseline to 52 weeks. 
Patients should be on a stable dose (no dose change for at least 3 months) metformin alone or 
metformin plus an SGLT-2i.  Patients will be randomized in a 1:1:1:1 ratio (LY3298176 5 mg 
QW, 10 mg QW, 15 mg QW, or insulin degludec once daily [QD]).  Patients will be stratified at 
randomization based on HbA1c (≤8.5%, >8.5% [69 mmol/mol]), country, and use of 
concomitant oral antidiabetic treatments (metformin alone, metformin plus an SGLT-2i).
Insulin degludec will be injected QD, as a single SC injection, ideally at bedtime at 
approximately the same time every night.  The initial dose will be 10 IU/day and will be adjusted 
weekly per a treat-to-target (TTT) algorithm, based on the last 3 fasting blood glucose (FBG) 
values.
Study governance considerations are described in detail in Appendix 3.
Figure GPGH.1 illustrates the study design.

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Abbreviations:  FBG = fasting blood glucose; QD = once daily; QW = once weekly; 
SGLT-2i = sodium-glucose co-transporter-2 inhibitor; TTT = treat to target.
a
Stable doses of metformin (≥1500 mg/day) ± SGLT-2i for ≥ 3 months prior to 
Visit 1 and during the screening/lead-in period.
b
The starting dose of insulin degludec will be 10 IU/day ideally at bedtime, 
titrated to a FBG <90 mg/dL, following a TTT algorithm.  
Figure GPGH.1.
Illustration of study design for Clinical Protocol I8F-MC-GPGH.
Study Period I (Screening and Lead-in)
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility at Visit 2. The patient 
will sign the informed consent form (ICF) before any study procedures are performed.  
Procedures at this visit will be performed as shown in the Study Schedule of Activities, 
Section 2. Patients who meet all applicable inclusion criteria and none of the applicable 
exclusion criteria (Section 6) at Visit 1 will continue on their prestudy therapy between Visits 1 
and 2. 
Lead-in (Visit 2 to Visit 3)
At Visit 2, the screening laboratory results will be reviewed. For those patients meeting all other 
eligibility requirements, a dilated fundoscopic examination performed by an ophthalmologist or 
optometrist, must be completed between Visit 2 and Visit 3 to ensure that patients with 
proliferative diabetic retinopathy, diabetic maculopathy, or nonproliferative diabetic retinopathy 

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who require acute treatment, are identified and not enrolled. Additionally, at Visit 2, patients 
and their caregiver(s), if applicable, will receive a glucometer and training on how to perform 
self-monitoring of blood glucose (SMBG).  The SMBG plan will include daily measurements of 
FBG, one weekly 4-point BG profile and two 7-point SMBG profiles done on 2 nonconsecutive 
days in the 2-week period prior to Visit 3 (randomization), Visit 17 (Week 24), Visit 19 (Week 
40) and Visit 21 (end of treatment).  Patients will be provided diaries and will be trained as 
appropriate to record BG values, hypoglycemic events. During this period, patients will also be 
trained on disease management and study procedures; this training can be repeated at subsequent 
visits as deemed appropriate. During the lead-in period, patients should continue their prestudy 
therapy and should not change the type of OAMs used or their doses, in order to allow reliable 
assessment of HbA1c at baseline (Visit 3).  If patients develop a condition that is a 
contraindication for the use of OAMs, they will be considered ineligible and must be 
discontinued from the trial before randomization.  
Study Period II (52-Week Treatment Period)
Randomization (Visit 3)
At Visit 3, eligible patients will perform all required baseline study procedures (including the 
collection of all baseline laboratory measures) prior to randomization and prior to taking the first 
dose of study drug.  Patient should arrive to the clinic in the fasting state; the fasting state should 
have lasted at least 8 hours without having taken any doses of their study drug, metformin and 
SGLT-2i (if used). The questionnaires (European Quality of Life [EQ-5D-5L], Ability to 
Perform Physical Activities of Daily Living [APPADL], Impact of Weight on Self-Perception
[IW-SP], and Diabetes Treatment Satisfaction Questionnaire status [DTSQs]) should be 
completed before any other study procedures if the patient is not adversely affected by the 
fasting condition or completed after the patient has sufficiently recovered from the preceding 
visit procedures. 
During the first 4 weeks, patients assigned to groups receiving LY3298176 QW will administer 
LY3298176 2.5 mg QW subcutaneously.  Patients will be instructed on how to use the 
single-dose pen (SDP) and will inject their first dose of LY3298176 while in the clinic for Visit 
3.  Patients randomized to the insulin degludec group will be trained on how to use the 
FlexTouch device and will administer insulin degludec once daily ideally at bedtime. The date 
and time of the first dose of study drug should be recorded on the electronic case report form 
(eCRF).
Following randomization, patients will participate in a 52-week treatment period.  
Postrandomization period (end of Visit 3 to Visit 21):
The starting dose of LY3298176 will be 2.5 mg QW for 4 weeks, followed by an increase to 
5 mg QW, for the duration of the study in the 5 mg group.  For the 10-mg group, the starting 
dose of LY3298176 will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg 
every 4 weeks (2.5 to 5 to 7.5 to 10 mg) until the 10-mg dose is reached and maintained for the 
duration of the study.  For the 15-mg group, the starting dose of LY3298176 will be 2.5 mg QW 

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for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 to 
12.5 to 15 mg) until the 15-mg dose is reached and maintained for the duration of the study.  
The initial dose of insulin degludec will be 10 IU/day ideally at bedtime, titrated to a FBG 
<90 mg/dL, following a TTT algorithm (Philis-Tsimikas et al. 2013; Pan et al. 2016; Aroda et al. 
2016) (see Section 7.2.1.2, Table GPGH.4).
Most of the insulin degludec titration should occur during the first 16 weeks of the study, 
followed by a 36-week maintenance period.  The maintenance period is defined as a part of the 
titration period when the insulin degludec dose is expected to be stable and optimized (Weeks 
16-52 [Visits 15-21]).
During the first 8 weeks, the insulin degludec dose adjustment will be determined by the 
investigator in discussion with the patient and this time will be used as preparation and training 
for implementation of the patient self-titration according to the TTT algorithm (Section 7.2.1.2, 
Table GPGH.4).  After Week 8, the decision of the titration will be made and implemented by 
the patient in a weekly manner.  Between Week 8 and Week 16, investigators or study site 
personnel will contact the patient every 2 weeks (office or telephone visit) and will review the 
insulin dose adjustment made by the patient at each of these visits.  Investigators may perform 
additional telephone visits if necessary, or perform additional office visits if the investigator 
deems additional training is necessary.
During the treatment period, office visits will occur weekly or every other week during the first 
16 weeks, and thereafter, every 4 to 8 weeks to enable the site to properly monitor patients’ 
usage of the TTT algorithm.
At each of the 6 scheduled telephone visits, procedures will include assessments of SMBG, 
compliance with insulin titration algorithm, insulin dose, LY3298176 compliance (will be 
re-assessed at the office visit), hypoglycemic events, concomitant medications, and AEs (see 
Schedule of Activities Section 2).  The data obtained at these telephone visits will be entered into 
the eCRFs at the next office visit.  
Throughout the treatment period, patients will collect all data on SMBG, insulin dose
assessments, insulin doses administered, dates when study drug was administered, hypoglycemic 
events, in the patient diary to be reviewed with the study site personnel at the next office visit.  
For that purpose, at each visit, study diaries for the period after the previous office visit, will be 
collected, and instructions will be reviewed at each visit.  Study drug and injection supplies will 
be returned per the Schedule of Activities (Section 2) and according to local requirements.  New 
supplies will be dispensed as needed.  
Results of SMBG and hypoglycemic events will be used by the patient to assess insulin degludec 
doses per the TTT algorithm. Insulin degludec dose assessments must be performed once per 
week (see Section 7.2.1.2).  Additional assessments may be requested by the investigator based 
on his/her clinical judgment. Outcome of the assessment will be recorded in patient diaries.
Compliance with the LY3298176 administration schedule and compliance with the insulin 
degludec TTT algorithm will be assessed at every office visit and collected in the eCRF at

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prespecified visits (Section 2). Based on the outcome of these reviews, the site staff should 
discuss additional insulin degludec dose adjustments while the patient is still at the site and 
provide retraining, if needed.
Patients should be instructed to contact the investigative site for assistance as soon as possible if 
they experience any difficulties administering their study medication or with the TTT algorithm 
at any time during the study treatment period. Patients should also be advised about the 
appropriate course of action in the event that study drug is not taken at the required time 
(late/missing doses).
Study Period III (Safety Follow-up Period)
Safety follow-up (Visit 801) visits:
All patients who complete the treatment period are required to complete Visit 801, a safety 
follow-up visit, approximately 4 weeks after their last visit.  Patients discontinuing the study 
early and performing an early termination (ET) visit will also be asked to perform the safety 
follow-up visit, so that the safety follow-up visit will be their final visit.  During the safety 
follow-up period, patients will not receive study drug.  Patients will be treated with another 
glucose-lowering intervention decided upon by the investigator.  Initiation of new 
antihyperglycemic therapy for the safety follow-up period will not be classified as “rescue 
therapy.” Patients are also required to return any remaining study diaries to the study site at the 
end of this period.
Study Procedures
Patients will perform study procedures listed in the Schedule of Activities (Section 2).  
Patients will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments.  Antihyperglycemic medications other than study drugs 
are not allowed at any time during the study except as allowed for rescue therapy and/or after 
early study drug discontinuation.  Rescue therapy with other glucose-lowering agents, including 
prandial insulin, may be medically indicated in certain situations after randomization due to
severe, persistent hyperglycemia or early discontinuation of study treatment.  Glucagon-like 
peptide-1 receptor agonists, dipeptidyl peptidase (DPP-4) inhibitors, and pramlintide are 
prohibited medications and are not allowed as rescue therapies.  No other basal insulins are 
allowed during the course of the study (except for LY3298176 groups).
Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Sections 7.2.1.2 and 9.2.2.2) will receive a new glucose-lowering intervention (“rescue therapy”) 
and will also continue to administer study drug.  Patients who need hyperglycemic rescue 
therapy will continue in the study until they complete all study visits.  
Study governance considerations are described in detail in Appendix 3.

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5.2.
Number of Participants
A total of approximately 1420 patients will be randomized in a 1:1:1:1 ratio to receive 
LY3298176 doses:  

5 mg QW (355 patients), 

10 mg QW (355 patients),

15 mg QW (355 patients), or

insulin degludec QD (355 patients).
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Study GPGH is designed to determine the comparative benefits and risks of QW LY3298176
5 mg, 10 mg, or 15 mg versus insulin degludec in patients with T2DM who have inadequate 
glycemic control on stable doses of metformin with or without an SGLT-2i.
An active comparator rather than placebo was selected for this study because it includes patients 
with uncontrolled T2DM despite use of oral antihyperglycemic therapies (HbA1c 7.0% [53 
mmol/mol] to 10.5% [91 mmol/mol], inclusive).  Insulin degludec was selected as the 
comparator because it is a widely used therapy prescribed in this patient population, with similar 
efficacy to insulin glargine while providing benefits in terms of hypoglycemia (Vora et al. 2015, 
Ratner et al.2013).  Metformin and SGLT-2i were chosen as the concomitant antihyperglycemic 
medication as they are commonly used in clinical practice, also in combination, and its use in 
patients who initiate insulin therapy is frequent and the risk of hypoglycemia is low.  To ensure a 
valid comparison of the randomized study treatments, it is important that insulin degludec is 
titrated optimally throughout the entire study.  Patients will be required to use a TTT algorithm, 
which has been shown to be effective in enabling a high proportion of patients with T2DM to 
achieve their therapeutic targets when treated with insulin degludec (Philis-Tsimikas et al. 2013, 
Pan et al. 2016, Aroda et al. 2016) as described in Section 7.2.1.2.  The frequency of clinic and 
telephone visits postrandomization is intended to allow patients and investigators frequent 
assessment of study treatments, including optimal insulin degludec dose adjustments as needed 
for the attainment of glycemic goals within a short time period.  
The parallel-group design for treatment comparison was chosen to avoid any interaction between 
treatments that may interfere with the interpretation of the study outcome.  To minimize the 
potential confounding effect of changes to concomitant medications, patients will be permitted to 
use concomitant medications that they require during the study.  Medications that may interfere 
with the assessment of efficacy and safety characteristics of the study treatments will not be 
allowed (see Section 7.7).  An open-label design was chosen due to the different dosing 
frequency, titration scheme and injection device of insulin degludec compared with LY3298176.

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The planned duration of treatment for the primary endpoint at 52 weeks is considered appropriate 
to assess the full effects and benefit/risk of each maintenance dose of LY3298176 on both 
glycemic control and body weight.  Moreover, the duration of the study is considered sufficient 
and appropriate for patients to optimize dosing of insulin degludec for comparison with the 
LY3298176 treatment groups with respect to change in HbA1c. 
5.5.
Justification for Dose
LY3298176 doses of 5 mg, 10 mg, and 15 mg administered subcutaneously QW will be 
evaluated in this study. 
These doses and associated escalation schemes were selected based on assessment of safety, 
efficacy (glycemic and weight loss benefit), and GI tolerability data followed by exposure 
response modeling of data in patients with T2DM in Phases 1 and 2 studies.  Dosing algorithms 
starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5 mg increments every 
4-week would permit time for development of tolerance to GI events and are predicted to 
minimize GI tolerability concerns.
The maximum proposed dose of 15 mg maintains an exposure multiple of 1.6 to 2.4 to the 
no-observed adverse effect level doses in 6-month monkey and rat toxicology studies.
The selected dose and escalation scheme would enable further evaluation of benefit/risk 
considerations for 5 mg, 10 mg, and 15 mg doses of LY3298176.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Type of Patient and Disease Characteristics
[1] Have been diagnosed with T2DM based on the World Health Organization
classification or other locally applicable diagnostic standards
Patient Characteristics
[2] Have HbA1c ≥7.0% (53 mmol/mol) to ≤10.5% (91 mmol/mol), as determined by 
the central laboratory at Visit 1
[3] Are insulin-naive (except for the use of insulin for treatment of gestational 
diabetes or short-term use [14 days] for acute conditions)
[4] Are on stable diabetes treatment with metformin or metformin plus an SGLT-2i
(metformin ≥1500 mg/day and no more than the maximum approved dose per 
country-specific label) for at least 3 months prior to Visit 1 and between Visit 1 
and Visit 3
[5] Are of stable weight (±5%) ≥3 months prior to Visit 1 and agree to not initiate a 
diet and/or exercise program during the study with the intent of reducing body 
weight other than the lifestyle and dietary measures for diabetes treatment
[6] Have body mass index ≥25 kg/m2 at Visit 1
[7] Are 18 years old or of an acceptable age to provide informed consent according to 
local regulations, whichever is older
Male patients (see Appendix 6 for more details):

Male patients should be willing to use reliable contraceptive methods throughout 
the study and for at least 3 months after last injection 
Female patients:

Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation), congenital anomaly 
(i.e. Mullerian agenesis) or menopause.
o
Women with an intact uterus are deemed postmenopausal if they are at 
least 45 years old, and

have not taken hormones or oral contraceptives within the last year 
and had cessation of menses for at least 1 year,
OR

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
have had at least 6 months and less than 12 months of spontaneous 
amenorrhea with follicle-stimulating hormone (FSH) and estradiol 
levels consistent with a postmenopausal state (FSH ≥40 mIU/mL 
and estradiol <30 pg/mL).
o
Female patients of child-bearing potential (not surgically sterilized and
between menarche and 1-year postmenopausal) must:

test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
AND

if sexually active, agree to use two forms of effective 
contraception, where at least one form is highly effective for the 
duration of the trial and for 30 days thereafter 

not be breastfeeding
[8] In the investigator’s opinion, are well-motivated, capable, and willing to: 
(a)
perform fingerstick BG monitoring, including scheduled BG profiles with up to 7 
measurements in 1 day 
(b)
learn how to self-inject treatment (LY3298176 or insulin degludec), as required for 
this protocol (visually impaired persons who are not able to perform the injections 
must have the assistance of a sighted individual trained to inject the study drug; 
persons with physical limitations who are not able to perform the injections must 
have the assistance of an individual trained to inject the study drug) 
(c)
are willing and able to inject LY3298176 QW or insulin degludec QD
(d)
maintain a study diary, as required for this protocol
(e)
have a sufficient understanding of one of the provided languages of the country 
such that they will be able to complete the patient questionnaires
Informed Consent
[9] Have given written informed consent to participate in this study in accordance 
with local regulations and the Ethical Review Board (ERB) governing the study 
site
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Medical Conditions
[10] Have type 1 diabetes mellitus (T1DM)
[11] Had chronic or acute pancreatitis any time prior to study entry (Visit 1)
[12] Have history of:

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
proliferative diabetic retinopathy 
or 

diabetic maculopathy 
or

nonproliferative diabetic retinopathy that requires acute treatment
(a dilated fundoscopic examination performed by an ophthalmologist or
optometrist between Visit 2 and Visit 3 is required to confirm eligibility)
[13] Have a history of severe hypoglycemia and/or hypoglycemia unawareness within 
the 6 months prior to Visit 1
[14] Have a history of ketoacidosis or hyperosmolar state/coma 
[15] Have a known clinically significant gastric emptying abnormality (for example, 
severe diabetic gastroparesis or gastric outlet obstruction), have undergone or 
plan to have during the course of the study:  a gastric bypass (bariatric) surgery 
or restrictive bariatric surgery (for example, Lap-Band®), or chronically take 
drugs that directly affect GI motility
[16] Have any of the following CV conditions within 2 months prior to Visit 1:  acute 
myocardial infarction, or cerebrovascular accident (stroke) or hospitalization due 
to congestive heart failure (CHF)
[17] Have New York Heart Association Functional Classification III and IV CHF
[18] Have acute or chronic hepatitis, signs and symptoms of any other liver disease 
other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase 
(ALT) level >3.0 times the upper limit of the reference range, as determined by 
the central laboratory at study entry; patients with NAFLD are eligible for 
participation in this trial only if their ALT level is ≤3.0 times the upper limit of 
normal (ULN) for the reference range
[19] Have an estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than 
the country-specific threshold for using the protocol-required dose of metformin 
per local label), calculated by Chronic Kidney Disease-Epidemiology, as 
determined by central laboratory at Visit 1
[20] Have evidence of a significant, uncontrolled endocrine abnormality (for 
example, thyrotoxicosis or adrenal crises), in the opinion of the investigator
[21] Have family or personal history of medullary thyroid carcinoma (MTC) or 
multiple endocrine neoplasia syndrome type 2
[22] Have a serum calcitonin level of ≥35 ng/L, as determined by central laboratory at 
Visit 1
[23] Known or suspected hypersensitivity to trial product(s) or related products
[24] Have evidence of a significant, active autoimmune abnormality (for example, 
lupus or rheumatoid arthritis) that, in the opinion of the investigator, is likely to 
require concurrent treatment with systemic glucocorticoids in the next 12 months

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[25] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant
[26] Have a history of an active or untreated malignancy or are in remission from a 
clinically significant malignancy (other than basal or squamous cell skin cancer, 
in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years
[27] Have a history of any other condition (such as known drug, alcohol abuse, or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
patient from following and completing the protocol
[28] Have any hematological condition that may interfere with HbA1c measurement 
(for example, hemolytic anemias and sickle cell disease)
Prior/Concomitant Therapy
[29] Treatment with any glucose-lowering agent(s) other than stated in the inclusion 
criteria [4] in a period of 3 months prior to Visit 1 and between Visit 1 and 
Visit 3
[30] Have been treated with prescription drugs that promote weight loss (for example, 
Saxenda [liraglutide 3.0 mg], Xenical® [orlistat], Meridia® [sibutramine], 
Acutrim® [phenylpropanolamine], Sanorex® [mazindol], Apidex® [phentermine], 
BELVIQ® [lorcaserin], Qsymia™[phentermine/topiramate combination], 
Contrave® [naltrexone/bupropion], or similar other body weight loss medications 
including over-the-counter medications [for example, allī®]) within 3 months 
prior to Visit 1 and/or between study entry (Visit 1) and randomization (Visit 3)
[31] Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy 
(excluding topical, intraocular, intranasal, or inhaled preparations) or have 
received such therapy within 1 month of Visit 1 or between Visits 1 and 3
Prior/Concurrent Clinical Trial Experience
[32] Are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study
[33] Have participated, within the last 30 days in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed
[34] Have previously completed or withdrawn from this study or any other study 
investigating LY3298176
Other Exclusions
[35] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[36] Are Lilly employees 

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[37] Are unwilling or unable to comply with the use of a paper diary to directly 
record data from the subject
6.3.
Lifestyle Restrictions
Per the Schedule of Activities (Section 2), qualified medical staff will provide diabetes 
management counseling, which will include instructions on diet and exercise and education 
about the signs, symptoms, and treatment of hypoglycemia, should it occur.  
Patients should continue their usual exercise habits and generally follow a healthy meal plan 
(with consistent meal size and time of day) throughout the course of the study.  Dietary 
counseling may be reviewed throughout the study, as needed.  Per inclusion criterion [5] 
(Section 6.1), patients should not initiate during the study an organized diet and/or exercise 
weight reduction program other than the lifestyle and dietary measures for diabetes treatment.
Study participants should be instructed not to donate blood or blood products during the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) must not 
be rescreened.  

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7. Treatments
7.1.
Treatments Administered
Patients will be randomized in a 1:1:1:1 ratio to receive LY3298176 5 mg, 10 mg, 15 mg, or 
insulin degludec.  LY3298176 will be administered QW as SC injection in patients with T2DM
who are already treated with a stable dose of at least 1 and no more than 2 oral 
antihyperglycemic medications:  metformin alone or metformin plus sodium-glucose 
co-transporter-2 inhibitors.
Table GPGH.3. shows the randomized treatments for the entire treatment period.
The starting dose of LY3298176 will be 2.5 mg QW for 4 weeks, followed by an increase to 
5 mg QW, for the duration of the study for the 5-mg group.  For the 10-mg group, the starting 
dose of LY3298176 will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg 
every 4 weeks (2.5 to 5 to 7.5 to 10 mg) until the 10-mg dose is reached and maintained for the 
duration of the study.  For the 15-mg group, the starting dose of LY3298176 will be 2.5 mg QW 
for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 to 
12.5 to 15 mg) until the 15-mg dose is reached and maintained for the duration of the study.  
The starting dose of insulin degludec will be 10 IU/day at bedtime, titrated to a FBG <90 mg/dL, 
following a TTT algorithm (Philis-Tsimikas et al. 2013, Pan et al. 2016, Aroda et al. 2016).  
Patients will titrate the insulin degludec dose in a weekly manner and will make the dose 
decision with the investigator for the first 8 weeks (phone or clinic visit).  For further dose 
titration, from Week 8 to Week 16, patients will have a phone or clinic visit every other week.
Table GPGH.3.
Study Treatments
Name of Drug
Dosage
Frequency
Drug 
Formulation
Route of 
Administration
Investigational Compound
LY3298176
5 mga
QW
Single-dose pen
SC
10 mga
QW
Single-dose pen
SC
15 mga
QW
Single-dose pen
SC
Comparators
Insulin degludec
TTT dosingb
QD
FlexTouch 
pre-filled penc
SC
Abbreviations:  QD = once daily; QW = once weekly; SC = subcutaneous; TTT = treat-to-target.

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a
The starting dose of LY3298176 will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg QW, for the 
duration of the study for the 5-mg group.  For the 10-mg group, the starting dose of LY3298176 will be 2.5 mg 
QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 mg) until the 
10-mg dose is reached and maintained for the duration of the study.  For the 15-mg group, the starting dose of 
LY3298176 will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 
7.5 to 10 to 12.5-15 mg) until the 15-mg dose is reached and maintained for the duration of the study.
b The starting dose of insulin degludec will be 10 IU/day ideally at bedtime, titrated to a FSG ≤90 mg/dL, 
following a TTT algorithm.  Insulin dose adjustments will be made in Study Period II per the TTT algorithm.
c    Prefilled device containing 3 mL (U100/mL).
The investigator or his or her designee is responsible for the following:

Explaining the correct use of study drugs to the patient or patient representative, 
and SDP or insulin degludec (Tresiba) FlexTouch training. For the SDP a 
demonstration device will be used.

Explaining the correct use of concomitant metformin and SGLT-2i (if used) to the 
patient, including any contraindications and appropriate dosing per 
country-specific labeling 

Verifying that instructions are followed properly

Maintaining accurate records of investigational product dispensing and collection
Patients should return all study drugs to the site according to the Schedule of Activities, 
Section 2.  Patients should be instructed to discard all used SDPs and insulin degludec (U100) 
FlexTouch in a closeable, puncture-resistant container according to local regulations.
7.1.1. Packaging and Labeling
The sponsor will provide LY3298176 in SDPs and insulin degludec (Tresiba U100) in prefilled 
pens.  These will be dispensed via an interactive web-response system (IWRS).  Single dose pens 
and prefilled pens will be packaged in cartons to be dispensed.  Clinical study materials will be 
labeled according to the country’s regulatory requirements.
7.1.2.
Medical Devices 
The combination products provided for use in the study are LY3298176 investigational 
single- dose pen and a marketed insulin degludec prefilled pen.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the study treatment 
groups at Visit 3.  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an IWRS.  Patients will be randomized in a 1:1:1:1 ratio to receive 
LY3298176 5 mg, 10 mg, 15 mg, or insulin degludec.  
7.2.1. Selection and Timing of Doses
7.2.1.1.
LY3298176
Assignment to LY3298176 (3 doses) or insulin degludec will occur at randomization.  

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There are no restrictions on the time of day each weekly dose of LY3298176 is given, but it is 
advisable to administer the SC injections on the same day and same time each week.  The actual 
date and time of all dose administrations will be recorded by the patient.  If a dose of 
LY3298176 is missed, the patient should take it as soon as possible unless it is within 72 hours 
of the next dose, in which case, that dose should be skipped and the next dose should be taken at 
the appropriate time.  
7.2.1.2.
Insulin Degludec
Dosing for patients randomized to insulin degludec will start at 10 units once daily. Patients 
should administer their daily doses at the time of day agreed upon between the patient and the 
investigator, ideally at bedtime.  Patients assigned to the insulin degludec treatment group will be 
instructed to adjust insulin degludec doses to a target FBG of <90 mg/dL (5.0 mmol/L) based on 
the median value of the last 3 SMBG values according to the schedule below (Philis-Tsimikas et 
al. 2013, Pan et al. 2016, Aroda et al. 2016).  Insulin degludec dose adjustments should occur 
once a week.  During the first 8 weeks, patients will titrate the dose of insulin degludec together 
with the investigator per the titration algorithm; the insulin degludec dose will be also reviewed 
and revised, as needed, at subsequent office visits (see Table GPGH.4). If a dose of insulin 
degludec is missed, the patient should wait until the next scheduled dose, and not inject twice on 
the same day.  Add-on glycemic rescue therapy should be considered for patients who met 
prespecified criteria for severe, persistent hyperglycemia. (see Section 9.2.2.2).
Table GPGH.4.
Titration of Insulin Degludec
Abbreviation:  SMBG = self-monitored blood glucose.
a  If only 2 prebreakfast SMBG values are available, the average of these 2 values will be used.  If only one 
prebreakfast SMBG value is available, the patient should contact the investigator site for instructions on adjusting 
insulin dose
Dose should also be decreased by 2 to 4 units in the following situations:

If multiple episodes of nonsevere hypoglycemia were recorded during the assessment period at any time 
during the day; and/or

If at least 1 episode that met the criteria for severe hypoglycemia (events requiring assistance to administer 
therapy) or was associated with SMBG value <54 mg/dL (<3.0 mmol/L) was recorded during the 
assessment period.
If only 1 hypoglycemic episode with SMBG value ≥54 mg/dL (≥3.0 mmol/L) and ≤70 mg/dL (≤3.9 mmol/L) was 
recorded, insulin dose should not be changed.
Adapted from:  Philis-Tsimikas et al. 2013, Pan et al. 2016, Aroda et al. 2016.
Median of 3 Prebreakfast SMBG Valuesa
Adjustment:  Units
≤70 mg/dL
(≤3.9 mmol/L)
Decrease by 2 to 4 units 
71 to 90 mg/dL
(4.0 to 5.0 mmol/L)
No adjustment
91 to 126 mg/dL
(5.1 to 7.0 mmol/L)
Increase by 2 units
127 to 144 mg/dL
(7.1 to 8.0 mmol/L)
Increase by 4 units
145 to 162 mg/dL
(8.1 to 9.0 mmol/L)
Increase by 6 units
>162 mg/dL
(>9.0 mmol/L)
Increase by 8 units

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7.3.
Blinding
This trial is an open-label study due to the differences in dosing schedule, titration, and devices 
between once-weekly LY3298176 and QD insulin degludec.
7.4.
Dosage Modification
7.4.1. Study Drugs
Details about dose administration of LY3298176 during the study are described in Sections 7.2.1
and 8.1.2.
Insulin degludec will be adjusted according to the TTT method (see Section 7.2.1.2 Table 
GPGH.4).
7.4.2. Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications
After randomization, discontinuation of metformin or SGLT-2i (if used) or change in dosage is 
not permitted, except in the following situations:
1) In the event of a hypoglycemic episode(s) (clinical symptoms of hypoglycemia and/or 
BG-confirmed symptomatic hypoglycemia [glucose concentration ≤3.0 mmol/L 
{54 mg/dL}]):

Patients in the LY3298176 groups on dual oral treatment of metformin and SGLT-2i 
may reduce/discontinue the dose of either metformin or SGLT-2i. When 
hypoglycemia develops in patients on LY3298176 and metformin monotherapy, the 
dose of this oral medication may be reduced or discontinued.

Patients in the insulin degludec group must adjust the dose of insulin degludec 
following the TTT algorithm recommendations (Section 7.2.1.2). In the event of 
recurrent hypoglycemic episodes despite reductions of the insulin dose, the 
investigator may consider a reduction in the dose of the OAM. In that case, patients 
on dual oral treatment of metformin and SGLT-2i may reduce or discontinue the dose 
of either metformin or SGLT-2i. If the patient is on metformin monotherapy, the 
dose of this oral medication may be reduced or discontinued.
2) In certain situations that require short-term discontinuation in line with the product(s) 
labeling for each respective country (for example, for metformin: severe dehydration, 
elective surgery, or need for radiologic examination involving IV iodinated contrast dye).  
Once the situation that led to temporary discontinuation of the drug resolved, treatment 
should be restarted at investigator discretion.
3) If a patient develops contraindications to metformin or SGLT-2i (if used), such that the 
use of the drug is contraindicated according to the country-specific label, the drug should 
be discontinued; in this case, the insulin degludec dose may need to be further adjusted.

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A patient will be considered noncompliant with the protocol (protocol deviation) if he or she
changes the dose or discontinues metformin or SGLT-2i (if used) for reasons other than those 
described here. In the case of noncompliance that lasts >14 days during the treatment period, the 
patient will not be included in the per-protocol (PP) analyses.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation and final disposition records).
The study site must store the study drug in a locked and secure environment. Please refer to the 
study drug label for specific storage conditions.  Patients will receive insulated bags with cooling 
gel packs for use in transporting the study drug carton from the site to home. 
Study site staff must regularly assess whether the patient is correctly administering the assigned 
study drug and storing the study drug according to the provided instructions. 
7.6.
Treatment Compliance
Study drug compliance will be determined by the following: 

Study drug administration data will be recorded by the patient and reviewed by 
the investigator at each study visit.

The patients will be instructed to return any unused study drug and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability.
In the 3 LY3298176 treatment groups, as well as the insulin degludec group, treatment 
compliance for each visit interval is defined as taking at least 75% of the required doses of study 
drug.  Similarly, a patient will be considered significantly noncompliant if he or she is judged by 
the investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication.  
In addition to the assessment of a patient’s compliance with the study drug administration, other 
aspects of compliance with the study treatments will be assessed at each visit based on the 
patient’s adherence to the visit schedule, compliance with the concomitant antihyperglycemic 

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medication regimen, completion of study diaries, the results of home BG monitoring, and any 
other parameters the investigator considers necessary.
Patients considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol. 
7.7.
Concomitant Therapy
Patients will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments.
Investigative site staff will inform patients that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study.  This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
patient will inform the investigator or a designated site staff member as soon as possible.  Any 
additional medication initiated during the course of the study (including over-the-counter [OTC] 
drugs, such as paracetamol or aspirin) must be documented, and the name of the drug and the 
date(s) of administration must be recorded on the “Concomitant Medications” section of the 
eCRF. 
Antihyperglycemic medications other than study drugs are not allowed at any time during the 
study except as allowed for rescue therapy.  Rescue therapy with other glucose-lowering agents, 
including prandial insulin, may be medically indicated in certain situations after randomization 
due to severe, persistent hyperglycemia or early discontinuation of study treatment. 
Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and pramlintide are prohibited 
medications and are not allowed as rescue therapies. No other basal insulins are allowed during 
the course of the study (except for LY3298176 groups).
All nonstudy medications will be recorded on the eCRF at all visits.
Nonstudy medications taken by patients who are screened but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure (see Table GPGH.5).

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Table GPGH.5.
Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments in Study GPGH
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; N = no; 
N/A = not applicable; SGLT-2i = sodium-glucose co-transporter 2 inhibitor; Y = yes.
a
Acute therapy = treatment for up to 14 days.
b Includes Saxenda® (liraglutide 3.0 mg), Xenical® (orlistat), Meridia® (sibutramine), Sanorex® (mazindol), 
Apidex® (phentermine), BELVIQ® (lorcaserin), Qsymia® (phentermine/topiramate combination), Contrave®
(naltrexone/buproprion), or similar other body weight loss medications including over-the-counter medications 
(for example; allī®) within 3 months prior to Visit 1 or any time during the trial. 
c
From 1 months prior to Visit 1 or between Visits 1 and 3; does not apply to topical, intraocular, intranasal, 
intra-articular, or inhaled preparations. 
d Switching metformin manufacturers is allowed as long as the dosage is the same.  Changing to a metformin 
formulation with a different action profile (for example, from short-acting to long-acting metformin) is not 
permitted.
e
For rescue therapy, metformin dose can be increased if the dose is below maximum approved dose per 
country-specific label and is well tolerated.
7.7.1. Management of Patients with Gastrointestinal Symptoms
In the Phase 2 program, the most commonly reported treatment-emergent AEs (TEAEs) for 
patients receiving LY3298176 were nausea, vomiting, and diarrhea.  
The LY3298176 dose escalation scheme has been designed to minimize the development of 
intolerable GI symptoms.  The escalation period is considered to be 24 weeks, which allows 
20 weeks to escalate to 15 mg and additional 4 weeks to reach steady state.  During the dose 
escalation period, every effort should be made by the investigator to be able to escalate and 
maintain patients on the corresponding study drug dosage. 
To mitigate GI symptoms and manage patients with intolerable GI AEs, the investigator should:
Drug Class
Use during
Screening/Lead-In
Conditions for Use after Randomization
Acute 
Therapya
Rescue 
Therapy 
During Safety 
Follow-Up Period
Drugs with approved weight loss 
indicationb
Excluded
N
N/A
Y
Systemic glucocorticoid therapyc
Excluded except for 
acute therapya
Y
N/A
Y
Antihyperglycemia medications
Other GLP-1 RAs
Excluded
N
N
N
DPP-4 inhibitors
Excluded
N
N
N
Pramlintide
Excluded
N
N
N
SGLT-2i
Allowed
N
Y
Y
Insulinsa
Excluded except for 
short term use
Y
Y
Y
Meglitinides
Excluded
N
Y
Y
Alpha-glucosidase inhibitors
Excluded
N
Y
Y
Sulphonylureas
Excluded
N
Y
Y
Thiazolidinediones
Excluded
N
Y
Y
Metformind
Required
N/A
Ye
Y

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
Advise patients to eat smaller meals, for example, splitting 3 daily meals into 4 or 
more smaller meals, and to stop eating when they feel full.

Prescribe symptomatic medication (for example, anti-emetic or anti-diarrheal 
medication) per local country availability and individual patient needs.  Use of 
symptomatic medication should be captured as concomitant medication in the 
eCRF.

Temporarily interrupt LY3298176 (omit 1 dose, the patient will take 3 of 4 doses 
at that dose level). The data related to temporary interruption of study treatment 
should be documented in source documents and entered on the eCRF.  

After the interruption, restart at the same dose with the patient taking medication 
to alleviate their GI symptoms (Section 8.1.2).  
If intolerable GI symptoms or events persist despite the above measures, the investigator may 
decide to continue treatment at a lower, tolerated maintenance dose of LY3298176 (5 mg or 
10 mg).  

Patients at 5 mg or lower will be discontinued from LY3298176.

Patients at 7.5 mg or 10 mg will decrease the dose to 5 mg.

Patients at 12.5 mg or 15 mg will decrease the dose to 10 mg.
If de-escalation of the LY3298176 dose is necessary, the investigator will use the IWRS to 
receive the appropriate LY3298176 dispensing information.  If de-escalation is needed between 
scheduled visits, the IWRS will have unscheduled visits (for example, Visit 13a) dedicated to 
provide dispensing information for patients whose dose has been de-escalated. Those patients,
who have their dose de-escalated, will not be escalated again. The dose can be de-escalated only 
once.  After that, the patients will have to discontinue LY3298176 if intolerable GI AE persists.  
Please see the Manual of Operations for more detailed instructions.
If intolerable persistent GI symptoms occur after Week 24, the investigator should take the above 
measures to keep the patient on study treatment. However, after the escalation period 
(Week 24), dose decreases will not be allowed.
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion 
Study completion will occur after all patients complete the follow-up visit.  Investigators will 
continue to follow Schedule of Activities (Section 2) for all patients until notified by Lilly that 
study completion has occurred.
LY3298176 will not be made available after conclusion of the study to patients.
7.8.2. Special Treatment Considerations 
Investigators will be trained on how to apply decision criteria for the timing and method of 
intervention in patients who do not reach glycemic targets during the treatment period.  An 
additional therapeutic intervention should be considered for patients with persistent 
hyperglycemia as described in Section 9.2.2.2.

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

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
Any other TEAE, SAE, or clinically significant laboratory value for which the 
investigator believes that permanent study drug discontinuation is the appropriate 
measure to be taken

If female patient becomes pregnant

If a patient is diagnosed with T1DM
Patients who stop the study drug permanently will receive another glucose-lowering intervention
(Section 7.4.2) and will continue participating in the trial according to the protocol to collect all
planned efficacy and safety measurements.
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 Schedule of Activities, Section 9.2
Adverse Event, and Section 9.4 Safety of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment 
In certain situations after randomization, the investigator may need to temporarily interrupt study 
drug.  Every effort should be made by the investigator to maintain patients on study drug and to 
restart study drug after any temporary interruption, as soon as it is safe to do so.  
For patients assigned to LY3298176:

If the number of doses missed is ≤2, the treatment can be restarted at the same dose, if the 
drug was well tolerated prior to discontinuation.

If the number of missed doses is ≥3, then the treatment should be restarted at 5 mg 
irrespective of the dose the patient was receiving before the interruption and subsequently 
escalated as required by protocol (See Manual of Operations for further details).
If study drug interruption is due to an AE, the event is to be documented and followed according 
to the procedures in Section 9.2 of this protocol.  If the study drug interruption is due to 
intolerable persistent GI AE (for example, nausea, vomiting, or diarrhea), the patients should be 
treated as suggested in Section 7.7.1.
The data related to temporary interruption of study treatment will be documented in source 
documents and entered on the eCRF.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor clinical research physician (CRP) agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor CRP to allow the inadvertently enrolled patient to continue in the study with or without 
treatment with investigational product. Safety follow-up is as outlined in Section 2 (Schedule of 
Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.

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

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

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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments and Procedures
The primary efficacy measurement in this study is mean change in HbA1c from baseline to 
52 weeks, as determined by the central laboratory.  Blood samples for HbA1c measurements will 
be collected at specific clinic visits as summarized in the Study Schedule, Section 2. 
9.1.2. Secondary Efficacy Assessments and Procedures
The following secondary efficacy measures will be assessed at 52 weeks based on data collected 
at the times shown in the Study Schedule.

Change in HbA1c from baseline

Change in weight from baseline

Proportion of patients achieving a target HbA1c <7% (53 mmol/mol)

Fasting serum glucose measured in the central laboratory 

Change in 7-point SMBG profiles

Proportion of patients who achieved weight loss ≥5%, ≥10%, and ≥15% from baseline
o
Patient-reported outcomes:
o
Diabetes Treatment Satisfaction Questionnaire status and Diabetes Treatment 
Satisfaction Questionnaire change
o
Impact of Weight on Self-Perception
o
Ability to Perform Physical Activities of Daily Living
9.1.3. Exploratory Efficacy Assessments and Procedures
The following secondary efficacy measures will be calculated based on data collected at the 
times shown in the Study Schedule.

Change in lipids (total cholesterol, high-density lipoprotein (HDL), very low-density 
lipoprotein (VLDL), and triglycerides)

Change in waist circumference

Biomarkers

European Quality of Life dimensions (EQ-5D-5L) scores

I 8 F-M C -G P G H ( c) Cli ni c al Pr ot o c ol
P a g e 5 2
L Y 3 2 9 8 1 7 6
9. 1. 4.
A p pr o pri at e n e s s of A s s e s s m e nt s
Efficac y a n d safet y assess me nts i ncl u de d i n t his st u d y are ge nerall y re gar de d as relia ble a n d 
acc urate wit h res pect t o t he efficac y a n d safet y assess me nts i n i n di vi d uals a n d p o p ulat i ons wit h 
T 2 D M.
9. 2.
A d v er s e E v e nt s
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of pat ient s w h o ha ve e ntere d t his st u d y  
a n d f or alerti n g Lill y  or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he pati e nt .
T he i n vest i gat or is res p o nsi ble f or t he a p pr o priate me dical care of pat ient s d uri n g t he st u d y.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.
T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o us or ot her wise me dicall y i m p orta nt, c o nsi dere d relate d t o t he i n vest i gati onal 
pr o d uct or t he st u d y, or t hat ca use d t he pati e nt t o disc o nti n ue t he i n vesti gati onal pr o d uct bef ore 
c o mplet i n g t he st u d y.  T he pati e nt s h o uld be f ol l owe d u nt il t he e ve nt res ol ves or sta bilizes wit h 
a p pr o priate dia g n ostic e val uati o n. F or e ve nts t hat are n ot a ntici pate d t o res ol ve or sta bilize, t he 
pati e nt s h o uld b e f ol l owe d u nt il t he treati n g p h ysicia n (i n c o ns ultati on wi t h t he s p o ns or)
deter mi nes t hat a p pr o priate f o ll ow- u p has bee n c o m plete d. T he fre q ue nc y o f f oll ow- u p 
e val uat i ons of t he A E is left t o t he d iscreti on of t he i n vest i gat or.
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h treat me nt effect.
After t he I C F is si g ne d, st u d y  site pers o n nel will rec or d via t he eC R F , t he occ urre nce a n d nat u re 
of  eac h pati e nt ’s pree xisti n g c o n diti ons, i ncl u di n g cli nicall y si g nifica nt si g ns a n d s y m pt o ms of 
t he disease u n der treat me nt i n t he st u d y.  I n a d diti on, site pers o n nel will rec or d a n y c ha n ge i n t he 
c o n ditio n(s) a n d a n y  ne w c o n ditio ns as A Es . F or eac h A E, t he o nset a n d d urati o n, t he 
serio us ness a n d se verit y,  a n d t he acti ons ta ke n wit h res pect t o st u d y treat me nt will be rec or de d.
I n vesti gat ors s h o ul d rec or d t heir assess me nt of t he p ote ntial relate d ness of eac h A E t o pr ot oc ol 
pr oce d ure, i n vest i gati onal pr o d uct, vi a electr o nic case re p ort f or m ( eC R F ).
Pr oce d ures a n d assess me nts perf or me d pri or t o Visit 3 are c o nsi dere d scree ni n g pr oce d ures. T he 
res ults of t hese pr oce d ures a n d assess me nts s h o ul d be c o nsi dere d pre-e xist i n g c o n diti ons a n d 
s h o uld be re p orte d as me dical hist or y or c o nc o mita nt ill ness.   
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi bility 
of  bei n g relate d t o st u d y treat me nt, st u d y de vice, or a st u d y pr oce d ure, ta kin g i nt o acc o u nt t he 
di sease, c o nc o mitant  treat me nt or pat h ol o gies.
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use a n d effect relat i ons hi p bet wee n t he 
i n vesti gati onal pr o d uct, st u d y  de vice a n d/ or st u d y pr oce d ure a n d t he A E.
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt.

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Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via the CRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Patients with a serious hepatic AE should have additional data collected using the 
eCRF. (see Section 9.4.5.1)
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 

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

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
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, it needs to be recorded as serious on the AE 
CRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive BG values ≤70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al.
2010; Danne et al. 2013).  
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated.  The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established.  The patient should receive additional 
education, if deemed appropriate.  The dose of concomitant antihyperglycemic medications may 
need to be reduced as outlined in Section 7.4.2.
9.2.2.2.
Severe, Persistent Hyperglycemia
Severe, persistent hyperglycemia will be collected during the trial to assess the risk of extreme 
imbalance in glycemic control.
Investigators will be trained on the application of criteria for deciding when and how to intervene 
with patients who do not reach glycemic targets.  An additional therapeutic intervention should 
be considered in patients who develop severe, persistent hyperglycemia after randomization at 
the discretion of investigator in accordance with American Diabetes Association/European 
Association for the Study of Diabetes guidance (Inzucchi et al. 2015).  Rescue medication will 
be prescribed as add-on to randomized treatment, and patients will continue to follow the 
protocol-specified visit schedule.
Add-on glycemic rescue therapy will be allowed for patients who met any one of the following 
prespecified criteria for severe, persistent hyperglycemia and no intercurrent cause of the 
hyperglycemia could be identified (investigators should first confirm that the patient is fully 

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compliant with the assigned therapeutic regimen and that he or she does not have an acute 
condition causing severe hyperglycemia): 
(a) average daily BG from the once-weekly 4-point SMBG profile >270 mg/dL 
(>15.0 mmol/L) over at least a consecutive 2-week period any time during the first 8 
weeks post randomization; 
OR 
(b) average daily BG from the once-weekly 4-point SMBG profile >240 mg/dL 
(>13.3 mmol/L) over a consecutive 2-week period at any time 9 to 16 weeks post 
randomization; 
OR
(c) average daily BG from the once-weekly 4-point SMBG profile >200 mg/dL 
(>11.1 mmol/L) over a consecutive 2-week period at any time beyond the first 16 weeks 
post randomization.
OR
(d) HbA1c ≥8.5% at 24 weeks, with inadequate response to the existing regimen defined as 
improvement in HbA1c over the last 3 months (week 12 to week 24) that is <0.3%
Rescue therapy option:
For the insulin degludec group, patients can further titrate the insulin degludec.  The criteria 
described above for severe, persistent hyperglycemia will only be applicable after Week 16.  The 
first choice before initiating any rescue therapy for those patients during the initial 16 weeks will 
be to follow the TTT algorithm to increase the dose of insulin degludec. 
Rescue treatment with pramlintide, DPP-4 inhibitors, or GLP-1 receptor agonists will not be 
allowed.  Additionally, use of other basal insulins will not be allowed in the insulin degludec
group.
9.2.2.3.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with LY3298176 including this 
trial.  Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases [Banks and 
Freeman 2006; Koizumi et al. 2006]; the pain is often associated with nausea and 
vomiting);

serum amylase (total and/or pancreatic) and/or lipase ≥3X ULN

characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed).  

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Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed.  If laboratory values and/or abdominal imaging support the 
diagnosis of acute pancreatitis, the patient must discontinue therapy with investigational 
product(s), but will continue in the study on another glucose-lowering regimen (details on rescue 
intervention will be provided).  The most appropriate diabetes therapeutic regimen will be 
decided by the investigator, based on the patient’s clinical status.  A review of the patient’s 
concomitant medications should be conducted to assess any potential causal relationship with 
pancreatitis.
Each case of AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE.  For a potential case that 
does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to study drug(s).
Each patient will have measurements of p-amylase and lipase (assessed at the central laboratory) 
as shown on the Schedule of Activities (Section 2) to assess the effects of the investigational 
doses of LY3298176 on pancreatic enzyme levels. Serial measures of pancreatic enzymes have 
limited clinical value for predicting episodes of acute pancreatitis in asymptomatic patients 
(Nauck et al. 2017; Steinberg et al. 2017a; Steinberg et al. 2017b). Thus, further diagnostic 
follow-up of cases of asymptomatic pancreatic hyperenzymemia (lipase and/or pancreatic 
amylase ≥3X ULN) is not mandated but may be performed based on the investigator’s clinical 
judgment and assessment of the patient’s overall clinical condition. Only cases of pancreatic 
hyperenzymemia that undergo additional diagnostic follow-up and/or are accompanied by 
symptoms suggestive of pancreatitis will be submitted for adjudication.
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee (CEC). In addition, AEs of severe or serious abdominal pain of 
unknown etiology will also be submitted to the adjudication committee to assess for possible 
pancreatitis or other pancreatic disease. Relevant data from patients with acute or chronic 
pancreatitis and those with severe or serious abdominal pain will be entered into a specifically 
designed eCRF page by study site or Lilly staff. The adjudication committee representative will 
enter the results of adjudication in a corresponding eCRF page.
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or multiple endocrine neoplasia type 2 
(MEN-2) will be excluded from the study.  The assessment of thyroid safety during the study
will include reporting of any case of thyroid malignancy including MTC and papillary carcinoma
and measurements of calcitonin.  This data will be captured in specific eCRFs. The purpose of 
calcitonin measurements is to assess the potential of LY3298176 to affect thyroid C-cell 
function, which may indicate development of C-cell hyperplasia and neoplasms.  LY3298176
should be discontinued (after first confirming the value) if postrandomization calcitonin value is 
≥35 ng/L and has increased at least 50% over baseline.  A consultation with a thyroid specialist 
(if not available, an endocrinologist) should be obtained.

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If the increased calcitonin value (≥35 ng/L and increases by ≥50% compared with baseline) is 
observed in a patient who has administered a medication that is known to increase serum 
calcitonin, this medication should be stopped and calcitonin levels should be measured after an 
appropriate wash out period.  If the confirmed calcitonin value is <35 ng/L, LY3298176 should 
be restarted when it is safe to do so.  
9.2.2.5.
Major Adverse Cardiovascular Events
Deaths and nonfatal cardiovascular (CV) AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise.  The nonfatal CV AEs to be adjudicated include the 
following:  

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention)

cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders will be further evaluated. Patients who 
develop any event from this group of disorders should undergo an ECG which should be 
submitted to the central reading center. Additional diagnostic tests to determine exact diagnosis 
should be performed, as needed. The specific diagnosis will be recorded as an AE. Events that 
meet criteria for serious conditions as described in Section 9.2.1 must be reported as SAEs.
9.2.2.7.
Hypersensitivity Events
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Additional data, such as type of reaction and treatment 
received, will be collected on any AEs or SAEs that the investigator deems related to study 
drug(s) via a CRF created for this purpose. Additional samples should also be collected as 
outlined in Section 9.4.3.  Study drug(s) should be temporarily interrupted in any individual 
suspected of having a severe or serious allergic reaction to study drug(s).  Study drug(s) may be 
restarted when/if it is safe to do so, in the opinion of the investigator.  If study drug(s) is 
permanently discontinued, the patient will receive another glucose-lowering treatment, judged by 
the investigator to be appropriate based on the patient’s clinical status, and will continue in the 
trial to collect all planned efficacy and safety measurements. 
9.2.2.7.1. Injection Site Reactions
Injection site reactions will be collected on the eCRF separate from the hypersensitivity reaction 
eCRF.  At the time of AE occurrence in the LY3298176 group, samples will be collected for 
measurement of LY3298176 ADA and LY3298176 concentration.
9.2.2.7.2. Anti-Drug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 9.4.3. 

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9.2.2.8.
Diabetic Retinopathy Complications
Dilated retinal fundoscopic examination will be performed by a qualified eye care professional 
(ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 to exclude patients 
with proliferative retinopathy and/or maculopathy.  The results from this examination will be 
recorded on a specific retinopathy eCRF as a baseline measure of retinopathy.  
A follow-up dilated fundoscopic examination should be performed when clinically indicated by 
any AE suspected of worsening retinopathy, and the findings should be recorded on the 
retinopathy eCRF.  
9.2.2.9.
Hepatobiliary Disorders
All events of TE biliary colic, cholecystitis, or other suspected events related to gallbladder 
disease should be evaluated and additional diagnostic tests performed, as needed. In cases of 
elevated liver markers, hepatic monitoring should be initiated as outlined in Section 9.4.5.1 and 
Appendix 4.
9.2.2.10. Severe Gastrointestinal Adverse Events
LY3298176 may cause severe GI AEs, such as nausea, vomiting, and diarrhea.  Information 
about severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE 
form.  For detailed information concerning the management of GI AEs, please refer to 
Section 7.7.1.
9.2.2.11. Acute Renal Events
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal failure.  Gastrointestinal
AEs have been reported with LY3298176, including nausea, diarrhea, and vomiting. These are
consistent with other GLP-1 receptor agonists (Aroda and Ratner 2011). The events may lead to 
dehydration, which could cause a deterioration in renal function, including acute renal failure. 
Patients should be advised to notify investigators in case of severe nausea, frequent vomiting, or 
symptoms of dehydration.
9.2.2.12. Metabolic Acidosis, Including Diabetic Ketoacidosis
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been reported 
rarely in patients with T2DM.  Patients who present with signs and symptoms consistent with severe 
metabolic acidosis should be assessed for ketoacidosis regardless of presenting BG levels, as 
ketoacidosis may be present even if BG levels are less than 250 mg/dL. If ketoacidosis is suspected, 
SGLT-2i should be discontinued (if used), patient should be evaluated, and prompt treatment should 
be instituted.  Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
Lactic acidosis has been reported rarely in patients with T2DM associated with use of metformin, 
excessive alcohol intake and decrease renal function.  Routine bicarbonate assessment will be 
performed during the course of the study.  If lactic acidosis is suspected, metformin should be 
temporarily discontinued until the resolution of the event.
9.2.2.13. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as an AE.

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9.2.2.14. Major Depressive Disorder/Suicidal Ideation 
The prevalence of depressive symptoms and disorders is increased in patients with T1DM or T2DM 
(ADA Guideline, 2017). Any AE of major depressive disorder or suicidal ideation should be 
reported.
9.2.3.
Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Study drug overdose (more than the specified number of injections) will be reported as an AE.  
In the event of overdose, refer to the IB for LY3298176 and/or Product Label for insulin 
degludec (Degludec USPI, 2015 [WWW]).
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, electrocardiograms (ECGs) should be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms should be recorded according to the study-specific 
recommendations included in the Manual of Operations for the study.  
Electrocardiograms will initially be interpreted by a qualified physician (the investigator or 
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 
while the patient is still present, for immediate subject management, should any clinically 
relevant findings be identified.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the patient receives the first dose of the investigational treatment 
should be reported to Lilly or its designee as an AE via the eCRF.
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database. At a future time, the stored ECG data may be overread by a 
cardiologist at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements. The machine-read ECG intervals and heart rate may be used 
for data analysis and report-writing purposes, unless a cardiologist overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would 
be used).
9.4.2. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2) and following the study-specific recommendations included in.  

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Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
With the exception of laboratory test results that may unblind the study (if applicable), Lilly or 
its designee will provide the investigator with the results of laboratory tests analyzed by a central
vendor, if a central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.4. Immunogenicity Assessments 
Where local regulations and ERBs allow, blood samples for immunogenicity testing will be 
collected to determine antibody production against LY3298176 as specified in the Schedule of 
Activities (Section 2).
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against the LY3298176.  To interpret the 
results of immunogenicity, a PK sample will be collected at the same time points as the 
immunogenicity sample.  All samples for immunogenicity should be taken predose when 
applicable and possible.  In the event of drug hypersensitivity reactions (immediate or 
non-immediate), additional samples will be collected (including ADA, PK, and exploratory 
immune safety sample) as close to the onset of the event as possible, at the resolution of the 
event, and 30 days following the onset of the event.  Instructions for the collection and handling 
of blood samples will be provided by the sponsor.  Sample collected at Visit 801 will assess 
immunogenicity at washout of LY3298176 (5 half-lives post end of treatment).
Treatment-emergent ADAs are defined in Section 10.3.5.
Samples with LY3298176 ADA detected will be titered and evaluated for their ability to 
neutralize the activity of assigned treatment (LY3298176-neutralizing antibodies).  Samples with 
LY3298176 ADA detected will also be tested for cross-reactive binding to native GIP and 
GLP-1, and, if such is detected, then for neutralizing antibodies against native GIP and GLP-1, 
respectively.
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
LY3298176.  Any samples remaining after 15 years will be destroyed.

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9.4.5. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.5.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL 
≥2X ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels. 
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be a SAE
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
9.7.1. Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3298176 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 patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  

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Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards impose shorter time limits.  This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of LY3298176 or after LY3298176
become(s) commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore,
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized genotyping data generated will be used only for the specific research scope 
described in this section. 
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements.
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3298176, pathways associated with T2DM, mechanism of action of LY3298176, and/or 
research method or in validating diagnostic tools or assay(s) related to T2DM.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the course of the development and commercialization of both study drugs.
9.9.
Health Economics
The following questionnaires will be completed by the patients at specific clinic visits according 
to the Schedule of Events (Section 2). At these visits, the questionnaires should be completed 
before the patient has discussed their medical condition or progress in the study with the 
investigator and/or site staff and before any other study procedures if the patient is not adversely 
affected by their fasting condition.

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9.9.1. Diabetes Treatment Satisfaction Questionnaire 
The status (s) and change (c) versions of the DTSQ will be used during the study to assess the 
patients’ satisfaction with their diabetes treatment and the perceived frequency of hyperglycemia 
and hypoglycemia.  The questionnaire contains 8 items (Bradley 1994).  Each item is rated on a 
7-point Likert scale.  Six items (1 and 4 through 8) are summed to produce a measure of 
treatment satisfaction ranging from 0 “very dissatisfied” to 6 “very satisfied.”  The remaining 2 
items (2 and 3) are treated individually.  Item 2 measures the perceived frequency of 
hyperglycemia on a scale ranging from 0 “none of the time” to 6 “most of the time,” and Item 3 
measures the perceived frequency of hypoglycemia on the same scale.  The change version has 
the same 8 items as the status version with a small alteration of the wording of Item 7.  The 
DTSQ change response options differ from those of the DTSQ status to produce measures of 
relative change rather than absolute satisfaction.
9.9.2. Impact of Weight on Self-Perception Questionnaire
The IW-SP questionnaire contains 3 items that assess how often the patients’ body weight affects 
how happy they are with their appearance and how often they feel self-conscious when out in 
public (Hayes and DeLozier 2015).  Each item is rated on a 5-point scale ranging from “always” 
to “never.”  Total scores for the IW-SP are derived by summing the item scores and dividing by 
the number of items.  The score can also be transformed to a range from 0 to 100.  Higher IW-SP 
scores correspond to better self-perception (Hayes and DeLozier 2015).
9.9.3. Ability to Perform Physical Activities of Daily Living
The APPADL questionnaire contains 7 items that assess how difficult it is for patients to engage 
in certain activities considered to be integral to normal daily life, such as walking, standing, and 
climbing stairs (Hayes et al. 2011; Hayes et al. 2012).  Items are scored on a 5-point numeric 
rating scale, where 5 = “not at all difficult” and 1 = “unable to do.”  A raw overall score is 
calculated by simply summing the scores of the 7 items, and a transformed overall score is 
obtained by linearly transforming the raw overall score to a 0 to 100 scale.  A higher raw overall 
score and a higher transformed overall score are indicative of better ability to perform activities 
of daily living.  
9.9.4. European Quality of Life 
Generic health-related quality of life will be assessed using the EQ-5D-5L (EuroQoL Group 
2015).  The EQ-5D-5L is a standardized 5-item instrument for use as a measure of health 
outcome.  It provides a simple descriptive profile and a single index value for health status that 
can be used in the clinical and economic evaluation of health care as well as population health 
surveys.  The EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3251 possible health states.  In addition to the 
health profile, a single health state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension. This index value ranges between less than 0 

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(where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1 
(perfect health).  In addition, the EQ Visual Analog Scale records the respondent’s self-rated 
health status on a vertical graduated (0 to 100) visual analog scale.  In conjunction with the 
health state data, it provides a composite picture of the respondent’s health status.  
The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015). 

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10. Statistical Considerations
10.1. Sample Size Determination
Patients will be randomized in a 1:1:1:1 ratio to LY3298176 5 mg, 10 mg, 15 mg, or insulin
degludec.  Although the primary objective of the trial is to demonstrate that once-weekly 10 mg 
and/or 15 mg doses are noninferior to titrated insulin degludec relative to mean change in HbA1c 
from baseline (using a 0.3% noninferiority boundary), the study is powered to assess superiority 
of LY3298176 10 mg and 15 mg, each tested in parallel against titrated insulin degludec at a 
2-sided significance level of 0.025, relative to the primary endpoint (mean change in HbA1c 
from baseline to 52 weeks), under the following assumptions:  use of a 2-sample t-test utilizing 
HbA1c data collected before initiation of any rescue medication or premature treatment 
discontinuation with no more than 28% of subjects initiating any rescue medication or 
prematurely discontinuing treatment in each treatment group; 0.35% greater mean reduction in 
HbA1c from baseline for 10 and 15 mg LY3298176 compared with insulin degludec; 1:1:1:1 
randomization, a common standard deviation (SD) of 1.1%, and a superiority boundary of 
0.05%.  On the basis of these assumptions, a sample size of 1420 subjects is required to ensure at 
least 90% power to demonstrate that LY3298176 10 mg and/or 15 mg are superior to insulin 
degludec relative to the primary endpoint.  Furthermore, this sample size will ensure 90% power 
for the superiority evaluation conducted using an analysis of covariance (ANCOVA) utilizing all 
available HbA1c data at 52 weeks with missing data imputed with a conservative multiple 
imputation method (as described in the Efficacy Analysis section below), provided a 0.35% 
greater mean reduction in HbA1c from baseline for 10 and 15 mg LY3298176 compared with 
insulin degludec and SD increases to no more than 1.3% due to the inclusion of data on rescue 
medications and after premature treatment discontinuation, and imputation of missing data.
10.2. Populations for Analyses
For purposes of analysis, the following analysis sets are defined in Table GPGH.6:
Table GPGH.6.
Description of Analysis Sets
Analysis Set
Description
Screened patients
All participants who sign informed consent
Randomized patients
All patients who are randomly assigned a treatment group
modified intention-to-treat 
(mITT) set
All randomly assigned participants who are exposed to at least 1 dose of study 
drug.  In the event of a treatment error, participants will be analyzed according 
to the treatment they were randomized.
Efficacy analysis set (EAS)
Data obtained during Study Period II from the mITT set, excluding data after 
initiating rescue antihyperglycemic medication or stopping study drug.
Full analysis set (FAS)
Data obtained during Study Period II from the mITT set, regardless of 
adherence to study drug or initiation of rescue antihyperglycemic medication
Safety analysis set (SAS)
Data obtained during Study Periods II or III from the mITT set, regardless of 
adherence to study drug or initiation of rescue antihyperglycemic medication.

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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the
statistical analysis plan (SAP) or the clinical study report (CSR).  Additional exploratory 
analyses of the data may be conducted as deemed appropriate.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval (CI) will be calculated at 95%, 2-sided.  In statistical 
summaries and analyses, patients will be analyzed as randomized.
There will be 2 estimands of interest in comparing efficacy of LY3298176 doses with insulin 
degludec.  First estimand, the “efficacy” estimand, represents efficacy prior to discontinuation of 
study drug without confounding effects of antihyperglycemic rescue therapy.  Second estimand, 
the “treatment-regimen” estimand, represents the efficacy irrespective of adherence to study drug 
or initiation of rescue antidiabetic drugs.
The primary efficacy assessment, guided by the “efficacy” estimand, will be conducted using the 
efficacy analysis set (EAS).  The primary efficacy assessment, guided by the 
“treatment-regimen” estimand, will be conducted using the full analysis set (FAS).  As they are 
intended for different purposes, no multiplicity adjustments will be made for conducting 2 
primary efficacy assessments.
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3298176 doses with insulin degludec irrespective of adherence to study drug or initiation 
of antihyperglycemic rescue therapy.  Thus, safety analysis will be conducted using the SAS.  
Selected safety analyses will be conducted after excluding data on rescue therapy.
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model to make comparisons among treatment groups
relative to continuous measurements assessed over time will be a mixed model for repeated 
measures (MMRM), with terms:  treatment, visit, and treatment-by-visit interaction, country, 
SGLT-2 use (Yes or No), and baseline measurement as a covariate.  An unstructured covariance 
structure will model the relationship of within-patient errors.
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time, and cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments.
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages.  Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes.  Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes.  Summary statistics for discrete count 

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measures will include sample size, mean, SD, median, minimum, and maximum.  The negative 
binomial regression model will be used for the treatment comparison of discrete count measures.
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
Frequency counts and percentages of all patients screened, randomized, and receiving at least 1 
dose of study drug will be presented by treatment groups.  A listing of randomized patients not 
receiving study drug will be provided.  Of the patients in the mITT set, frequency, counts and 
percentages of patients completing the study, prematurely discontinuing the study, including the 
reason for premature discontinuation, will be presented by treatment groups.  A Kaplan-Meier 
analysis of time from randomization to premature discontinuation from study by treatment group 
will be provided.
10.3.2.2. Patient Characteristics
Demographics, medical history, and concomitant illness will be summarized by treatment group 
using the mITT set.
10.3.2.3. Concomitant Therapy 
Concomitant medications, including previous therapy for diabetes, will be summarized by 
anatomical therapeutic chemical classification and treatment group using the mITT set.  In 
particular, the incidence of initiation of rescue therapy for severe, persistent hyperglycemia will 
be analyzed as an exploratory safety endpoint.  Dose modifications of oral antihyperglycemic 
therapy will also be compared between treatment groups.
10.3.2.4. Treatment Compliance 
Of the patients in the mITT set, frequency counts and percentages of patients prematurely 
discontinuing study drug, including reason for premature discontinuation, will be presented by 
treatment group.  A Kaplan-Meier analysis of time from randomization to premature study drug 
discontinuation by treatment group will be provided. Treatment compliance for each visit 
interval is defined as taking at least 75% of required injections of study drugs.  Frequency counts 
and percentages of patients compliant to study drug will be summarized by treatment arms using 
the mITT set.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
As indicated in Section 10.3.1, there will be 2 primary efficacy analyses conducted to establish 
noninferiority of LY3298176 10 mg and LY3298176 15 mg to insulin degludec relative to mean 
change in HbA1c from baseline to the 52-week visit.
For the FDA, the primary efficacy analysis will be guided by the “treatment-regimen” estimand 
defined in Section 10.3.1.  This assessment will analyze change in HbA1c values obtained at the 

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52-week visit using ANCOVA with terms, treatment, country, baseline concomitant oral 
antidiabetic treatment (metformin alone, metformin plus an SGLT-2i), and baseline HbA1c as a 
covariate.  Missing change in HbA1c from baseline values at the 52-week visit will be imputed 
based on observed changes in HbA1c from baseline values at the visit from patients in the same 
treatment group who had their efficacy assessed after early discontinuation of study drug and/or 
initiation of rescue antihyperglycemic medication.  With the aid of the ANCOVA 2-sided 97.5% 
CI for the difference in mean change in HbA1c from baseline to the 52-week visit between 
LY3298176 10 mg and insulin degludec as well as between LY3298176 15 mg and insulin 
degludec will be constructed.  Analysis will be conducted with multiple imputations, and 
statistical inference over multiple imputations will be guided by the method proposed by Rubin 
(1987).  If the upper limit of the CI is below 0.3%, the LY3298176 dose will be declared 
non-inferior to insulin degludec.
For all other purposes, the primary efficacy analysis will be guided by the “efficacy” estimand 
defined in Section 10.3.1.  This assessment will be conducted using EAS.  The primary analysis 
model for HbA1c measurements over time will be an MMRM.  The response variable of 
MMRM will be change in HbA1c from baseline values obtained at each scheduled postbaseline 
visit.  The independent variables of the MMRM model are treatment, visit, and treatment-by-visit 
interaction, country, baseline concomitant oral antidiabetic treatment (metformin alone, 
metformin plus an SGLT-2 inhibitor) as fixed effects, and baseline HbA1c as a covariate.  
Two-sided 97.5% CIs will be constructed for the difference in mean change in HbA1c from 
baseline to the 52-week visit between LY3298176 10 mg and insulin degludec, as well as 
between LY3298176 15 mg and insulin degludec.  If the upper limit of the CI is below 0.3%, the 
LY3298176 dose will be declared noninferior to insulin degludec.
Since they are intended for different purposes, each of the 2 primary efficacy assessments will be 
conducted at a family-wise type 1 error rate of 0.05.  Additional details, including analysis 
methods for key secondary endpoints and a strategy for controlling the overall family-wise type 
1 error rate at an alpha of 0.05 for primary and key secondary endpoint evaluation will be 
provided in the SAP.
10.3.3.2. Secondary Analyses
The secondary study objectives subject to type 1 error rate control are as follows:

noninferiority of the 5 mg LY3298176 dose to insulin degludec relative to mean change 
in HbA1c from baseline to the 52-week visit

superiority of each LY3298176 dose to insulin degludec relative to mean change in 
HbA1c from baseline to the 52-week visit

superiority of each LY3298176 dose to insulin degludec relative to mean change in body 
weight from baseline to the 52-week visit

superiority of each LY3298176 dose to insulin degludec relative to proportion of patients 
achieving the target value of HbA1c <7% at the 52-week visit
The type I error-controlled strategy for the primary and secondary endpoints will be described in 
the SAP.  All type I error-controlled secondary efficacy analyses will be conducted relative to 
both estimands, the “efficacy” estimand and the “treatment-regimen” estimand.

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Analysis of change from baseline in body weight at the 52-week visit will be conducted in a 
manner similar to the primary efficacy analyses with change in weight from baseline as the 
response variable and baseline body weight as a covariate.
Comparisons among treatments relative to the proportion of patients achieving the HbA1c target 
value of <7.0% (53 mmol/mol) at the 52-week visit will be conducted using a logistic regression 
analysis with terms of treatment, country, SGLT-2i use (Yes or No), and baseline HbA1c as a 
covariate.  In the analysis of patients achieving the HbA1c target value relative to the “efficacy” 
estimand, subjects with missing values at the 52-week visit will be excluded.  In the analysis of 
patients achieving the HbA1c target value relative to the “treatment-regimen” estimand, missing 
values at the 52-week visit will be imputed based on observed data at respective visits from 
patients in the same treatment group who had their efficacy assessed after early discontinuation 
of study drug and/or initiation of rescue medication.  The analysis will be conducted with 
multiple imputations and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987).
10.3.3.3. Tertiary/Exploratory Analyses
All exploratory efficacy analyses will be guided by the “efficacy” estimand and will be 
conducted using the EAS.  Details will be provided in the SAP.
10.3.4. Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3298176 doses with insulin degludec irrespective of adherence to study drug or initiation 
of rescue therapy.  Thus, safety analyses will be conducted using the SAS.  Selected safety 
analyses will be conducted after excluding data on rescue therapy.
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Selected 
notable AEs of interest may be reported using high-level terms or Standardized MedDRA 
Queries.  Summary statistics will be provided for incidence of TEAEs, SAEs, study 
discontinuation due to AEs, study drug discontinuation due to AEs, deaths, and other CV 
endpoints.  Counts and proportions of subjects experiencing AEs will be reported for each 
treatment group, and Fisher’s exact test will be used to compare the treatment groups.
10.3.4.1. Hypoglycemic Events
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia in each 
category (either total or nocturnal) will be compared between LY3298176 doses and insulin 
degludec using negative binomial regression analysis. Selected safety analyses may be 
conducted excluding data after the introduction of another anti-hyperglycemic therapy (for 
example, rescue therapy).
10.3.4.2. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment.

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10.3.4.3. Adjudicated Cardiovascular Events
Listings of deaths, myocardial infarctions, strokes, and hospitalization for unstable angina 
confirmed by an independent CEC will be provided.  The dates of randomization, event, first 
dose and last dose of study drug, and time from randomization to the event will be listed.
10.3.4.4. Central Laboratory Measures, Vital Signs, and Electrocardiograms
Values and change from baseline to postbaseline values of central laboratory measures, vital 
signs, and selected ECG parameters will be summarized at each scheduled visit.  The analysis 
model to make comparisons among treatment groups relative to continuous change from baseline 
values assessed over time will be an MMRM similar to the primary efficacy analysis and with 
baseline measurement as a covariate.  An unstructured covariance structure will model 
relationship of within-patient errors.
The percentages of patients with TE abnormal, high, or low laboratory measures at any time will 
be summarized and compared between treatment groups by using Fisher’s exact test.  A TE
abnormal value is defined as a change from normal value at baseline to a value greater than the 
high limit at any time during Periods II and III.  A TE low result is defined as a change from a 
value greater than or equal to the low limit at baseline to a value less than the low limit at any 
time during Periods II and III.  The high and low limits will be provided in the SAP.
10.3.5. Evaluation of Immunogenicity 
The frequency and percentage of patients with preexisting ADA, with TE ADA, and with 
neutralizing TE ADA to LY3298176 will be tabulated by LY3298176 dose. 
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA).  For the TE ADA patients the distribution of maximum titers 
will be described.  The frequency of neutralizing antibodies to LY3298176 and/or cross-reactive 
and neutralizing antibodies to endogenous couterparts will be tabulated in TE ADA patients.
The relationship between the presence of antibodies and LY3298176 PK and PD response
including safety and efficacy to LY3298176 may be assessed.
10.3.6. Other Analyses
10.3.6.1. Health Economics
Analyses of actual and change from baseline in patient-reported outcome (PRO) scores will be 
conducted using linear models with baseline PRO scores, treatment and other factors that may be 
considered relevant.  These variables will be specified in the SAP.
10.3.6.2. Subgroup Analyses
Subgroup analyses of mean change in HbA1c from baseline to Visit 18 will be provided by age, 
race, ethnicity, gender, duration of diabetes, baseline HbA1c (≤8.5%, >8.5%), and baseline 
SGLT-2i.

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10.3.7. Interim Analyses
No interim analyses of efficacy are planned for this study.  If an unplanned interim analysis is 
deemed necessary, the appropriate Lilly medical director, or designee, will be consulted to 
determine whether it is necessary to amend the protocol.
A data monitoring committee (DMC) will have the responsibility to review unblinded interim 
analyses results in order to monitor the safety of the patients in the study.  A sponsor statistical 
analysis group external to the study team will perform the data analysis for the DMC.  As no 
efficacy analyses are planned by the DMC, the family-wise error rate will not be affected by any 
one of these interim analyses; hence no alpha spending is necessary.
Study sites will receive information about interim results ONLY if deemed necessary for the 
safety of their patients.

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11. References
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabet Med. 1998;15(7):539-553.
American Diabetes Association. Glycemic Targets. Sec 6. In Standards of Medical Care in 
Diabetes—2017. Diabetes Care. 2017;40(suppl 1):S48-S56. Available at:
http://care.diabetesjournals.org/content/40/Supplement_1/S48. Accessed August 6, 2018.
Aroda AR, Bailey TS, Cariou B, Kumar S, Leiter LA, Raskin P, Zacho J, Andersen TH, 
Philis-Tsmikas A. Effect of adding insulin degludec to treatment in patients with type 2 
diabetes inadequately controlled with metformin and liraglutide: a double-blind randomized 
controlled trial (BEGIN: add to GLP-1 study). Diabetes Obes Metab. 2016;18(7):663-670.
Asmar M, Simonsen L, Asmar A, Holst JJ, Dela F, Bulow J. Insulin plays a permissive role for 
the vasoactive effect of GIP regulating adipose tissue metabolism in humans. J Clin 
Endocrinol Metab 2016;101:3155-3162.
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379-2400.
Bradley C. The diabetes treatment satisfaction questionnaire: DTSQ. In: Bradley C, editor.
Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes 
research and practice. Chur, Switzerland: Harwood Academic Publishers; 1994.
Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, 
Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Giemeno RE, D’Alessio DA, 
Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2
diabetes nellitus: From discovery to clinical proof of concept. Molecular Metab. 2018
Available at:  https://doi.org/10.1016/j.molmet.2018.09.009.  Published October 2018.
Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
comparing the rate of hypoglycemia – assessed using continuous glucose monitoring – in 125 
preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601. 
EuroQoL Group. EQ-5D-5L User guide: basic information on how to use the EQ-5D-5L 
instrument. Version 2.1. Available at: 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf. Published
April 2015. Accessed August 6, 2018.
Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-
1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and 
active comparator-controlled phase 2 trial. [published online October 4, 2018]. Lancet.
https://doi.org/10.1016/S0140-6736(18)32260-8.
Hayes RP, DeLozier AM. Reliability, validity, and responsiveness of the Impact of Weight on 
Self-Perceptions Questionnaire (IW-SP) in individuals with type 2 diabetes and obesity. 
Diabetes Technol Ther. 2015;17(3):210-214.

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Hayes RP, Nelson DR, Meldahl ML, Curtis BH. Ability to perform daily physical activities in 
individuals with type 2 diabetes and moderate obesity: a preliminary validation of the Impact 
of Weight on Activities of Daily Living Questionnaire. Diabetes Technol Ther. 
2011;13(7):705-712.
Hayes RP, Schultz EM, Naegeli AN, Curtis BH. Test-retest, responsiveness, and minimal 
important change of the ability to perform physical activities of daily living questionnaire in 
individuals with type 2 diabetes and obesity. Diabetes Technol Ther. 2012;14(12):1118-1125.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas 
A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a 
patient-centered approach: update to a position statement of the American Diabetes 
Association and the European Association for the Study of Diabetes. Diabetes Care.
2015;38(1):140-149.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN. JPN Guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg.
2006;13(1):25-32.
Nauck M. Incretin therapies: highlighting common features and differences in the modes of 
action of glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors. Diabetes 
Obes Metab. 2016;18(3):203-216.
Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
acurte pancreatitis an/or pancreatic cancer: Reassuring data from cardio-vascular outcome 
trials. Diabetes Obes Metab. 2017;19(9): 1327-1328. 
Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab.
2018:20(Suppl.1):5-21.
Pan C, Gross JL,Yang W, Lv X, Sun L, Hansen CT, Xu H, Wagner R. A multinational, 
randomized, open-label, treat-to-target trail comparing insulin degludec and insulin glargine in 
insulin-naïve patients with type 2 diabetes mellitus. Drugs RD. 2016;16:239-249.
Philis-Tsimikas A, Brod M, Niemeyer M, Francisco AMO, Rothman J. Insulin degludec 
once-daily in type 2 diabetes: simple or step-wise titration (BEGIN: once simple use). Adv 
Ther. 2013; 30:607-622.
Ratner, RE, Gough SCL, Mathieu C, Del Prato S, Bode B, Mersebach H, Endahl L, Zinman B.
Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 
diabetes:a pre-planned meta-analysis of phase 3 trials. Diabetes, Obesity and Metabol. 
2013;15 (2):175-184.
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons Inc.; 
1987.
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people 
with type 2 diabetes treated with liraglutide: results from the LEADER Randomized Trial.
Diabetes Care. 2017a;40(7):966-972.

I 8 F-M C -G P G H ( c) Cli ni c al Pr ot o c ol
P a g e 7 5
L Y 3 2 9 8 1 7 6
Stei n ber g W M, R ose nst oc k J, Wa d de n T A, D o ns mar k M, Je nse n C B, De Vries J H. I m pact of 
lira glut i de o n a m ylase, li pase, a n d ac ute pa ncreatitis i n partici pa nts wit h o ver weig ht/ o besi t y 
a n d n or m o gl yce mia, pre dia betes, or t ype 2 di a betes: sec o n dar y a nal yses of p o ole d data fr o m 
t he S C A L E cli nical de vel o p me nt pr o gra m. Di a betes C are . 2 0 1 7 b ; 4 0( 7): 8 3 9- 8 4 8.
Tresi ba [ U S pac ka ge i nsert ( U S PI)]. I n dia na p o lis, I N: Eli Lill y a n d C om pa n y; 2 0 1 5. A vaila ble 
at: htt ps:// w w w.access data.f da. g o v/ dr u gsat f da _ d ocs/la bel/ 2 0 1 5/ 2 0 3 3 1 4l bl. pdf .
V ora J, C o he n N, E va ns M, H oc ke y  A, S peig ht J, W hatel y -S mi t h C. I nte nsif yi n g i ns uli n re gi me n 
after basal ins uli n o pti mizat i on i n a d ults wit h ty pe 2 dia betes: a 2 4 -wee k, ra n d o mize d, o pe n -
la bel trial c om par i n g i ns uli n glar gi ne pl us i ns uli n gl ulisi ne with bi p hasic i ns uli n as part 
( La n Sca pe). Di a betes, O besity a n d Met a b . 2 0 1 5; 1 7( 1 2): 1 1 3 3- 1 1 4 1.
Wei n ber g M E, Bacc hetti P, R us ha k off RJ. Fre q ue nt l y re peate d gluc ose m eas ure me nts 
o veresti mate t he i nci de nce of i n patie nt h y p o gl yce mia a n d se vere h y per gl yce mia. J Di a betes 
Sci Tec h n ol . 2 0 1 0; 4( 3): 5 7 7- 5 8 2.
Zi n ma n B, P hilis -Tsi mi kas A, Cari o u B, Ha n dels ma n Y, R o d bar d H W, J o ha nse n T, E da hl L, 
Mat hie u C o n be half of t he N N 1 2 5 0 -3 5 7 9 ( B E GI N O nce L o n g) Trial I n vest i gat ors. I ns uli n 
de gl u dec vers us i ns uli n glar gi ne i n i ns uli n -naï ve pati e nts wit h t ype 2 dia betes. A 1 -year, 
ra n d omize d, treat -t o-tar get trial ( B E GI N O nce L o n g). Di a betes C are . 2 0 1 2; 3 5: 2 4 6 4 -2 4 7 1.

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12. Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APPADL
Ability to Perform Physical Activities of Daily Living
AST
aspartate aminotransferase
BG
blood glucose
BP
blood pressure
CEC
clinical endpoint committee
CHF
congestive heart failure
CI
confidence interval
CKD-EPI
Chronic Kidney Disease-Epidemiology
CIOMS
Council for International Organizations of Medical Sciences
Companion diagnostic 
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
COVID-19
Coronavirus Disease 2019
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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CSR
clinical study report
CT
computed tomography
CV
cardiovascular
CVD
cardiovascular disease
DMC
data monitoring committee
DPP-4
dipeptidyl-peptidase-4
DTSQc
Diabetes Treatment Satisfaction Questionnaire change
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D-5L
European Quality of Life
ERB
ethical review board
ET
early termination
FAS
full analysis set
FBG
fasting blood glucose
FSH
follicle-stimulating hormone
GAD
glutamic acid decarboxylase
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c

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HDL
high-density lipoprotein
HR
heart rate
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
INR
international normalized ratio
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive voice-response system/interactive web-response system
IW-SP
Impact of Weight on Self-Perception
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intention-to-treat
MMRM
mixed-model for repeated measures
MTC
medullary thyroid carcinoma
NAFLD
nonalcoholic fatty liver disease
OAM
oral antihyperglycemic medications 
OTC
over the counter
PG
plasma glucose
PK/PD
pharmacokinetics/pharmacodynamics

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PP
per-protocol
PPS
per-protocol set:  The set of data generated by the subset of patients who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QTc
corrected QT interval
QD
once daily
QW
once weekly
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
safety analysis set
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SDP
single dose pen
SGLT-2i
sodium-glucose co-transporter-2 inhibitor
SMBG
Self-monitored blood glucose
SUSARs
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TG
triglycerides
TTT
treat-to-target

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Tx
treatment
ULN
upper limit of normal
VLDL
very low density lipoprotein

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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Testsa
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Mean cell volume
Mean cell hemoglobin concentration
Leukocytes (WBC)
Neutrophils, segmented
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Potassium
Bicarbonate
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Blood urea nitrogen (BUN)
Creatinine
Uric acid
Calcium
Glucose, fasting
Urinalysis
Albumin
Creatinine
Pregnancy Test (females only)b
Follicle-stimulating hormone (FSH)c
Estradiolc
HbA1c
eGFR (calculated by CKD-EPI equation)d
Endocrine
Calcitonin
Anti-GAD Antibodies
Pancreas (exocrine)
Serum pancreatic amylase
Serum lipase
Immunogenicity
LY3298176 anti-drug antibody
Nonpharmacogenetic Stored Samples:
EDTA plasma
Serum
P800 plasma
Pharmacogenetic Stored Sample
Lipid Panel (fasting)
Total cholesterol
LDL
HDL
VLDL
Triglycerides

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Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; EDTA = ethylenediaminetetraacetic acid; 
eGFR = estimated glomerular filtration rate; GAD = glutamic acid decarboxylase; HbA1c = hemoglobin A1c; 
HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; PK = pharmacokinetics; 
RBC = red blood cells; VLDL = very low-density lipoprotein cholesterol; WBC = white blood cells.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential; A 
urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first 
injection of study drug(s) for women of childbearing potential only. Additional pregnancy tests will be 
performed at Visits 13, 17, 19 and 21. Pregnancy tests may also be performed at the investigator’s discretion 
during the study.  If required per local regulations and/or institutional guidelines, pregnancy testing can also 
occur at other times during the study treatment period
c
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 45years of age with an 
intact uterus, not on hormone therapy, and who have had spontaneous amenorrhea for more than 6 months and 
less than 12 months and estradiol levels consistent with a postmenopausal state (FSH ≥40 mIU/mL and estradiol 
<30 pg/mL).
d
Estimated glomerular filtration rate will be calculated by the central laboratory at all visits and included in 
laboratory result reports.

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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

ensuring that informed consent is given by each patient or legal 
representative.  This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the patientmay have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

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
the protocol and related amendments and addenda, current Investigator’s
Brochure (IB) and updates during the course of the study

ICF

other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, internal medicine, family medicine, 
general medicine, or any other specialty physician who has experience treating type 2 diabetes
with clinical research experience will participate as investigators in this clinical study.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
A qualified investigator will serve as the CSR coordinating investigator.  If this investigator is 
unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

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

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

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

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

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

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Appendix 7.
Changes to Study Procedures due to the 
COVID-19 Pandemic
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel
COVID-19 pandemic, has caused numerous global restrictions to be enacted that may impact a 
patient’s ability and/or willingness to attend their onsite study visit as originally scheduled.  In 
such a situation, please follow the guidance below:  
1) Patients should come for the primary endpoint visit (Visit 21) at the originally planned 
52-week (±7 days) schedule whenever possible and safe to do so, at the investigator's 
discretion.  However, in order to maximize the ability for onsite visits for Visit 21, 
minimize missing data, and preserve the intended conduct of the study, the visit window 
for Visit 21 may be brought forward no sooner than 14 days (Week 50) or extended up to 
8 weeks (Week 60).  The subsequent safety follow-up visit (Visit 801) should take place 
4 weeks ±7 days after Visit 21.  
2) For patients requiring an extension for Visit 21 up to Week 60, additional IP will be 
provided to allow patients to remain on study drug uninterrupted during the extended 
treatment period, to ensure patient safety, and to maintain the overall integrity of the trial. 
3) Additional consent from the patient will be obtained per local regulations for those 
patients who will be dispensed additional IP during the extended treatment period.
4) The sites will need to identify and document the details of how all patients and visits 
were affected by the COVID-19 pandemic restrictions.
5) Mobile (in-home) healthcare visits: 

Mobile visits may be performed at patients’ homes when patients cannot travel to the 
site due to extenuating circumstances. These will be performed by a qualified home 
nursing service provider following sponsor approval, if permitted by local 
regulations. Procedures performed may include, but are not limited to, taking blood 
samples, conducting physical assessments, administering PROs, and collecting health 
information. Please note that requirements related to the reporting of SAEs remain 
unchanged. Every effort should be made for the patient to return to onsite visits as 
soon as reasonably possible, while ensuring the safety of the patient and 
investigational site staff. 

Additional consent from the patient will be obtained for those who participate in 
home health services.

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LY3298176
Appendix 8.
Protocol Amendment I8F-MC-GPGH(c)
A Randomized, Phase 3, Open-Label Trial Comparing 
the Effect of LY3298176 versus Titrated Insulin Degludec 
on Glycemic Control in Patients with Type 2 Diabetes 
(SURPASS-3)
Overview
Protocol I8F-MC-GPGH titled “A Randomized, Phase 3, Open-Label Trial Comparing the Effect 
of LY3298176 versus Titrated Insulin Degludec on Glycemic Control in Patients with Type 2 
Diabetes (SURPASS-3)” has been amended.  The new protocol is indicated by amendment (c) 
and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table.  

I8F-MC-GPGH(c) Clinical Protocol
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LY3298176
Amendment Summary for Protocol I8F-MC-GPGH Amendment (c)
Section # and Name
Description of Change
Brief Rationale
Appendix 7
Added language about the mobile 
(in-home) healthcare visits.
This provides an option to conduct a clinical 
trial visit and all the applicable procedures in a 
mobile healthcare facility or at the home of a 
patient when the patient is not able or not 
willing to go to the site due to COVID-19 
restrictions.

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