A Randomized, Double-Blind Trial Comparing the Effect of the Addition of Dulaglutide 1.5 mg Versus the Addition of Placebo to Titrated Basal Insulin on Glycemic Control in Chinese Patients With Type 2 Diabetes
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

 
 
 
Protocol H9X-MC-GBGO(a) 
 
 
A Randomized, Double-Blind Trial Comparing the Effect of the Addition of Dulaglutide 1.5 mg 
versus the Addition of Placebo to Titrated Basal Insulin on Glycemic Control in Chinese Patients 
with Type 2 Diabetes (AWARD-CHN3: Assessment of Weekly AdministRation of LY2189265 
in Diabetes-CHINA3)   
 
 
NCT04591626 
 
Approval Date: 30-Jul-2020 
 
 
 
 
 
 

H9X-MC-GBGO(a) Clinical Protocol
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Protocol H9X-MC-GBGO(a)
A Randomized, Double-Blind Trial Comparing the Effect of 
the Addition of Dulaglutide 1.5 mg versus the Addition of 
Placebo to Titrated Basal Insulin on Glycemic Control in 
Chinese Patients with Type 2 Diabetes
(AWARD-CHN3:  Assessment of Weekly AdministRation of 
LY2189265 in Diabetes – CHINA3)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
dulaglutide (LY2189265), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Dulaglutide (LY2189265)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 06 March 2020.               
Amendment (a) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 30-Jul-2020 GMT

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Table of Contents
Section
Page
Protocol H9X-MC-GBGO(a) A Randomized, Double-Blind Trial 
Comparing the Effect of the Addition of Dulaglutide 1.5 mg versus 
the Addition of Placebo to Titrated Basal Insulin on Glycemic 
Control in Chinese Patients with Type 2 Diabetes ...............................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.2.
Number of Participants.................................................................................................29
5.3.
End of Study Definition ...............................................................................................29
5.4.
Scientific Rationale for Study Design...........................................................................29
5.5.
Justification for Dose ...................................................................................................30
6.
Study Population...............................................................................................................31
6.1.
Inclusion Criteria..........................................................................................................31
6.2.
Exclusion Criteria ........................................................................................................33
6.3.
Lifestyle Restrictions....................................................................................................36
6.4.
Screen Failures.............................................................................................................36
7.
Treatments........................................................................................................................37
7.1.
Treatments Administered .............................................................................................37
7.1.1.
Packaging and Labelling ......................................................................................37
7.1.2.
Medical Devices...................................................................................................38
7.2.
Method of Treatment Assignment ................................................................................38
7.2.1.
Selection and Timing of Doses.............................................................................38
7.2.2.
Injecting Study Drug............................................................................................38
7.2.2.1.
Dulaglutide or Placebo ...................................................................................38
7.2.2.2.
Insulin Glargine..............................................................................................39
7.2.2.2.1.
Insulin Glargine Dose Titration Algorithm................................................39
7.3.
Blinding .......................................................................................................................40

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7.4.
Dosage Modification....................................................................................................40
7.5.
Preparation/Handling/Storage/Accountability...............................................................41
7.6.
Treatment Compliance .................................................................................................41
7.7.
Concomitant Therapy...................................................................................................42
7.7.1.
Antihyperglycemia Medications...........................................................................43
7.7.2.
Medications That Promote Weight Loss...............................................................44
7.7.3.
Systemic Glucocorticoids.....................................................................................44
7.7.4.
Antihypertensive Medications..............................................................................44
7.7.5.
Special Treatment Considerations ........................................................................44
7.7.5.1.
Standards of Medical Care..............................................................................44
7.7.5.2.
Management of Increased Hypoglycemia Risk ...............................................45
7.7.5.3.
Management of Patients with Severe, Persistent 
Hyperglycemia during the Treatment Period...................................................45
7.8.
Treatment after the End of the Study............................................................................46
7.8.1.
Continued Access.................................................................................................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........................................................................................................50
9.
Study Assessments and Procedures ...................................................................................51
9.1.
Efficacy Assessments...................................................................................................51
9.1.1.
Primary Efficacy Assessments .............................................................................51
9.1.2.
Secondary Efficacy Assessments..........................................................................51
9.1.3.
Exploratory Efficacy Measures ............................................................................51
9.1.4.
Appropriateness of Assessments ..........................................................................51
9.2.
Adverse Events ............................................................................................................52
9.2.1.
Serious Adverse Events........................................................................................52
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................53
9.2.2.
Adverse Event of Special Interest.........................................................................54
9.2.2.1.
Hypoglycemia ................................................................................................54
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................55
9.2.2.3.
Pancreatitis.....................................................................................................55
9.2.2.4.
C-Cell Hyperplasia and C-Cell Neoplasms .....................................................56
9.2.2.5.
Cardiovascular Events ....................................................................................57
9.2.2.6.
Allergic/Hypersensitivity Reactions................................................................57

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9.2.3.
Complaint Handling.............................................................................................57
9.3.
Treatment of Overdose.................................................................................................58
9.4.
Safety...........................................................................................................................58
9.4.1.
Electrocardiograms ..............................................................................................58
9.4.2.
Vital Signs ...........................................................................................................58
9.4.3.
Laboratory Tests ..................................................................................................59
9.4.4.
Body Weight, Height, and Body Mass Index........................................................59
9.4.5.
Safety Monitoring ................................................................................................59
9.4.5.1.
Hepatic Safety Monitoring..............................................................................59
9.4.5.1.1.
Close Hepatic Monitoring.........................................................................59
9.4.5.1.2.
Comprehensive Hepatic Evaluation ..........................................................60
9.4.5.1.3.
Hepatic Safety Data Collection .................................................................61
9.5.
Pharmacokinetics .........................................................................................................61
9.6.
Pharmacodynamics ......................................................................................................61
9.7.
Pharmacogenomics ......................................................................................................61
9.8.
Biomarkers...................................................................................................................61
9.9.
Health Outcome ...........................................................................................................62
9.9.1.
EuroQol 5-dimension 5-level (EQ-5D-5L) ...........................................................62
9.9.2.
Impact of Weight on Self-Perception (IW-SP)......................................................62
9.9.3.
Medication Delivery Device Assessment Battery (MDDAB) ...............................63
10.
Statistical Considerations ..................................................................................................64
10.1. Sample Size Determination ..........................................................................................64
10.2. Populations for Analyses..............................................................................................64
10.3. Statistical Analyses ......................................................................................................64
10.3.1.
General Statistical Considerations ........................................................................64
10.3.2.
Treatment Group Comparability...........................................................................65
10.3.2.1.
Patient Disposition..........................................................................................65
10.3.2.2.
Patient Characteristics ....................................................................................66
10.3.2.3.
Concomitant Therapy .....................................................................................66
10.3.2.4.
Treatment Compliance....................................................................................66
10.3.3.
Efficacy Analyses ................................................................................................66
10.3.3.1.
Primary Analyses ...........................................................................................66
10.3.3.2.
Secondary Analyses........................................................................................66
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................67
10.3.4.
Safety Analyses....................................................................................................67
10.3.4.1.
Study Drug Exposure......................................................................................68
10.3.4.2.
Adverse Events...............................................................................................68
10.3.4.3.
Hypoglycemic Episodes .................................................................................68

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10.3.4.4.
Severe, Persistent Hyperglycemia...................................................................68
10.3.4.5.
Vital Signs......................................................................................................69
10.3.4.6.
Electrocardiogram ..........................................................................................69
10.3.4.7.
Laboratory Analyses.......................................................................................69
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................69
10.3.6.
Evaluation of Immunogenicity .............................................................................69
10.3.7.
Other Analyses.....................................................................................................69
10.3.7.1.
Health Economics...........................................................................................69
10.3.7.2.
Subgroup Analyses.........................................................................................69
10.3.8.
Interim Analyses..................................................................................................70
11.
References ........................................................................................................................71
12.
Appendices .......................................................................................................................74

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List of Tables
Table
Page
Table GBGO.1. Schedule of Activities....................................................................................13
Table GBGO.2. Objectives and Endpoints...............................................................................20
Table GBGO.3. Study Treatments and Concomitant Insulin....................................................37
Table GBGO.4. Insulin Glargine Treatment-to-Target Algorithm............................................40
Table GBGO.5. Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments...................................................................42
Table GBGO.6. Populations for Analyses ...............................................................................64
Table GBGO.7. Populations for Analyses .............................................................................113

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List of Figures
Figure
Page
Figure GBGO.1. Illustration of study design for Clinical Protocol H9X-MC-GBGO. ...............24

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................75
Appendix 2.
Clinical Laboratory Tests...............................................................................80
Appendix 3.
Study Governance Considerations..................................................................82
Appendix 4.
Liver Safety: Suggested Actions and Follow-Up Assessments .......................86
Appendix 5.
World Health Organization Classification of Diabetes and Diagnostic 
Criteria ..........................................................................................................88
Appendix 6.
Classification of Contraceptive Methods........................................................89
Appendix 7.
Protocol Amendment H9X-MC-GBGO(a) Summary A Randomized, 
Double-Blind Trial Comparing the Effect of the Addition of 
Dulaglutide 1.5 mg versus the Addition of Placebo to Titrated Basal 
Insulin on Glycemic Control in Chinese Patients with Type 2 Diabetes .........90

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1. Synopsis
Title of Study:
A Randomized, Double-Blind Trial Comparing the Effect of the Addition of Dulaglutide 1.5 mg 
versus the Addition of Placebo to Titrated Basal Insulin on Glycemic Control in Chinese Patients 
with Type 2 Diabetes (T2D).
Rationale: 
Glucagon-like peptide-1 (GLP-1) receptor agonists and insulin are often recommended to be
used concomitantly in diabetes treatment guidelines, and several studies including AWARD-9 
(Study H9X-MC-GBDI) have provided efficacy and safety data of the addition of a GLP-1 
receptor agonist to basal insulin (Pozzili et al. 2017).  
The purpose of study H9X-MC-GBGO (GBGO) is to evaluate the effects of the addition of once 
weekly (QW) dulaglutide or the addition of placebo QW to titrated insulin glargine, with 
metformin and/or acarbose, on glycemic control and safety in adult Chinese patients with T2D.
Objectives:
Objectives
Endpoints
Primary

To show the superiority of the addition of 
dulaglutide 1.5 mg QW compared to the addition 
of placebo QW to titrated basal insulin glargine, 
with metformin and/or acarbose, on change from 
baseline in hemoglobin A1c (HbA1c) after 28 
weeks of treatment in patients with T2D. 

The change in HbA1c from baseline.
Key Secondary (controlled for Type I error)

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for other parameters of 
glucose control and body weight change after 28 
weeks of treatment in patients with T2D.

Proportion of patients achieving HbA1c target 
of <7.0%

Change from baseline in body weight

Change from baseline in FSG (central lab)
Additonal Secondary

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for the following parameters 
after 28 weeks of treatment in patients with T2D.

Proportion of patients achieving HbA1c target 
of ≤6.5%; 

Proportion of patients achieving HbA1c target 
of <7.0% and with no weight gain (<0.1 kg) 
at 28 weeks and without documented 
symptomatic hypoglycemia (BG <3.0 
mmol/L) during the maintenance period 
(Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% at 28 weeks and without 
documented symptomatic hypoglycemia (BG

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<3.0 mmol/L) during the maintenance period
(Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% and without weight gain (<0.1 kg);

Changes from baseline in BG from daily self-
monitored blood glucose (SMBG) profiles;

Changes from baseline in daily mean insulin 
glargine doses
Safety:

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for selected safety 
parameters through 32 weeks in patients with T2D 
(unless noted otherwise).

Incidence of treatment-emergent adverse 
events (TEAEs), serious adverse events 
(SAEs) and discontinuation of study drug due 
to adverse events (AEs);

Incidence of adverse event of special interest 
(AESI)
o
Occurrence of hypoglycemic 
episodes;
o
Incidence of initiation of rescue 
therapy due to severe, persistent 
hyperglycemia;
o
Incidence of adjudicated and 
confirmed pancreatitis;
o
Incidence of thyroid neoplasm 
o
Incidence of deaths and nonfatal 
cardiovascular (CV) events;
o
Incidence of allergic and 
hypersensitivity AEs

Change from baseline in electrocardiograms, 
laboratory and vital sign measurements.
Abbreviations: BG = blood glucose; CV = Cardiovascular; FSG = fasting serum glucose; HbA1c = hemoglobin 
A1c; SMBG = self-monitored plasma glucose; T2D = type 2 diabetes.
Summary of Study Design:  
Study GBGO is a Phase 3b, multicenter, randomized, double-blind, parallel-arm trial that 
investigates the effect of the addition of dulaglutide 1.5 mg QW or the addition of placebo QW
to titrated insulin glargine, with metformin and/or acarbose, on change in HbA1c from baseline
in Chinese patients with T2D over a 28-week treatment period.
Treatment Arms and Duration:  
Study GBGO will consist of 3 periods:  an approximately 3-week screening/lead-in period, 
followed by a 28 week treatment period, and a 4-week safety follow-up period. Patients will be 

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randomized in a 1:1 ratio to (1) dulaglutide 1.5 mg QW as add-on to insulin glargine, or (2) 
placebo QW as add-on to insulin glargine, with metformin and /or acarbose. Patients will be 
stratified at randomization based on HbA1c (<8.5%, ≥8.5%) and oral antihyperglycemic 
medications (OAMs) usage (metformin alone, acarbose alone, metformin and acarbose).
Number of Planned Patients:

Entered: 483

Enrolled/Randomized: 290 

Completed: 246
Statistical Analysis:
Determination of Sample Size:  
A total of approximately 290 patients (145 per group) will be randomized to have approximately 
246 completers (123 per group) to show dulaglutide as add-on to titrated insulin glargine is 
superior to placebo as add-on to titrated insulin glargine with 90% power assuming a treatment 
difference of 0.5% in HbA1c reduction, standard deviation (SD) = 1.2%, and dropout rate of 
15%.  The screen failure rate ( including lead in failure) is estimated as 40%.  Approximately 
483 patients will be screened.
Efficacy Analyses:
The primary analysis model for HbA1c will be mixed-model for repeated measures (MMRM) 
analysis using restricted maximum likelihood (REML) with treatment, OAM usage (metformin 
alone, acarbose alone, metformin and acarbose), visit, and treatment-by-visit as fixed effects, 
baseline as a covariate, and patient as random effect.  An unstructured covariance structure will 
be used to model the within-patient variability and implicitly adjust for missing data.  
The primary evaluation of change from baseline for body weight will be performed using 
MMRM on the intention to treat (ITT) population.  The analyses of other secondary efficacy 
measures that are continuous variables will be performed using MMRM on the ITT population.  
For percent of patients achieving the target HbA1c of <7.0% and ≤6.5%, repeated measures 
logistic regression with generalized linear mixed model will be used.  The model includes 
treatment, OAM usage (metformin alone, acarbose alone, metformin and acarbose), visit, and 
treatment-by-visit as fixed effects and baseline HbA1c as a covariate.
Safety Analyses:  
Listings and summaries of safety data will be generated.  Summary statistics will be provided for 
TEAEs, SAEs, and study discontinuation due to AEs or death during the treatment period.  
Counts and proportions of patients experiencing AEs will be reported for each treatment group, 
and Fisher’s exact tests will be used to compare the treatment groups.  
For continuous laboratory analytes, the change from baseline to endpoint will be analyzed using 
an analysis of variance (ANOVA) on the rank-transformed data, with treatment as a fixed effect.  
Last observation carried forward will be used to impute missing postbaseline values.  For 

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subjective (qualitative) laboratory analytes, counts and proportions of patients with normal and 
abnormal values will be analyzed using Fisher’s exact tests.
Treatment differences in incidence of hypoglycemic episodes will be assessed by a Fisher’s 
exact test.  Treatment differences in rates of hypoglycemic episodes will be assessed by the 
generalized linear mixed-effects (GLM) model for negative binomial distribution.  The model 
will include treatment, OAM usage (metformin alone, acarbose alone, metformin and acarbose), 
visit, treatment-by-visit interaction, and baseline hypoglycemia rate.  
Time to initiation of rescue therapy due to severe, persistent hyperglycemia will be analyzed 
using the semiparametric proportional hazard Cox model with treatment, and OAM usage 
(metformin alone, acarbose alone, metformin and acarbose) as fixed effects and baseline HbA1c 
as a fixed covariate.  The proportions of patients initiating rescue therapy due to severe, 
persistent hyperglycemia will be analyzed using Fisher’s exact tests.  

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 1 3
L Y 2 1 8 9 2 6 5
2. S c h e d ul e of A cti viti e s
T a bl e G B G O . 1.
S c h e d ul e of A cti viti e s
Scree ni n
g/ Le a d I n
Tre at me nt Peri o d
S afet y
F oll o w -U p
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
E T
b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
4
5
6
7
8
1 0
1 2
1 5
1 8
2 1
2 4
2 8
3 2
All o w a ble De vi ati o n ( ± D a ys)
± 7
± 3
0
± 3
± 3
± 4
± 2
± 4
± 2
± 4
± 2
± 7
± 2
± 7
± 2
± 7
± 7
± 7
F asti n g visit c
X
X
X
X
T ele p h o ne visit
X
X
X
X
X
I nf or me d co nse nt
X
Ra n d o mizati o n
X
Cli nic al Assess me nts
De m o gra p h y d
X
Me dical hist or y
X
Pre vi o us dia betes t hera p y
X
P h ysical e xa mi nati o n
X
X  
X
Hei g ht
X
Wei g ht
X  
X
X
X  
X  
X  
X  
X  
X  
X
Vital si g ns ( B P a n d P R e)  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Electr ocar di o gra m
f
X
X  
X
Pree xisti n g c o n diti o ns a n d a d verse 
e ve nts
X  
X  
X  
X  
X  
X  
X g
X  
X g
X  
X g
X  
X g
X  
X g
X  
X  
X  
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C o nc o mita nt me dicati o ns
X  
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X  
X  
X  
X  
X h
X  
X h
X  
X h
X  
X h
X  
X h
X  
X  
X  
X
Re vie w/rec or d h y p o gl yce mic e ve nts
-  
X  
X  
X  
X  
Xi
X  
X i
X  
X i
X  
X i
X  
X i
X  
X  
X  
X
Patie nt s u m mar y
X  
X  
X
P atie nt E d uc ati o n
Dietar y  a n d e xercise c o u nseli n g a n d
B G ma na ge me nt trai ni n g j
X  
X
B G meter a n d S M B G trai ni n g
X  
X
S U P trai ni n g a n d S ol o Star pe n trai ni n gk
X  
X
Dis pe nse B G meter/s u p plies l
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dis pe nse st u d y diar y, i nstr uct i n use
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X m
X

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 1 4
L Y 2 1 8 9 2 6 5
Scree ni n
g/ Le a d I n
Tre at me nt Peri o d
S afet y
F oll o w -U p
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
E T
b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
4
5
6
7
8
1 0
1 2
1 5
1 8
2 1
2 4
2 8
3 2
All o w a ble De vi ati o n ( ± D a ys)
± 7
± 3
0
± 3
± 3
± 4
± 2
± 4
± 2
± 4
± 2
± 7
± 2
± 7
± 2
± 7
± 7
± 7
F asti n g visit c
X
X
X
X
T ele p h o ne visit
X
X
X
X
X
Re vie w a n d tra nsfer t o e C R F/ret ur n 
st u d y diar y
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re mi n d patie nts a b o ut 7 p oi nt S M B G n
X
X
X
Re vie w/rec or d 7 -p oi nt S M B G val ues
X
X
X  
X o
Re vie w fasti n g/ 4 -p oi nt B G fr o m 
S M B G p
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re vie w st u d y dr u g usa ge
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re vie w i ns uli n d ose a n d a dj ust me nt
per T T T al g orit h m q
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dis pe nse st u d y dr u g a n d i njecti o n 
s u p plies
X
X
X
X
O bser ve patie nt i nject d ula gl uti de Q W 
X
Patie nt ret ur ns st u d y dr u g a n d i njecti o n 
s u p plies
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Assess d ula gl uti de c o m plia nce
X
X  
X  
X  
X  
X  
X
Assess c o m plia nce wit h wee kl y i ns uli n 
d ose a dj ust me nt per T T T al g orit h m 
X  
X  
X  
X r
X r
X r
X  
X  
X  
X
L a b or at or y tests
Ser u m pre g na nc y test s
X
Uri ne pre g na nc y test t
X
X  
X  
X
F ollicle -sti m ulati n g h or m o ne testu
X
C he mistr y pa nel
X
X v
X v
Ser u m creati ni ne, e G F R ( C K D -E PI) w
X  
X
X  
X
Uri nar y al b u mi n/creati ni ne
X
X  
X
Calcit o ni n
X  
X
X  
X
He mat ol o g y
X
X  
X

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 1 5
L Y 2 1 8 9 2 6 5
Scree ni n
g/ Le a d I n
Tre at me nt Peri o d
S afet y
F oll o w -U p
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
E T
b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
4
5
6
7
8
1 0
1 2
1 5
1 8
2 1
2 4
2 8
3 2
All o w a ble De vi ati o n ( ± D a ys)
± 7
± 3
0
± 3
± 3
± 4
± 2
± 4
± 2
± 4
± 2
± 7
± 2
± 7
± 2
± 7
± 7
± 7
F asti n g visit c
X
X
X
X
T ele p h o ne visit
X
X
X
X
X
Fasti n g ser u m gl uc ose
X
X
X  
X
H b A 1c
X  
X
X
X  
X
Li pi d pa nel
X
X  
X
Pa ncreatic e nz y mes
X  
X
X  
X  
X
He alt h O utc o mes
E Q - 5 D- 5 L
X
X
X  
X
I W-S P
X
X
X  
X
M D D A B M o d ule 1:  S U P Ease of Use
X
X  
X
M D D A B M o d ule 2:  S U P De vice 
Feat ures
X
X  
X
M D D A B M o d ule 3a:  S U P E x perie nce 
(i nteri m e val uati o n)
X
M D D A B M o d ule 3 b:  S U P E x perie nce 
(e n d of st u d y e val uati o n)
X  
X
M D D A B M o d ule 4:  Glar gi ne Deli ver y 
De vice E x perie nce
X  
X
A b bre viati o ns:  8 0 1 = safet y f oll o w -u p visit; B G = bl o o d gl uc ose; B P = bl o o d press ure; C V = car di o vasc ular; D = da ys; e C R F = electr o nic case re p ort f or m; E Q -
5 D -5 L = E ur o Q ol 5 -di me nsi o n q uesti o n naire; E T = earl y ter mi nati o n; F S H = f ollicle-sti m ulati n g h or m o ne; G A D = gl uta mic aci d decar b o x ylase; H b A 1c = 
he m o gl o bi n A 1c; I C A = islet cell a nti b o dies; I W R S = i nteracti ve we b res p o nse s yste m; I W -S P = I m pact of W ei g ht on Self -Perce pti o n Scale; M D D A B = 
Me dicati o n Deli ver y De vice Assess me nt Batter y; P R = p ulse rate; Ra n d = ra n d o mizati o n; S M B G = Self -M o nit ore d Plas ma Gl uc ose; S U P = Si n gle -Use Pe n; 
T T T = treat -t o-tar get.
a. I W R S f or ra n d o mizati o n s h o ul d be accesse d after all baseli ne assess me nts ha ve bee n c o m plete d.
b.
Patie nts w h o are u na ble or u n willi n g t o c o nti n ue i n t he st u d y f or a n y reas o n will perf or m a n E T visit.  If t he patie nt is dis c o nti n ui n g d uri n g a n u nsc he d ule d 
visit, t hat visit s h o ul d be perf or me d as t h e E T visit.  If t he patie nt is disc o nti n ui n g d uri n g a sc he d ule d visit, t hat visit s h o ul d be perf or me d as a n E T visit. 8 0 1
( Safet y F oll o w-U p Visit) s h o ul d be perf or me d 4 wee ks after t he E T visit as t he fi nal st u d y visit.
c.
Bef ore visits at w hic h la b orat or y tests will be c o n d ucte d, patie nts s h o ul d be re mi n de d t o re p ort t o t he site i n a fasti n g c o n diti o n, after a peri o d of 
a p pr o xi matel y 8 h o urs wit h o ut eati n g, dri n ki n g (e xce pt water), or a n y si g nifica nt p h ysical acti vit y, a n d bef ore ta ki n g t heir st u d y dr u g, metf or mi n a n d/ or 

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acarbose, and insulin glargine, if administered before breakfast.
d. Demographics include patient birth year, sex.
e.
Site should record all results on the eCRF
f.
Single tracing, performed locally (see Section 9.4.1).
g.
Preexisting conditions and adverse events will be reviewed during telephone contacts but recorded on the eCRF at subsequent office visits.
h. Concomitant medications will be reviewed during telephone contacts but recorded on the eCRF at subsequent office visits.
i.
Hypoglycemic events will be reviewed during telephone contacts but recorded on the eCRF at subsequent office visits.
j.
Patient training should occur at Visit 2.  Additional training can also be performed at Visit 3, when needed.  Patient training will include training on TTT 
insulin dose adjustment algorithm.
k.
Retraining and review of device training to be performed as needed.
l.
Dispense only as needed.
m Safety data to be captured after discontinuation of study drug during safety follow-up period.
n. Patients will be asked to perform two 7-point SMBG profiles on two nonconsecutive days, in the 2-week period prior to Visit 3, as well as prior to Visit 12 
and Visit 17.  A 7-point SMBG consists of measurements before and 2 hours after each of 3 main meals within the same day and at bedtime.  If 7-point 
SMBG is not performed, then data from the most recent nonconsecutive 4-point SMBG (3 before each meal and one at bedtime) profiles can be used.  If more 
than 2 SMBG profiles are available, the 2 most recent profiles on nonconsecutive days should be used.  In the weeks that the 7-point profiles are performed, 
the 4-point SMBG profiles will not be needed.
o. Review/record 7-point SMBG profile(s), only if applicable, based on previous study visit.
p. 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.
q. Insulin dose assessment and dose adjustment should be done at least 3 days prior to Visit 3 to ensure the collection of at least 3 days of FBG for patient 
eligibility assessment prior to randomization.  The insulin glargine dose should be reduced by 20% at Visit 3 if baseline HbA1c ≤8.0%.  Further dose 
adjustments are to start at Visit 6 per the TTT algorithm, and before that only in certain situations (for details see Section 5.1).  The TTT algorithm should be 
used for dose adjustments until the last visit on randomized treatment (Visit 17 or ET Visit).  After discontinuation of study drug, the investigator will decide 
on the most appropriate therapeutic regimen, and if applicable, the most appropriate insulin dose adjustment schedule.  Refer to Protocol Section 7.2.2.2 for 
complete instructions on insulin dose adjustment.
r.
Assessment of the patient’s compliance to the TTT algorithm will be collected in the eCRF at Visits 8, 10, and 12 for the period since the previous visit.
s.
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
t.
A urine pregnancy test will be performed at Visit 3, with the result available prior to randomization and first injection of study drug, and at additional visits as 
shown in the schedule, for women of childbearing potential only. Additional pregnancy tests will be performed at the investigator’s discretion or if required 
per local regulations and/or institutional guidelines during the study.  
u. Follicle-stimulating hormone test will be collected 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).  After Visit 1, additional tests may be performed at the investigator’s discretion during the study.
v.
For those visits when fasting glucose is required, glucose will not be included in the chemistry panel.
w. Chronic Kidney Disease-Epidemiology (CKD-EPI) equation will be used to estimate the glomerular filtration rate.

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3. Introduction
3.1.
Study Rationale
Initial pharmacological therapy for T2D is based on stepwise addition of oral antihyperglycemic 
medications (OAMs) when patients become persistently hyperglycemic despite treatment with 
lifestyle measures (Inzucchi et al.2012). With further progression of the disease, many patients 
eventually require injectable therapies, a GLP-1 receptor agonist, or insulin to maintain adequate 
glycemic control. Basal insulin, such as insulin glargine, is a common choice when initiating 
injectable therapy, but there are drawbacks to treating patients with T2D with a single injection 
of basal insulin. For instance, a significant proportion of patients is not able to achieve glycemic 
targets (Rosenstock et al. 2008; Nichols et al.2012), and hypoglycemia and weight gain are
common side effects of therapy with insulin (ADA 2019). To address these issues in basal 
insulin-treated patients with T2D, addition of a GLP-1 receptor agonist to insulin glargine has 
been investigated in randomized, clinical trials (Buse et al. 2011; Pozzili et al. 2017). Compared 
to the titrated basal insulin glargine, the addition of a GLP-1 receptor agonist resulted in 
improved glycemic control, reduced insulin dose, similar risk of hypoglycemia, and smaller 
increases or reduction in body weight.
Combination therapy can be administered using separate preparations of each component 
(flexible‐dosing strategy) or using combination preparations containing both agents (fixed‐ratio 
strategy) (Ahmann A et al. 2015; Buse JB et al. 2011; Rosenstock J et al. 2012). Flexible 
combination therapy requires the patient to administer basal insulin and the GLP-1 receptor 
agonist subcutaneously separately, using 2 different devices.  In order to reduce the number of 
injections required with flexible dosing (daily injection of basal insulin and separate once or 
twice daily injection of GLP-1 receptor agonists), a single daily injection of both agents in a 
fixed-ratio combination has also been investigated and is available in some countries (Gough et 
al. 2014).  Published data of clinical trials assessing the efficacy and safety of fixed-ratio
combinations of a GLP-1 receptor agonist and a basal insulin such as the combination of 
liraglutide with insulin degludec (IDegLira, Xultophy) and lixisenatide with insulin glargine 
(iGlarlixi/LixiLan) demonstrated a significant HbA1c reduction, with potential weight benefit in 
patients with T2D failing one or more OAMs (Gough et al. 2014; Aroda et al. 2016). There are 
several limitations of the fixed-ratio combination, including chronic administration of 
subtherapeutic doses (drug exposure with no proven glycemic efficacy and unapproved) of 
GLP-1 receptor agonist in patients who require only a small dose of insulin, and difficulties with 
insulin dose adjustments in patients who require a greater dose of insulin or have an increased 
risk of hypoglycemia.  The use of GLP-1 receptor agonists with long duration of action, such as 
dulaglutide, in a flexible combination with basal insulin may overcome these issues.  This 
combination requires once weekly administration of the GLP-1 receptor agonist, with the 
possibility of daily insulin dose adjustment that more closely matches the needs of patients than 
is the case with the fixed-dose combination.

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3.2.
Background
A GLP-1 receptor agonist, dulaglutide is a biosynthetic fusion protein molecule produced using 
mammalian cell cultures, and consists of 2 identical, disulphide-linked chains, each containing 
an N-terminal glucagon-like peptide-1 (GLP-1) analogue sequence covalently linked to a 
modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker (Trulicity™ 
USPI, 2015).  These structural features of the dulaglutide molecule (1) decrease the rate of 
clearance, (2) increase the duration of pharmacologic activity, (3) may reduce immunogenic 
potential, and (4) decreased unwanted antibody-mediated effector function (Barrington et al. 
2011; Trulicity USPI, 2015).  The molecular design of dulaglutide makes it suitable for once-
weekly dosing.
Dulaglutide exhibits GLP-1 mediated effects, including glucose-dependent potentiation of 
insulin secretion, inhibition of glucagon secretion, delay of gastric emptying, and weight loss 
(Trulicity USPI, 2015).  Preclinical and clinical experience to date support the use of dulaglutide 
as a once-weekly injection to improve glycemic control in patients with T2D (Barrington et al. 
2011).  Dulaglutide received regulatory approval in the United States on 18 September 2014 and 
in the European Union on 21 November 2014 for treatment of adult patients with T2D, including
the combination with insulin.  Dulaglutide has been approved in China on 22 February 2019 for 
use as monotherapy, or in combination with metformin and/or sulfonylurea for treatment of adult 
patients with T2D.
Insulin glargine, a recombinant human insulin analog, has up to a 24-hour duration of action, and 
is used as a basal insulin.  Designed to have a low aqueous solubility at neutral pH but 
completely soluble at pH 4, the acidic solution is neutralized after injection into the subcutaneous 
(SC) tissue.  The neutralization leads to formation of microprecipitates from which small 
amounts of insulin glargine are slowly released.  As a result, a relatively constant 
concentration/time profile over 24 hours is produced when compared to human neutral protamine 
Hagedorn (NPH) insulin.  Such a profile makes it suitable as a once-daily basal insulin. The 
treat-to-target (TTT) trial demonstrated that the addition of once daily insulin glargine to OAM 
therapy in patients with T2D results in similar glycemic control and lower risk of hypoglycemia 
compared to human NPH insulin (Riddle et al. 2003).  A meta-analysis of data from 2304 
patients with T2D from 4 randomized clinical trials supports these observations (Rosenstock et 
al. 2005).
Thus, Study H9X-MC-GBGO (GBGO) will assess the effects of the addition of dulaglutide 1.5 
mg QW or the addition of placebo QW to titrated insulin glargine, with metformin and/or 
acarbose, on glycemic control and safety in Chinese patients with T2D.  The primary objective is 
to show superiority of dulaglutide as add-on to titrated insulin glargine to placebo as add-on to 
titrated insulin glargine for change from baseline in HbA1c after 28 weeks of treatment.
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of dulaglutide can be found in the Investigator’s Brochure (IB).

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In addition, detailed information about the known and expected benefits and risks of dulaglutide 
can be found in the Trulicity® China Package Insert (2019).

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4.
Objectives and Endpoints
Table GBGO.2 presents the objectives and endpoints of the study.
Table GBGO.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To show the superiority of the addition of 
dulaglutide 1.5 mg QW compared to the addition 
of once weekly placebo to titrated insulin 
glargine, with metformin and/or acarbose, for
change from baseline in HbA1c after 28 weeks of 
treatment in adult Chinese patients with T2D.

The change in HbA1c from baseline.
Key Secondary (controlled for Type I error)
Efficacy:

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for other parameters of 
glucose control and body weight change after 28 
weeks of treatment in patients with T2D.

Proportion of patients achieving HbA1c target 
of <7.0%

Change from baseline in body weight

Change from baseline in FSG (central lab)
Additonal Secondary
Efficacy

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for the following 
parameters after 28 weeks of treatment in 
patients with T2D.


Prortion of patients achieving HbA1c target of 
≤6.5%; 

Proportion of patients achieving HbA1c target 
of <7.0% and with no weight gain (<0.1 kg) at 
28 weeks and without documented 
symptomatic hypoglycemia (BG <3.0 mmol/L) 
during the maintenance period (Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% at 28 weeks and without documented 
symptomatic hypoglycemia (BG <3.0 mmol/L)  
during the maintenance period (Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% and without weight gain (<0.1 kg) at 
28 weeks;

Changes from baseline in BG from daily 
SMBG profiles;

Changes from baseline in daily mean insulin 
glargine doses.
Safety:

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for selected safety 

Incidence of TEAEs, SAEs and 
discontinuation of study drug due to AEs;

H9X-MC-GBGO(a) Clinical Protocol
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parameters through 32 weeks in patients with 
T2D (unless noted otherwise).

Change from baseline in electrocardiograms, 
laboratory and vital sign measurements.

Incidence of AESI
o
Occurrence of hypoglycemic 
episodes;
o
Incidence of initiation of rescue 
therapy due to severe, persistent 
hyperglycemia;
o
Incidence of adjudicated and 
confirmed pancreatitis;
o
Incidence of thyroid neoplasm 
o
The incidence of deaths and nonfatal 
CV events;
o
Incidence of allergic and 
hypersensitivity AEs
Exploratory
Efficacy:

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for exploratory efficacy 
parameters after 28 weeks of treatment in 
patients with T2D.

Frequency of insulin dose adjustments through 
28 weeks; 

Number of insulin dose assessments per TTT 
algorithm and compliance with the TTT 
algorithm at 6, 8, and 12 weeks;

Proportion of patients achieving HbA1c target 
of <7.0% and with no weight gain (<0.1 kg) at 
28 weeks and without documented 
symptomatic hypoglycemia (BG <3.9 mmol/L) 
during the maintenance period (Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% and without weight gain (<0.1 kg) at 
28 weeks;

Proportion of patients achieving HbA1c target 
of <7.0% at 28 weeks and without documented 
symptomatic hypoglycemia (BG <3.9 mmol/L) 
during the maintenance period (Weeks 12-28);
Safety:

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for exploratory safety 
parameters through 32 weeks in patients with 
T2D.

Assessments of time to onset and duration of 
diarrhea, nausea, abdominal distension and 
vomiting in dulaglutide-treated patients.
Health Outcome/Quality of Life Measures:

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
To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for the following HO/QoL 
parameters in patients with T2D.

Changes from baseline in patient-reported 
health status as measured by the EuroQol 5-
dimension 5-level questionnaire (EQ-5D-5L) 
at 12 and 28 weeks;

Changes from baseline in patient-reported 
weight-related self-perception as measured by 
the Impact of Weight on Self-Perception Scale 
(IW-SP) at 12 and 28 weeks;

Assessments of patient perceptions regarding 
use and specific features of the delivery 
devices using the following modules of the 
Medication Delivery Device Assessment 
Battery (MDDAB):
o
Module 1: Single-Use Pen (SUP) 
Ease of Use Module (6 and 28 weeks)
o
Module 2: SUP Device Features 
Module (6 and 28 weeks)
o
Module 3a: SUP Experience Module 
(6 weeks)
o
Module 3b: SUP Experience Module 
(28 weeks)
o
Module 4: Glargine Delivery Device 
Experience Module (28 weeks).
Abbreviations:  BG = blood glucose; CV = Cardiovascular; EQ-5D-5L = EuroQol 5-dimension 5-level 
questionnaire; FSG = fasting serum glucose; HbA1c = hemoglobin A1c; IW-SP = Impact of Weight on Self-
Perception Scale; MDDAB = Medication Delivery Device Assessment Battery; SMBG = self-monitored plasma 
glucose; SUP = Single-Use Pen; T2D = type 2 diabetes; TTT = treat-to-target.

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5. Study Design
5.1.
Overall Design
Study GBGO is a multicenter, randomized, double-blind, parallel-arm Phase 3b trial that
compares the effect of the addition of dulaglutide 1.5 mg QW with the addition of placebo QW 
to titrated basal insulin glargine, with metformin and/or acarbose, on glycemic control and safety 
in adult Chinese patients with T2D.  
Eligible patients are those with HbA1c at screening ≥7.0% and ≤11.0% despite treatment with 
stable doses of basal insulin glargine, stable doses of metformin and/or acarbose for at least 3 
months prior to Visit 1 (See Section 6.1, inclusion criterion [4] for more detail).  The primary 
objective of the study is to show superiority of dulaglutide 1.5 mg as add-on to titrated insulin
glargine to placebo as add-on to titrated insulin glargine with regard to change from baseline in 
HbA1c at 28 weeks. The study will consist of 3 periods:  an approximately 3-week 
screening/lead-in period followed by a 28-week treatment period and a 4-week safety follow-up 
period.  
Patients who meet all inclusion criteria and none of the exclusion criteria will enter a 2-week 
lead-in period.  Only those patients who require further up-titration of the insulin glargine dose 
per TTT algorithm at the end of lead-in period (FBG ≥5.6 mmol/L in the prior week before Visit 
3) will then be randomized to 1 of the following treatment groups at Visit 3:  (1) dulaglutide 1.5 
mg QW as add-on to insulin glargine or (2) placebo QW as add-on to insulin glargine.  Insulin 
glargine will be titrated using the treat-to-target (TTT) algorithm (Section 7.2.2.2.1).  Metformin
and/or acarbose dose must be kept unchanged for at least 3 months prior to Visit 1, and the dose 
should be within the inclusive range of half maximum to maximum approved daily dose per the 
locally-approved label during this period. Patients will be required to continue pretrial 
metformin and/or acarbose during the lead-in and treatment periods.  Patients will be treated for 
28 weeks (a 4-week stabilization period followed by a 24-week titration period); after which 
patients will be required to complete a safety follow-up visit (801) approximately 4 weeks later.
Figure GBGO.1 illustrates the study design.  

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 2 4
L Y 2 1 8 9 2 6 5
Fi g ur e G B G O . 1.
Ill u str ati o n of st u d y d e si g n f or Cli ni c al Pr ot o c ol H 9 X -M C -G B G O .
a Patie nts s h o ul d c o nti n ue t heir prest u d y re gi me n a n d s h o ul d n ot c ha n ge t he t y pe of a nti h y per gl yce mia me dicati o ns 
use d or t heir d oses, e xce pt w he n all o we d per pr ot oc ol.  
b At Wee ks 5, 7 , 1 0, 1 5 a n d 2 1 ( Visits 7, 9, 1 1, 1 3 a n d 1 5 ), st u d y sites will co ntact patie nts b y tele p h o ne a n d perf or m 
pr oce d ures per t he Sc he d ule of Acti vities ( Secti o n 2 ).
Sta bilizati o n Peri o d = first 4 wee ks after ra n d o mizati o n, wit h restricte d i ns uli n d ose a dj ust me nts.  
Glar gi ne titrati o n Peri o d = Wee ks 4 t o 2 8 (e n d of treat me nt), wit h u nrestricte d i ns uli n d ose a dj ust me nts.  

In te nsi ve Titrati o n Peri o d = Wee ks 4 t o 1 2 , i ns uli n is titrate d t o reac h t he o pti mal d ose.  

Mai nte na nce Peri o d = Wee ks 1 2 t o 2 8 , t he peri o d w he n basal i ns uli n d ose is e x pecte d t o be sta ble.
St u d y Peri o d I ( Scree ni n g a n d Le a d -I n)
Scree ni n g ( Visit 1)
T he p ur p ose of Visit 1 is t o i nit iate t he assess me nt of patie nt eli gi bility f or partici pat i on i n the 
trial.  T he patie nt will si g n t he i nf or me d c o nse nt f or m (I C F) a n d recei ve a patie nt ide nt ificati on 
n u m ber bef ore a n y  st u d y pr oce d ures are perf or me d.  Pr oce d ures at t his visit will be perf or me d as 
s h o w n i n t he Sc he d ule of Act i vities ( Secti o n 2 ).  Patie nts w h o meet all a p plica ble i ncl usi o n 
criteria a n d n o ne of t he a p plica ble e xcl usi on cri teria ( Secti o n 6 ) at Visit 1 will e nter a n 
a p pr o xi matel y 2-wee k lea d -i n peri o d.  D uri n g t his peri o d, patie nts will be re q uire d t o c o nti n ue 
sta ble i ns uli n a n d O A M treat me nt .
Le a d -i n ( Visit 2 to Visit 3) 
T he s cree ni n g la b orat or y res ults will be re vie we d at Visit 2, a n d patie nt eli gi bilit y will  b e 
esta blis he d. Pr oce d ures at t his visit will be perf or me d as s h o w n i n t he Sc he d ule of Act i vities
(Secti o n 2 ).  

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 2 5
L Y 2 1 8 9 2 6 5
At  Visit 2, patie nts a n d t heir care gi ver(s), if a p plica ble, will recei ve a gl uc o met er a n d trai ni n g o n 
h o w t o perf or m S M B G a n d h o w t o rec or d B G val ues i n t he diaries. Pati e nts will be pr o vi de d 
visit -s pecific diaries a n d will be trai ne d as a p pr o priate t o rec or d B G val ues , i ns uli n d ose 
assess me nts per T T T al g ori t h m, i ns uli n d oses, h y p o gl yce mic e ve nts, me dicati ons, a n d a d verse 
e ve nts. After Visit 2, patie nts will start i ns uli n d ose assess me nts o nce wee kl y f or t he re mai n der 
of  t h e lea d-i n peri o d (t he use of t he al g orit h m is restricte d d uri n g t he lea d -i n a n d sta bilizati on 
p eri o ds, as descri be d bel o w ). If nee de d, ot her trai ni n gs will  be pr o vide d, as well , a n d trai ni n gs 
c o uld be re peate d i n ot her visits.
P ati e nts will be re q uest e d t o perf or m t w o 7-p oi nt S M B G pr ofiles o n t wo n o n c o nsec uti ve da ys 
bef ore Visit 3 per Sc he d ule of Act i vities ( Secti o n 2 ).  
D uri n g t he l ea d-i n peri o d, patie nts s h o ul d c o nti n ue t heir prest u d y t hera p y a n d s h o uld n ot c ha n ge 
t he t yp e of  O A Ms use d or t hei r d oses i n or der t o all o w relia ble assess me nt of H b A 1c at baseli ne 
( Visit 3).  If patie nts de vel o p a c o n diti on t hat i s a c o ntrai n dicati on f or t he use of O A Ms, t he y will 
be c o nsi dere d i neli gi ble a n d m ust disc o nt i n ue fr o m t he trial bef ore ra n d om izati on.  I ns uli n d oses 
s h o uld be a dj uste d o nl y f or t he safet y of  patie nts ( occ urre nce of h y p o gl yce mia [fasti n g bl o o d 
gl uc ose ( F B G ) < 3. 9 m m o l/ L] d ue t o i ns uli n d ose or se vere h y per gl yce mia, defi ne d as mea n dail y  
B G fr o m 4-p oi nt S M B G pr ofile > 1 5 m m o l/ L or mea n wee kl y F B G > 1 5 m m o l/ L).  I n t hese 
sit u atio ns, t he i ns uli n d ose will be a dj uste d per t he T T T al g orit h m at t he discretio n of  t he 
i n vesti gat or (see Secti o n 7. 2. 2. 2. 1 ).  
St u d y Peri o d II ( Tre at me nt Peri o d):
R a n d o miz ati o n ( Visit 3)
At  Visit 3 , p at ient  s h o uld arri ve t o t he cli nic i n t he fast i n g state, w hic h s h o uld last at l east 8 
h o urs, wit h o ut ha vi n g ta ke n a n y d oses o f t heir st u d y dr u g, O A Ms a n d i ns uli n glar gi ne.  
Pr oce d ures at t his visit will be perf or me d as s h o w n i n t he Sc he d ule of Acti vit ies (Secti o n 2 ).  
T he q uest i on naires ( E Q -5 D- 5 L a n d I W-S P) s h o ul d be c o m plete d bef ore a n y ot her st u d y  
pr oce d ures if t he patie nt is n ot a d versel y  affecte d b y t h e fast i n g c o n diti on or c o m plete d after t he 
pati e nt has s ufficie nt l y rec o vere d fr om t he prece di n g visit pr oce d ures.  
I n vesti gat ors will re vie w t h e diar y a n d assess pat ient  eli gi bility ( Secti on 6. 1 a n d 6. 2 ).  I ns uli n 
d ose s h o ul d be ke pt u nc ha n ge d f or at  least 3 da ys pri or t o Visit 3 , s o as t o ha ve at least 3 dail y
F B G val ues rea d y f or eli gi bilit y assess me nt at Visit 3. Patie nts w h o c o nti n ue t o be eli gi ble will 
be ra n d o mize d i n a 1: 1 rati o t o o ne of t he f o ll owi n g treat m e nt gr o u ps:  ( 1) d ula glut i de 1. 5 m g
Q W as a d d-o n t o i ns uli n glar gi ne or ( 2) place b o Q W as a d d-o n t o i ns uli n glar gi ne, wi t h 
met f or mi n a n d/ or acar b ose. 
P ati e nts will be i nstr ucte d o n h o w t o use t he si n gle -use pe n ( S U P) a n d will i nject t heir first d ose 
of  st u d y dr u gs u n der t he s u per visi o n of t he pers o n nel w hile i n t h e cli nic f or Visit 3.  Pati e nts will 
als o be trai ne d o n h o w t o use t he S ol o S T A R ™ pe n a n d will a d mi nister i ns uli n glar gi ne o nce 
dail y  ideall y at be dt i me.  T he date a n d ti me of t he first d osi n g of  st u d y dr u g s h o uld be rec or de d 
o n t he e C R F.
F o ll owi n g ra n d o miz at i on, pati e nts will p artici pate i n a 2 8- wee k treat me nt peri o d.  

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Treatment Period – General Considerations
The treatment period starts with a 4-week stabilization period immediately after randomization,
followed by a 8-week intensive titration period and a 16-week maintenance period.  In the 4 
weeks of stailization period (Week 0 to Week 4), randomized study drug (dulaglutide or placebo) 
will be introduced in a safe manner, and insulin glargine dose will be reduced or remain stable. 
In the initial 8 weeks of intensive titration period (Week 4 to Week 12), most of the insulin 
glargine titration should occur, and insulin will be titrated to reach the optimal dose. In the final 
16 weeks of maintenance period (Week 12 to Week 28), insulin glargine dose is expected to be 
stable and optimized.
Throughout the treatment period, patients will collect all data on SMBG, insulin dose 
assessments, insulin doses administered, dosing dates, hypoglycemic events, AEs, and 
concomitant medications in the patient diary to be reviewed with the study site personnel at the 
next office visit.  For that purpose, at each office visit, study diaries for the period after the last
office visit will be collected, new study diaries will be dispensed, and instructions will be 
reviewed at each visit.  Used and unused 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.  At Week 28 or ET visit, all used and unused study drug(s) will be returned.
Results of SMBG and hypoglycemic events will be used by the patient to assess insulin glargine 
doses per the TTT algorithm.  Insulin glargine dose assessments will be required to perform once 
or twice per week (see Section 7.2.2.2). 
Compliance with the dulaglutide administration schedule and compliance with the insulin 
glargine TTT algorithm will be assessed at every office visit and collected in the eCRF at 
prespecified visits (Section 7.6).  Based on the outcome of these reviews, the site 
personnelshould discuss additional insulin glargine dose adjustments while the patient is still at 
the site and provide retraining, if needed.  Patients should be instructed to contact the study 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.  
Patients are required to continue using their concomitant OAMs throughout the treatment period.  
Discontinuation of these medications or dose changes are not permitted, except in certain 
situations (see Sections 7.7.1 and 7.7.5.2 for details). 
Patients will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments (Section 7.7).  
Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Sections 7.7.5.3 and 9.2.2.1) will receive a new glucose-lowering intervention (“rescue therapy”) 
and will also continue with study drug.  Patients who need hyperglycemic rescue therapy will 
continue in the trial until they complete all study visits. Patients who permanently discontinue 
study drug prior to the Safety Follow-Up Period will also be required to continue in the trial and 
should receive a new glucose-lowering intervention (Section 7.7.1).

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 2 7
L Y 2 1 8 9 2 6 5
St u d y  g o ver na nce c o nsi derati o ns are descri be d i n detail i n A p pe n di x 3 .
St a biliz ati o n Peri o d ( E n d of Visit 3 t o Visit 6 [ Weeks 0 t o 4])  
T he m ai n p ur p oses of t his perio d are t o i ntr o d uce ra n d o mize d st u d y  dr u g ( d ula glut i de or 
pl ace b o) i n a safe ma n ner a n d t o e ns ure re g ular a n d c orrect use of t he self-m o nit ori n g a n d i ns uli n 
d ose a dj ust me nt pr oce d ures a n d st u d y  diaries d uri n g t he e nt ire st u d y.  I n a n eff ort t o all o w 
a p pr o priate ti me f or d ula gl ut i de t o reac h stea d y state, i ns uli n glar gi ne d ose a dj ust me nts d uri n g 
t he 4-wee k sta bilizat i on peri o d s h o ul d be restricte d t o pa tie nts wi t h si g nifica nt safety ris ks d ue t o 
i ns uli n d ose:  ( 1) occ urre nce of h y p o gl yce mia (F B G < 3. 9 m m o l/L ; see Sect i on 7. 2. 2. 2. 1 ); i n t his 
case, t he i ns uli n glar gi ne d ose will be decrease d per t he T T T al g orit h m; or ( 2) de vel o p me nt of 
se vere h y per gl yce mia, defi ne d as mea n dail y B G fr o m 4- p oi nt S M B G pr ofile > 1 5 m m o l/ L; i n 
t his case, i ns uli n d ose will be i ncrease d per t he T T T al g orit h m.  I n a d dit i on, f or patie nts wit h 
baseli ne H b A 1c ≤8. 0 %, t he i ns uli n glar gi ne d ose will be decrease d b y 2 0 % i m me diatel y after 
ra n d omizat i on, a n d will t he n re mai n u nc ha n ge d d uri n g t he sta bilizati on peri o d t o decrease t he 
ris k of h y p o gl yce mia.  T he i ns uli n glar gi ne d ose will re mai n u nc ha n ge d d uri n g t he sta bilizati o n 
p eri o d if baseli ne H b A 1c is > 8. 0 %.  If t he baseli ne H b A 1c val ue f or a patie nt is n ot a vaila ble 
wi t hi n t he first 7 da ys after ra n d o mizati o n, t he st u d y sit e s h o uld i m me diatel y c o ns ult t he 
res p o nsi ble Lill y p h ysicia n ( n ot later t ha n t he date of Visit 4) t o disc uss if a n a dj ust me nt i n 
i ns uli n d ose w o ul d be a p pr o priate base d o n t he a vaila ble cli nical data f or t he patie nt.  
T he pl a n ne d visit s for t hi s perio d, Visi ts 4, 5, a n d 6, will ta ke place 1 wee k ( ± 3 da ys), 2 wee ks 
( ± 3 da ys), a n d 4 wee ks ( ±4 da ys) after ra n d o mizati o n, res pecti vel y.  St u d y  pr oce d ures will be 
perf or m e d per t he Sc he d ule of Act i vities ( Sectio n 2 ).  
Titr ati o n Peri o d ( E n d of Visit 6 t o Visit 1 7 [ Weeks 4 t o 2 8 ])   
At  t he be gi n ni n g of t he titrati o n peri o d, t he patie nt will be i nstr ucte d t o start t o use t he T T T 
alg ori t h m wit ho ut restri ct i ons i n or der t o reac h t he o pti mal d ose of i ns uli n glar gi ne as s o o n as 
p ossi ble.  
T he pl a n ne d of fice visits d uri n g t his peri o d (e xcl u di n g t he fi nal visit), Visit s 8 t hr o u g h 1 6 , will 
ta ke place at Wee k 6 ( ± 4 d a y s), 8 ( ±4 da ys), 1 2 ( ± 7 da y s), 1 8 ( ± 7 da y s), a n d 2 4 wee ks ( ± 7 da ys) 
after ra n d o mizati on. I n a d diti o n t o t he office visits, 5 tele p h o ne visits will be sc he d ule d at Visit 
7 ( Wee k 5), Visit 9 ( Wee k 7), Visit 1 1 ( Wee k 1 0), Visit 1 3 ( Wee k 1 5), a n d Visit 1 5 ( Wee k 2 1).  
At eac h of t hese visits, pr oce d ures will i ncl u de assess me nts of S M B G, c o mplia nce wi t h ins uli n 
titr atio n al g ori t h m, i ns uli n d ose, d ula gl uti de c om p lia nce ( will be re-assesse d at t he office visit), 
h y p o gl yce mic e ve nts, c o nc o mita nt me dicat i ons, a n d A Es.  T he da ta o btai ne d at t hese tele p h o ne 
visit s will be e ntere d i nt o t he e C R Fs at t he ne xt office visit.  
Bet wee n Wee k 4 a n d Wee k 8, t he i ns uli n glar gi ne d ose a dj ust me nt will be disc usse d wi t h t he 
pati e nt s a n d deter mi ne d b y t he i n vesti gat or , a n d t his pr oce d ure will be use d as pre parati o n a n d 
trai ni n g f or i m ple me ntati o n of t he patie nt self-titr atio n acc or di n g t o t he T T T al g orit h m
(Ta ble G B G O. 4 ).  After Wee k 8, t he decisi o n o f t he titratio n will be m a de a n d i m ple me nte d b y 
t he patie nt i n a wee kl y ma n ner.  Bet wee n Wee k 8 a n d Wee k 1 2, patie nts will be c o ntacte d b y  t he 
st u d y sit e pers o n nel e ver y 2 wee ks (eit her tele p h o ne or office visit).  I n vest i gat ors or st u d y site 

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personnel will review the insulin dose adjustment made by the patient at each office visit or 
telephone visit.  From Week 12 , patients will be contacted by the study site personnel every 3-4 
weeks (either telephone or office visit), to enable the site to properly monitor patients’ usage of 
the TTT algorithm. Investigators may perform additional telephone visits if necessary, or 
perform additional office visits if deemed necessary by the investigator. Also, more frequent 
insulin dose assessments may be requested by the investigator if clinically appropriate.
At Visit 8 (Week 6) only, MDDAB modules 1, 2, and 3a should be completed by the patient 
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.
At Visit 12 (Week 12), questionnaires (EQ-5D-5L and IW-SP) 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.  
The final office visit, Visit 17, will take place at Week 28 (±7 days).  Study procedures at this 
visit are shown in the Schedule of Activities (Section 2).  The EQ-5D-5L, IW-SP, and MDDAB 
modules 1, 2, 3b, and 4 questionnaires will 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.  A final physical examination will be 
performed, including weight and vital signs (sitting blood pressure [BP] and pulse rate [PR]) 
measurements and electrocardiogram (ECG) testing using the existing equipment at the site.  
Study drug will be discontinued and an appropriate diabetes treatment regimen will be prescribed 
per the investigator’s judgment.  A patient summary eCRF will be completed.
Study procedures will be performed per the Schedule of Activities (Section 2).  
Study Period III (Safety Follow-Up Period):
Safety Follow-Up (801) Visit
All patients who complete the treatment period are required to complete Visit 801, a safety 
follow-up visit approximately 4 weeks after 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 may be treated with another 
glucose-lowering intervention decided upon by the investigator (see Section 7.7.1).  Initiation of 
new antihyperglycemic therapy for the safety follow-up period will not be classified as “rescue 
therapy”.  Patients are required to return any remaining study diaries to the study site at the end 
of this period.
Early Termination Visit (If Necessary)
Every attempt will be made to keep patients in the trial irrespective of their adherence to 
treatment with study drug. At any time after Visit 3 (randomization), a patient who is to 
discontinue from the study before Visit 17 will have an early termination (ET) visit conducted.  
At this visit, procedures will occur as shown in the Schedule of Activities (Section 2).  Patients 

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should be instructed to return any remaining used or unused study drug supplies and patient 
diaries to the study site at this visit.  Study drug will be discontinued, and an appropriate glucose 
management regimen (Section 7.7.1) will be prescribed by the investigator. Patients will be 
asked to perform the Safety Follow-Up visit (801) approximately 30 days after the ET visit, so 
that the Safety Follow-Up visit will be their final visit.  If the patient is not able to perform the 
Safety Follow-Up visit, the ET visit will be the final study visit.  A patient summary eCRF will 
be completed.
5.2.
Number of Participants  
Approximately 483 patients will be screened to achieve approximately 290 randomized and 246
evaluable patients with an estimated total of 123 evaluable patients in the dulaglutide as add-on 
to insulin glargine treatment group, and 123 evaluable patients in placebo as add-on to insulin 
glargine treatment group.
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
Combination therapy of basal insulin and GLP-1 receptor agonist is broadly used and previous 
studies have demonstrated the efficacy and safety of this combination. In the AWARD-9 clinical 
trial (Study H9X-MC-GBDI), a significantly greater proportion of patients treated with 
dulaglutide added to basal insulin with or without metformin (66.7%) achieved HbA1c <7.0% 
compared to the addition of placebo with further titration of insulin glargine (33.3%).  The better 
glycemic control with the addition of dulaglutide was achieved without increasing the risk of 
hypoglycemia and with weight benefit (Pozzili et al. 2017).
This study (H9X-MC-GBGO) is designed to compare the benefits and risks of dulaglutide 1.5 
mg QW as add-on to titrated insulin glargine with placebo QW as add-on to titrated insulin 
glargine, with metformin and/or acarbose, in Chinese patients with T2D.  The trial design will 
enable assessment of the effects of these interventions on daily and long-term glycemic control, 
as well as on safety variables.  
Patients selected to participate in this study will be those who require intensification of their 
current basal insulin regimen due to inadequate glycemic control, as indicated by HbA1c value 
above the ADA/EASD established target of 7.0%.  
To ensure that patients randomized to receive placebo also have the opportunity for effective 
treatment (ie, basal insulin optimization) during the treatment period, only patients who require 
insulin glargine dose up-titration will be randomized to continue in the treatment period of this 
study.
To ensure a valid comparison of the randomized study treatments, it is important that insulin 
glargine is titrated in an optimal way 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 

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with T2D to achieve their therapeutic targets when treated with insulin glargine (Davies et al. 
2005).  
The treatment period is 28 weeks, including 4 weeks of stabilization period to introduce 
randomized study drugs (dulaglutide or placebo), 8 weeks of intensive insulin glargine titration 
period to reach the optimal insulin dose, and 16 weeks of maintenance period when insulin 
glargine dose is expected to be stable. The 28-week period was chosen based on experience 
from AWARD-9 dulaglutide trial.  It should enable a sufficient time period for insulin titration 
and to assess the full effect of study treatments after the majority of the patients reach a stable 
insulin dosage.  
Furthermore, the frequency of postrandomization office and telephone visits is intended to allow 
patients and investigators to frequently assess study treatments and to make insulin dose 
adjustments as needed, to attain glycemic goals within a short time period.
5.5.
Justification for Dose
The approved Product Information in China for dulaglutide includes 2 approved doses, 0.75 mg 
and 1.5 mg once weekly (Trulicity® China Package Insert 2019).  Dulaglutide 1.5 mg was 
selected as the optimal dose for the purposes of exploring the safety and efficacy in combination
with basal insulin glargine in Study GBDI and other Phase 3 trials.  Therefore, dulaglutide 1.5 
mg will be used in Study GBGO.
The TTT algorithm (Section 7.2.2.2.1), adapted from Davies et al. (2005), is a broadly accepted 
approach to insulin glargine dose adjustments and will be used in this study to target a FBG <5.6 
mmol/L.

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6.
Study Population
Prospective approvals 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 for enrollment in the study only if they meet all of the following criteria:
Type of Patient and Disease Characteristics
[1] have type 2 diabetes (based on the World Health Organization’s [WHO] 
diagnostic criteria Appendix 5);
Patient Characteristics
[2] are men or nonpregnant women aged ≥18 years at Visit 1;
[3] have been treated with basal insulin glargine once daily and metformin and/or
acarbose for at least 3 months prior to Visit 1;
[4] doses of once daily insulin glargine and OAMs must be stable during the 3-
month period prior to Visit 1.  Insulin glargine dose is considered stable when 
all doses during this period are within the range defined by ±20% of the most 
commonly used insulin glargine dose during this same period. Doses of 
metformin and/or acarbose are considered stable when doses are unchanged 
during the same period, and the doses should be in the inclusive range of the 
half maximum to maximum approved daily dose per the locally-approved 
label;
[5] have an HbA1c value ≥7.0% and ≤11.0% as assessed by the central laboratory 
at Visit 1;
[6] require further insulin glargine dose increase at Visit 3 per the TTT algorithm 
based on the SMBG data (FBG ≥5.6mmol/L) collected during the prior week;
[7] have stable weight (±5%) ≥3 months prior to Visit 1; 
[8] have body mass index (BMI) between ≥19.0 and ≤35.0 kg/m2 at Visit 1;
[9] are able and willing to administer once weekly randomized therapy;
[10] in the investigator’s opinion, are well motivated, capable, and willing to:
[a] perform fingerstick BG monitoring, including scheduled BG profile 
with up to 7 measurements in 1 day;

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[b] learn how to self-inject 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] maintain a study diary as required for this protocol;
[11] Women of child-bearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same sex relationship 
(as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same sex relationship without sexual relationships with 
males. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence just for the duration of a trial, 
and withdrawal are not acceptable methods of contraception.
Otherwise, women of child-bearing potential participating must agree to use 
one highly effective (less than 1% failure rate) method of contraception or use 
a combination of two effective methods of contraception until plasma 
concentration equals or is lower than the [NOAEL for embryo fetal effects]. 
[a] Women of child-bearing potential participating must test negative for 
pregnancy prior to initiation of treatment as indicated by a negative serum
pregnancy test at the screening visit followed by a negative urine
pregnancy test within 24 hours prior to exposure. 
[b] Either one highly effective method of contraception (such as 
combination oral contraceptives implanted contraceptives or intrauterine 
devices) or a combination of two effective methods of contraception (such 
as male or female condoms with spermicide, diaphragms with spermicide 
or cervical sponges) will be used. The subject may choose to use a double 
barrier method of contraception.  Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method. 
Thus, each barrier method must include use of a spermicide. It should be 
noted that the use of male and female condoms as a double barrier method 
is not considered acceptable due to the high failure rate when these 
methods are combined.
Women not of childbearing potential may participate and include those who 
are:
[a] infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as mullerian 
agenesis; or 
[b] post-menopausal – defined as either

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i. A woman at least 40 years of age with an intact uterus, not on 
hormone therapy, who has cessation of menses for at least 1 year 
without an alternative medical cause, AND a follicle-stimulating 
hormone >40 mIU/mL; or
ii. A woman 55 or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea; or
iii. A woman at least 55 years of age with a diagnosis of menopause prior 
to starting hormone replacement therapy.
Not be breastfeeding.
[40] No male contraception required except in compliance with specific local 
government study requirements.
Informed Consent
[12] 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 the study if they meet any of the following criteria at Visit 1 
(screening), or when indicated below for specific criteria, at Visit 3 (baseline) or at any time 
during the screening and lead-in periods (Visits 1-3):
Medical Conditions
[13] have type 1 diabetes (T1D);
[14] have a history of ≥1 episode of ketoacidosis or hyperosmolar state/coma; 
[15] have a history of severe hypoglycemia and/or hypoglycemia unawareness 
within the 6 months prior to Visit 1;
[16] have had any of the following CV conditions within the 2 months prior to 
Visit 1:  acute myocardial infarction (MI), New York Heart Association 
(NYHA) Class III or Class IV heart failure, or cerebrovascular accident 
(stroke);
[17] have a known clinically significant gastric emptying abnormality (eg, severe 
diabetic gastroparesis or gastric outlet obstruction) or have undergone or plan 
to have a gastric bypass (bariatric) surgery or restrictive bariatric surgery (eg, 
Lap-Band®) during the course of the study, or chronically take drugs that 
directly affect gastrointestinal (GI) motility;

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 3 4
L Y 2 1 8 9 2 6 5
[ 1 8] h a ve ac ute or c hr o nic he pat itis, si g ns a n d s y m pt o ms of a n y ot her li ver disease 
ot her t ha n n o nalc o h o lic fatt y li ver disease ( N A F L D), or ala ni ne 
a mi n otra nsferase ( A L T) le vel > 2. 5 ti mes t he u p per li mit of t he refere nce
ra n ge, as deter mi ne d b y t he ce ntral la b orat or y at st u d y e ntr y (V isit 1); patie nts 
wi t h N A F L D are eli gi ble f or partici pati on i n t his trial o nl y if t heir A L T le vel 
is ≤2. 5 ti mes t he u p per li mit of n or mal ( U L N) f or t he refere nce ra n ge;
[ 1 9] ha ve a hist or y  of c hr o nic pa ncreat itis or ac ute i di opat hi c pa ncreat itis, or were 
di a g n ose d wit h a n y t ype of ac ute pa ncreat itis withi n t he 3 m o nt hs pri or t o 
Vi sit 1;
[ 2 0] f or p atie nts o n met f or mi n or m et f or mi n a n d acar b ose , ha ve re nal disease or 
re nal d ysf u ncti o n (e G F R [ C K D-E PI] < 4 5 m L/ mi n/ 1. 7 3 m 2), as deter mi ne d b y 
t he ce ntral la b orat or y (Gl uc o p ha ge C hi na PI , 2 0 1 7; Gl uc o ba y C hi na PI , 2 0 1 8; 
Tr ulicit y C hi na PI 2 0 1 9 ); f or patie nts o n acar b ose, ha ve re nal disease or re nal 
d y sf u ncti on (e G F R [ C K D -E PI] < 2 5 m L/ mi n/ 1. 7 3 m 2), as deter mi ne d b y t he 
ce ntral la b orat or y (Gl uc o ba y C hi na PI , 2 0 1 8; Tr ulici t y C hi na PI 2 0 1 9);   
[ 2 1] ha ve e vi de nce of a si g nifica nt, u nc o ntr olle d e n d ocri ne a b n or malit y (e g, 
t h yr ot o xic osis, a dre nal crisis), i n t he o pi ni o n of t he i n vest i gat or;
[ 2 2] ha ve a n y self or fa mil y hist or y  of t ype 2 A or t y p e 2 B m ul tiple e n d ocri ne 
ne o pl asia ( M E N 2 A or 2 B) s y n dr ome i n t he a bse nce of k n o w n C-cell 
h y per plasia (t he o nl y e xce pt i on f or t his e xcl usio n will  be for p ati e nts w h ose 
fa mil y me m bers with M E N 2 A or 2 B s y n dr o me ha ve a k n o w n R E T m utati o n 
a n d t he p ote ntial pat ient  for t he st u d y  is ne gati ve f or t he R E T m utati o n);
[ 2 3] ha ve a n y self or fa mil y hist or y  of me d ullar y C-cell h yp er pl asia, fo c al  
h y per plasia, or carci n o ma (i ncl u di n g s p ora dic, fa milial, or part of M E N 2 A or 
2 B s y n dr o me) ;
[ 2 4] ha ve ser u m calcit o ni n ≥2 0 p g/ m L at V isit 1 , as deter mi ne d b y t he ce ntral 
la b orat or y;
[ 2 5] ha ve e vi de nce of a si g nifica nt, acti ve a ut oi m m u ne a b n or malit y ( e g, lu p us, 
r he u mat oid art hri tis);
[ 2 6] ha ve a hist or y  of tra ns pla nte d or ga n (c or neal tra ns pla nts [ kerat o plast y]  are 
all o we d) , or a wai tin g a n or ga n tra ns pla nt ;
[ 2 7] ha ve a hist or y  of acti ve or u ntreate d mali g na nc y, or ha ve bee n i n re missi on 
fr om a cli nicall y si g nifica nt mali g na nc y ( ot her t ha n basal or s q ua m o us cell 
s ki n ca ncer, i n sit u carci n omas of t he cer vi x, o r i n sit u pr ostate ca ncer) f or less 
t ha n 5 y e ars prior t o Visit 1;
[ 2 8] ha ve a hist or y  of a n y ot her c o n diti on (e g, k n o w n dr u g or alc o h ol a b use or 
ps yc hiatric dis or der), w hic h, i n t he o pi ni o n of t he i n vesti gat or, ma y precl u de 
t he patie nt fr o m fol l owi n g a n d c o m pl et i n g t he pr ot oc ol;

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[29] have any hematologic condition that may interfere with HbA1c measurement 
(eg, hemolytic anemias, sickle-cell disease);
Prior/Concomitant Therapy
[30] have been treated with any other antihyperglycemia regimen, other than basal 
insulin glargine once daily and metformin and/or acarbose, within the 3 
months prior to Visit 1 or between Visits 1 and 3;
[31] per the TTT algorithm, do not require insulin glargine dose increase at Visit 3 
based on the SMBG data (FBG <5.6mmol/L) collected during the prior week;
[32] have any other condition not listed in this section that is a contraindication for 
use of insulin glargine, or, for patients using metformin and/or acarbose, have 
a condition that is a contraindication for the use of metformin and/or acarbose
and would require metformin and/or acarbose discontinuation per label;
[33] have been treated with drugs that promote weight loss (e.g.,Saxenda  
(liraglutide 3.0 mg), Xenical® [orlistat], Meridia® [sibutramine], Acutrim® 
[phenylpropanolamine], Sanorex® [mazindol], Apidex®[phentermine], 
BELVIQ® [lorcaserin], Qsymia™ [phentermine/topiramate combination], 
contrave® [naltrexone/bupropion] or similar other body weight loss 
medications including over-the-counter [OTC] medications [e.g., allī®]) 
within the 3 months prior to Visit 1 or between Visits 1 and 3; or current (or 
within the last 3 months) participation in, or planned intent to initiate within 
timeframe of the study, an organized diet and/or exercise weight reduction 
program other than the lifestyle and dietary measures for diabetes treatment;
[34] are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding 
topical, intraocular, intranasal, intra-articular, or inhaled preparations) or have 
received such therapy within the 4 weeks prior to Visit 1 or between Visits 1 
and 3;
Prior/Concurrent Clinical Trial Experience
[35] are currently enrolled in or discontinued within the 30 days prior to Visit 1 
from any other clinical study involving an investigational product, or are 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study. If the previous 
investigational product has a long half-life, 3 months or 5 half-lives 
(whichever is longer) should have passed;
[36] have previously screen failed, withdrawn, discontinued from, or completed 
this study or been randomized in any clinical trial of dulaglutide.
Other Exclusions

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[37] 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);
[38] are Lilly employees;
[39] 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 includes 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 Exclusion Criterion [33] 
(Section 6.2), 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.
Patients should be instructed not to donate blood or blood products during the study or for 4 
weeks following their last study visit.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened for this study.

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 3 7
L Y 2 1 8 9 2 6 5
7. Tr e at m e nt s
7. 1.
Tr e at m e nt s A d mi ni st er e d
T his st u d y  in v o l ves a c o m paris o n of d ula gl uti de 1. 5 m g vers us place b o gi ve n o nce wee kl y as a 
s u bc uta ne o us i njecti on , b ot h as a d d-o n s t o titrate d basal i ns uli n glar gi ne, wit h metf or mi n a n d/ or 
acar b ose, o n gl yce mic c o ntr ol a n d safet y i n C hi nese pati e nts wit h T 2 D. Ta ble G B G O. 3
s u m marizes t he ra n d omize d st u d y  treat me nts a n d titrate d i ns uli n glar gi ne.  
T a bl e G B G O. 3.
St u d y Tr e at m e nt s a n d C o n c o mit a nt I n s uli n
N a me of Dr u g
D os a ge
Fre q ue nc y
Dr u g F or m ul ati o n
R o ute of A d mi nistr ati o n
I n vesti g ati o n al C o m p o u n d
D ula gl uti de
1. 5 m g
O nce wee kl y
Si n gle -Use Pe n a
S u bc uta ne o us i njecti o n
C o m p ar at or
Place b o 
Place b o
O nce wee kl y
Si n gle -Use Pe n a
S u bc uta ne o us i njecti o n
C o nc o mit a nt i ns uli n f or b ot h tre at me nt ar ms
I ns uli n glar gi ne
T T T d osi n g
O nce dail y
S ol o S T A R ™ Pe n
S u bc uta ne o us i njecti o n
A b bre viati o n: T T T = treat -t o-tar get.
a
Prefille d de vice c o ntai ni n g 1 d ose of st u d y dr u g.  
T he i n vest i gat or or his/ her desi g nee is res p o nsi ble f or t he f oll owi n g:
•
E x plai ni n g t he c orrect use of t he st u d y dr u g t o t he patie nt or patie nt 
re prese ntati ve;
•
E x plai ni n g t he c orrect use of met f or mi n a n d/ or acar b ose t o t he patie nt, i ncl u di n g 
a n y c o ntrai n dicat i ons a n d a p pr o priate d osi n g per la bel i n C hi na ;
•
Verif yi n g t hat treat me nt i nstr uctio ns descri be d a b o ve are f o ll owe d pr o perl y;
•
Mai ntai ni n g acc urate rec or ds of st u d y dr u g dis pe nsi n g a n d c o llecti on;
•
P ati e nts s h o uld ret ur n all  u n use d st u d y dr u g t o t he site acc or di n g t o t he Sc he d ule 
of  Acti vities (Secti o n 2 ).  T he patie nts s h o uld be i nstr ucte d t o discar d all use d 
S U Ps a n d S ol o S T A R ™ Pe ns i n a cl osea ble, p u nct ure-resista nt c o ntai ner, a n d 
di s p ose acc or di n g t o l ocal re g ulati ons.  Sites ma y  be a ut h orize d t o destr o y use d 
a n d u n use d S U Ps l ocall y per a p plica ble l o c al  or natio nal  re q uire me nts.
7. 1. 1.
P a c k a gi n g a n d L a b elli n g
T he s p o ns or will pr o vi de d ula gl uti de a n d place b o i n si n gle-use pe ns (S U Ps ), w hic h will be 
di s pe nse d via a n I nteracti ve We b Res p o nse S yst e m (I W R S).  Eac h S U P will be pac ka ge d i n 
cart o ns t o be dis pe nse d.  Eac h cart o n c o ntai ns a 4-wee k s u p pl y, as eac h pe n pr o vi des a wee kl y 
d ose. I nject i ons are t o be a d mi nistere d as descri be d i n Sect i on 7. 2. 2 .   

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Commercial insulin glargine will be provided, in 3 mL (100 units/mL) prefilled delivery devices 
(SoloSTAR™ Pen) during the treatment period, and will also be dispensed via an IWRS.  
Clinical study materials will be labeled according to China’s regulatory requirements.
7.1.2. Medical Devices 
The manufactured medical devices provided for use in the study will be SUPs containing 
dulaglutide 1.5 mg (0.5 mL at 3.0 mg/mL) or placebo, SoloSTAR™Pen containing insulin
glargine (per TTT dose). 
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the 2 study treatment 
arms at Visit 3.  Assignment to treatment arms will be determined by a computer-generated 
random sequence using an IWRS.  The IWRS will be used to assign cartons containing double-
blind study drug to each patient.  Site personnel will confirm that they have located the correct 
cartons by entering a confirmation number found on the label into the IWRS .
Patients will be randomized in a 1:1 ratio to (1) dulaglutide 1.5 mg QW as add-on to insulin 
glargineor (2) placebo QW as add-on to insulin glargine, with metformin and/or acarbose.  
Patients will also be stratified by HbA1c at Visit 1 (screening) (<8.5% vs. ≥8.5%) and OAM 
usage (metformin alone, acarbose alone, metformin and acarbose) at Visit 3 (randomization) to 
achieve between-group comparability and to mitigate against the confounding effects of the 
treatments with severity of disease or treatment with metformin and/or acarbose.
7.2.1. Selection and Timing of Doses
Details of the dosing strategy and administration timing for injectable study drug and insulin 
glargine are provided in the following sections and are designed to achieve HbA1c <7.0%, a 
standard treatment goal in this population.  In order to optimize insulin glargine dose, patients in 
both groups will be targeting FBG <5.6 mmol/L.
7.2.2. Injecting Study Drug
7.2.2.1.
Dulaglutide or Placebo
No adjustment in injectable study drug dose (dulaglutide or placebo) will be allowed.  All 
patients will inject study drug subcutaneously in the skin fold of the left or right abdominal wall 
or the thigh using the injection supplies provided; a caregiver may administer the injection in the 
patient’s upper arm.  A new SUP will be used for each injection.
It is recommended that patients inject the study drug at approximately the same time of day on 
the same day each week.  If the injection is not given on the scheduled day, the missed dose 
should be given as soon as possible after the scheduled day if there are at least 3 days (72 hours) 
until the next scheduled injection.  If less than 3 days remain before the next scheduled injection, 
the missed dose should be skipped and the next dose given at the regularly scheduled time and 
day.  The day of administration can be changed if necessary, as long as the last dose was 
administered 3 or more days before.

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 3 9
L Y 2 1 8 9 2 6 5
T he da y  a n d ti me of all d ula gl uti de i njecti ons will be rec or de d i n t he patie nt’s diar y a n d e C R F.
7. 2. 2. 2.
I n s uli n Gl ar gi n e
I ns uli n glar gi ne will be i njecte d Q D, as a si n gle s u bc uta ne o us i njecti on, al wa ys at be d time at 
a p pr o xi matel y the sa me ti me e ver y ni g ht .  The d ose will be a djuste d wee kl y per T T T al g orit h m 
(Ta bl e G B G O. 4 ), base d o n F B G val ues a n d rec or de d h y p o gl yce mic e pis o des (see bel o w f or 
details).  For t his p ur p ose, patie nts will be re q uir e d t o meas ure t heir F B G eac h m o r ni n g a n d t o 
c ollect 4 -p oi nt  S M B G pr ofiles at least o nce wee kl y, starti n g at Visit 2 t hr o u g h t he e n d of  the 
treat me nt perio d ( Visi t 1 7 [ Wee k 2 8 ]).  
D uri n g t he lea d -i n peri o d (bet wee n Visi ts 2 a n d 3 [ baseli ne]), i ns uli n d oses s h o ul d be a dj uste d per 
T T T al g orit h m ( Ta ble G B G O. 4 ) o nl y w he n nee de d t o pr otect t he safety o f pat ient s ( occ urre nce of
h y p o gl yce mia or s e v er e h y per gl yce mia).  Ins uli n d ose assess me nts d uri n g t his p eri o d wi ll o c c ur 
o nce per wee k ( Secti o n 5. 1 ).  
D uri n g t he treat me nt peri o d, office visit s will occ ur wee kl y or e ver y ot her wee k d uri n g t he first 2 
m o nt hs a n d t hereafter e ver y 4 t o 6 wee ks t o e na ble t he site t o pr o perl y mo ni t or p atie nts’ usa ge of 
t he T T T al g orit h m.  After ra n d o mizati o n, d uri n g t he 4- wee k sta bilizati o n peri o d, t he basal i ns uli n 
d ose will re mai n u nc ha n ge d if t he patie nt’s baseli ne ( Visit 3) H b A 1c is > 8. 0 %. F or pati e nts wit h 
baseli ne H b A 1c ≤8. 0 %, t he basal i ns uli n d ose will be decrease d b y 2 0 % i m me diatel y aft er 
ra n d omizat i on a n d will t he n re mai n u nc ha n ge d d uri n g t he sta bilizati on peri o d.  A d dit i onal i ns uli n 
d ose a dj ust me nts d uri n g t he sta bilizati on p eri o d will o nl y be all o we d usi n g t he T T T al g orit h m 
(Ta bl e G B G O. 4 ) i n case of  the occ urre nce of  hy p o gl yce mia or t he de vel o p m e nt of  se v er e 
h y per gl yce mia.  Patie nts will be re q ueste d t o perf or m i ns uli n d ose assess me nts t wice per w e e k 
d uri n g t hi s perio d.
F o ll owi n g sta bilizati on, pati e nts will be treate d f or a n a d dit i onal 2 4 wee ks, a n d t he y will be 
re q uire d t o assess t heir basal i ns uli n d ose o nce wee kl y, usi n g t he S M B G val ues f or t hat wee k. 
D uri n g t his p eri o d, t he i ns uli n d ose will be a djuste d per t he T T T alg ori t h m wi t h no restrictio n. 
T he ma i n tr eat me nt tar get f or basal i ns uli n d os e a dj ust me nt t hr o u g h t he treat me nt peri o d (2 8 
wee ks) i s F B G < 5. 6 m m ol / L.
C o m plia nce wi t h t he st u d y dr u g ( d ula gl ut i de or place b o) a d mi nistrati o n sc he d ule a n d c om p lia nce 
wi t h t he basal i ns uli n T T T al g orit h m (at selecte d visits; see Sc he d ule of Act i vities; Sect i on 2 ) will 
be assesse d a n d c ollecte d i n t he e C R F.
I n s uli n Gl ar gi n e D o s e Titr ati o n Al g orit h m
T he decisi o n t o a dj ust i ns uli n glar gi ne d oses will be base d u p o n t he me dia n o f the last 3 dail y F B G 
(S M B G ) val ues ( pr efera bl y mos t rece nt rea di n gs) c ollecte d after t he pre vi o us d ose assess me nt.  If 
fe wer t ha n 3 val ues are a vaila ble f or assess me nt, t he n t he a v era ge val ue will be calc ulate d a n d 
use d t o a dj ust t he d ose.  If t he m e dia n or a vera ge F B G val ue is wi t hi n t he tar get F B G ra n ge, t he n 
t here will be n o res ulti n g c ha n ge i n d ose.  If t hat val ue is ≥5. 6 m m o l/L, t he d ose will be i ncrease d 
base d o n t he titr atio n al g orit h m pr o vi de d i n Ta ble G B G O. 4 (Da vies et al. 2 0 0 5).   I n t he case of  
rec or de d h y p o gl y ce mic e pis o des a n y time d ur i n g t he p eri o d i ncl u de d i n t he assess me nt, t he crit eria 
pr o vi de d i n Ta ble G B G O. 4 s h o uld b e f ol l owe d .

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Table GBGO.4.
Insulin Glargine Treatment-to-Target Algorithm
Median or Average BG Before Breakfast (for Titration of 
Evening Dose)
Increase in Basal Dose (Units)
<70 mg/dL (<3.9 mmol/L)
Decrease to previous lower dose*
70-<100 mg/dL (3.9-5.6 mmol/L)
No adjustment
100-<120 mg/dL (5.6-6.7 mmol/L)
+1 to +2 U#
120-<140 mg/dL (6.7-7.8 mmol/L)
+ 2 U
140-<180 mg/dL (7.8-10.0 mmol/L)
+ 4 U
≥180 mg/dL (>10.0 mmol/L)
+6 to +8 U#
* The patient will be administered with the previous lower dose if he/she has documented hypoglycemia or probable 
symptomatic hypoglycemia.
# Insulin glargine dose adjustment will be discussed with the patient and determined by the investigator before Week 
8 as preparation and training for implementation of the patient self-titration according to the treatment-to-target
algorithm after Week 8 (Section 5.1).
Abbreviations:  BG = blood glucose; U = unit(s).
7.3.
Blinding
This is a double-blind study. To preserve the blinding of the study, a minimum number of Lilly 
personnel will see the randomization table and treatment assignments before the study is 
complete.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IWRS.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
Patient safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the patient to continue in the study.
7.4.
Dosage Modification
No adjustment in study drug doses will be allowed.  Further details about dose administration 
during the study are described in Section 7.2.1.  
Dosing of required concomitant metformin and/or acarbose is discussed in Section 7.7.1.

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 4 1
L Y 2 1 8 9 2 6 5
7. 5.
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y
T he st u d y  sit e must st ore t he S U P cart o ns i n a l oc ke d a n d sec ure e n vir o n me nt.  T he S U Ps m ust 
be refri gerate d ( n ot fr oze n) at 2° C t o 8° C u nt il use.  Dr y ice s h o ul d n ot be use d f or c o oli n g.  
P ati e nts will be pr o vide d wi t h cart o ns c o ntai ni n g 4 d ula gl utide or pl ace b o S U Ps at office visit s 
per t he Sc he d ule of Act i vities (Secti o n 2 ).  T he y will recei ve i ns ulate d ba gs wit h c o oli n g gel 
pac ks f or use i n tr a ns p orti n g t he S U P cart o n fr o m t he site t o h o me.  Pri or t o self-i njecti on, 1 S U P 
s h o uld be re m o ve d fr o m  t he cart o n a n d all o we d t o sit at r o o m te m perat ure f or a b o ut 3 0 mi n utes 
bef ore self -i njecti on.  I n vesti gati o nal pr o d uct will be la bele d acc or di n g t o t he C hi na’s re g ulat or y  
re q uire me nts.
P ati e nts will als o be pr o vide d wi t h a c o m merciall y a vaila ble P G meter a n d test stri ps t o use 
d uri n g t he st u d y .  S ufficie nt st u d y dr u g mat erial a n d gluc ose testi n g s u p plies will be dis pe nse d, 
as nee de d, at eac h visit.
St u d y  sit e pers o n nel m ust re g ularl y assess w het her t he patie nt is c orrectl y a d mi nisteri n g t he 
assi g ne d st u d y dr u g a n d st ori n g t he st u d y dr u g acc or di n g t o t he pr o vi de d i nstr ucti o ns.
7. 6.
Tr e at m e nt C o m pli a n c e
T he assess me nt of tre at me nt  c o m plia nce i n t his st u d y will i ncl u de assess me nt of a d mi nistrati o n 
of  t he st u d y dr u gs ( d ula gl ut i de or place b o), t he use of t he T T T al g orit h m, a d mi nistratio n of  
i ns uli n glar gi ne d oses, a n d fre q ue nc y of pr ot oc ol de viati ons relate d t o a n y  gluc ose -l ower i n g 
me dicat i ons.
T he assess me nt of treat me nt c o mplia nce wi t h st u d y dr u g will be deter mi ne d b y  t h e fol l owi n g:

I nf or mat i on a b o ut t he a d mi nistrati o n of o nce wee kl y st u d y dr u g i njecti o ns will be e ntere d 
i nto t he pati e nt diar y b y t he patient  a n d re vie we d b y t h e site pers o n nel at eac h st u d y visit; 
t his i nf or mati on will be c ollecte d i n t he e C R F;

St u d y  dr u gs acc o u nta bility will be c hec ke d acc or di n g t o t he Sc he d ule of Acti vit ies 
(Secti o n 2 ).  F or t hat p ur p ose, patie nts will be i nstr ucte d t o ret ur n t he st u d y dr u g cart o n at 
t he ne xt visit .  T he y will als o be i nstr ucte d t o ret ur n a n y u n use d st u d y dr u g at t he ne xt 
st u d y visit;

Treat me nt c o m plia nce f or o nce wee kl y st u d y  dr u g is defi ne d as ta ki n g at least 7 5 % of t he 
re q uire d i njecti ons o f st u d y dr u g, 
o
Bet wee n Visi t 3 (ra n d o mizati on) a n d Visit 6 ( Wee k 4),  an d
o
Si nce t he pre vi o us visit, assesse d at Visits 1 0 ( Wee k 8), 1 2 ( Wee k 1 2) , 1 4 
( Wee k 1 8) , 1 6 ( Wee k 2 4) a n d 1 7 ( Wee k 2 8 )
C o m plia nce i s assesse d b y site pers o n nel; t his i nf or mat i on will be e ntere d i n t he e C R F. 
C o m plia nce wi t h t he T T T alg ori t h m will be deter mi ne d b y t he f oll o wi n g:

T he st u d y  site will re vie w a n d d oc u me nt patie nts’ use of t he i ns uli n glar gi ne T T T 
alg ori t h m for a p pr o pri ate n u m ber of assess me nts, a p pr o priate assess me nt of t he i ns uli n 

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
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L Y 2 1 8 9 2 6 5
d ose, a n d s u bse q ue nt d ose a dj ust me nts at eac h visit fr o m ra n d omizat i on t o Visit 1 7 .  
T hese data will be e ntere d i nto t he e C R F f or t he pe rio d pri or t o Visits 8 ( Wee k 6), 1 0 
( Wee k 8), a n d 1 2 ( Wee k 1 2).
Ot her as pects of c o m plia nce wit h t he st u d y  treat me nts will als o be assesse d at eac h visit,
i ncl u di n g t he patie nt’s a d here nce t o t he visit sc he d ule, c o m plia nce with t he c o nc o mita nt 
met f or mi n a nd/ or acar b ose re q uire me nts a n d ot her me dicati on g ui da nces (Secti o n 7. 7 ), 
c o mplet i on of st u d y  diaries, res ults of S M B G , a n d a n y ot her para meters t he i n vesti gat or 
c o nsi ders necessar y.  P atie nts c o nsidere d t o be p o orl y  c o mplia nt wi t h t heir me dicati on a n d/ or t he 
st u d y pr oce d ures (f or e xa m ple, misse d visits or s pecific dia g n ostic tests) will recei ve a d diti on al  
trai ni n g a n d i nstr ucti o ns as re q uire d.
7. 7.
C o n c o mi t a nt T h er a p y
P ati e nts are per mitte d t o use c o nc o mita nt me dicat i o ns t hat t he y re q uire d uri n g t he st u d y, e xce pt 
certai n me dicat i ons t hat ma y i nterfere wit h t he assess me nt of efficac y a n d safet y c haracteristics 
of  st u d y dr u gs.
I n vest i gati ve site staff will i nf or m patient s t hat t he y m ust c o ns ult wit h t he i n vesti gat or or a 
desi g nate d site staff me m ber u p o n bei n g prescri be d a n y ne w me dicat i ons d uri n g t he st u d y .  T his 
ma y n ot be p ossi ble w he n i nit iate d f or treat me nt of me dical e mer ge ncies, i n w hic h case t he 
pati e nt will i nf or m t he i n vest i gat or or a desi g nate d site staff me m ber as s o o n as p ossi ble.
A n y a d dit i on al  me dicat i on i nitiate d d uri n g t he c o urse of t he st u d y (i ncl u di n g O T C dr u gs, s uc h as 
paraceta m o l or as pi rin) m ust be d oc u me nte d, a n d t he na me of t he dr u g, t he d osa ge ( met f or mi n 
a n d/ or acar b ose) a n d t he date(s) of a d mi nistrati o n m ust be rec or de d i n t he patie nt’s diar y a n d o n 
t he “ C o nc o mit a nt Me dicat i ons” sect i on of t he e C R F.  
N o n -st u d y me dicat i ons ta ke n b y pat ient s w h o are scree ne d b ut n ot ra n d o mize d will n ot be 
re p orte d t o Lill y u nless t he me dicatio n is ass oci ate d wit h a n S A E or A E t hat t he i n vesti gat or 
belie ves ma y ha ve bee n ca use d b y a st u d y  pr oce d ure.
Ta ble G B G O. 5 pr o vi des a s u m mar y  of crit eri a for use of c o nc o mita nt me dicat i ons t hat ma y 
i nterfere wit h pla n ne d assess me nts d uri n g t he st u d y.
T a bl e G B G O. 5.
Crit eri a f or U s e of C o n c o m it a nt M e di c ati o n s t h at M a y I nt erf er e wit h 
Effi c a c y a n d S af et y A s s e s s m e nt s
Dr u g Cl ass
Use D uri n g 
Scree ni n g/ Le a d -I n
C o n diti o ns f or Use after R a n d o miz ati o n
Ac ute 
t her a p ya
Resc ue 
t her a p y 
D uri n g S afet y 
F oll o w -U p Peri o d
Dr u gs wit h a p pr o ve d wei g ht l oss 
i n dicati o nb
E xcl u de d
N  
N/ A
N
S y ste mic gl uc oc ortic oi d t hera p yc
E xcl u de d d e xce pt f or 
ac ute t hera p y a
Y  
N/ A
N
A nti h y per gl yce mia me dicati o ns
Ot her G L P -1 R As a n d relate d
fi xe d-d ose c o m bi nati o n s
E xcl u de d
N
N
N

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 4 3
L Y 2 1 8 9 2 6 5
A b bre viati o ns:  D P P -4 = di pe pti d yl pe pti dase -4; G L P -1 R A = gl uca g o n -li ke pe pti de-1 rece pt or a g o nist; N = n o; N/ A 
= n ot a p plica ble; S G L T 2 = s o di u m -gl uc ose c o -tra ns p orter 2; Y = yes
a
Ac ute t hera p y = treat me nt f or u p t o 1 4 da ys.  
b
I ncl u des Sa xe n da ® [ lira gl uti de 3. 0 m g], Xe nical ® [ orlistat], Meri dia ® [si b utra mi ne], Ac utri m ® 
[ p he n yl pr o pa n ola mi ne], Sa n ore x ® [ mazi n d ol], A pi de x ®[ p he nter mi ne], B E L VI Q ® [l orcaseri n], Qs y mia ™ 
[ p he nter mi ne/t o pira mate c o m bi nati o n], c o ntra ve ® [ naltre x o ne/ b u pr o pi o n] or si milar ot her b o d y wei g ht l oss 
me dicati o ns i ncl u di n g o ver -t he-c o u nter [ O T C] me dicati o ns [e. g., allī ®] wit hi n 3 m o nt hs pri or t o Visit 1 or a n y 
ti me d uri n g t he trial. 
c
D oes n ot a p pl y t o t o pical, i ntra oc ular, i ntra nasal, i ntra-artic ular, or i n hale d pre parati o ns.
d
C hr o nic s y ste mic gl uc oc ortic oi d t hera p y ( > 1 4 da ys) s h o ul d be e xcl u de d wit hi n 4 wee ks pri or t o Visit 1 or 
bet wee n Visits 1 a n d 3.
e
Use of ins uli n glar gi ne is all o we d d uri n g s cr ee ni n g/lea d -i n peri o d F or ac ute t hera p y, resc ue t hera p y a n d t hera p y 
d uri n g safet y f oll o w -u p peri o d, u se of ot her basal i ns uli ns will n ot be all o we d i n b ot h treat me nt gr o u p s.  .
f
S witc hi n g metf or mi n or  acar b ose ma n ufact urers is all o we d as l o n g as t he d osa ge is t he sa me.  C ha n gi n g t o a 
metf or mi n f or m ulati o n wit h a differe nt acti o n pr ofile (f or e xa m ple, fr o m s h ort -acti n g t o l o n g -acti n g metf or mi n) 
is n ot per mitte d.
g
F or resc ue t hera p y, metf or mi n or acar b ose d ose c a n be i ncrease d if t he d ose is n o m ore t ha n ma xi m u m a p pr o ve d 
d ose per c o u ntr y -s pecific la bel a n d is well t olerate d.
7. 7. 1.
A nti h y p er gl y c e mi a M e di c ati o n s
A nt i-h y per gl yce mic me dicat i ons, ot her t ha n st u d y dr u g, met f or mi n a n d/ or acar b ose, are n ot 
all o we d at a n y time d uri n g t he st u d y , e xce pt t hose use d as resc ue t hera p y, a n d/ or use d aft er earl y 
st u d y dr u g disc o nti n uati on or d uri n g safet y f oll ow- u p peri o d , or i ns uli ns f or s h ort-t er m use.  
Resc ue t hera p y  wit h ot her gluc ose -l oweri n g a ge nts, i ncl u di n g i ns uli n, ma y  be me dicall y 
i n dicate d i n certai n sit uati ons after ra n d o mizat i on d ue t o se vere, persiste nt h y per gl yce mia or 
earl y disc o nti n uati on of st u d y  treat me nt.  T hese sit uati o ns are descri be d i n Sect i on 7. 7. 5. 3 a n d 
Secti o n 8. 1. 1 , res pecti vel y.  If a n y s uc h sit uati o n occ urs, t he patie nts ma y be treate d wit h a n y 
l ocall y-a p pr o ve d gluc ose -l oweri n g a ge nts. Ot her G L P -1 R As, a n ot her basal i ns uli n, or D P P -4 
i n hi bit ors, fi xe d-d ose c o m bi nat i on wi t h c o mp o ne nt of G L P -1 rece pt or a g o nists or D P P - 4 
i n hi bit or, a n d pra mli nt i de are pr o hi bite d me dicati o ns a n d are n ot all o we d as resc ue t hera pies .  
If a n y ne w a nt i-h y per gl yce mic me dicati o n is i nit iate d after ra n d o mizati o n at Visit 3 a n d pri or t o 
Vi sit 1 7 (e n d of Treat me nt Peri o d), ot her t ha n st u d y dr u g, resc ue t hera p y, dr u gs use d after earl y  
st u d y dr u g disc o nti n uati on or d uri n g safet y f oll ow- u p peri o d , or i ns uli ns f or s h ort-t er m use f or 
me dical e mer ge ncies, t he patie nt will be re q uire d t o i m me diatel y disc o nt i n ue t he me dicati on a n d 
t he a p pr o priate st u d y de viati on re p ort will be ge nerate d.  A n y s uc h vi o lati on of t he pr ot oc ol t hat 
D P P -4 i n hi bit ors a n d relate d
fi xe d-d ose c o m bi nati o n s
E xcl u de d
N
N
N
Pra mli nti de
E xcl u de d
N
N
N
S G L T 2 i n hi bit ors
E xcl u de d
N
Y
Y
I ns uli ns e
E xcl u de d
Y
Y
Y
Me gliti ni des
E xcl u de d
N
Y
Y
Al p ha- gl uc osi dase i n hi bit ors f
All o we d
N/ A  
Y g
Y
S ul p h o n yl ureas
E xcl u de d
N
Y
Y
T hiaz oli di ne di o nes
E xcl u de d
N
Y
Y
Metf or mi n
f
All o we d
N/ A  
Y e
Y

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lasts > 14 consecutive days will exclude the patient from the Per-Protocol (PP) Population for 
analyses.  
7.7.2. Medications That Promote Weight Loss
Prescription or OTC medications that promote weight loss are exclusionary if used within the 3 
months prior to Visit 1 (study entry), or between study entry and randomization at Visit 3 (see 
Section 6.2).  These medications are not allowed at any time during the treatment period.  If 
started, these medications should be immediately withdrawn.  In addition, patients should not 
receive an intensive diet/exercise program with the intent of reducing body weight at any time 
during the study, other than the lifestyle and dietary measures for diabetes treatment (see Section 
6.3).
Patients who use any medication from these groups during the treatment period will not be 
included in the PP analyses if the duration of use is >14 days (cumulative).
7.7.3. Systemic Glucocorticoids
Chronic systemic glucocorticoid therapy (>14 consecutive days; excluding topical, intraocular, 
intranasal, intra-articular, or inhaled preparations) is exclusionary if being in use or has been 
used during the 4-week period before study entry or between study entry and randomization at 
Visit 3.  If glucocorticoid therapy is needed for more than 14 consecutive days during the 
treatment period, then patients will not be included in the PP analysis.
7.7.4. Antihypertensive Medications
If used, anti-hypertensive therapy should be kept stable throughout the trial to allow assessments 
of the effect of randomized therapies on BP.  However, if adjustments to antihypertensive 
medications or dosages are needed for patient safety, this information should be recorded in the 
“Concomitant Medications” section of the patient’s eCRF.  As with all aspects of medical care, 
the physician’s clinical judgment and the well-being of the patient take precedence in clinical 
decisions.
7.7.5. Special Treatment Considerations
7.7.5.1.
Standards of Medical Care
Investigators and other study team members are expected to treat patients according to the 
nationally established standards of care for diabetes management (Chinese Diabetes Association
2019) or to international standard (American Diabetes Association 2019) except where the 
treatment would be in conflict with the protocol-provided treatment requirements.  
This section provides guidance on management of episodes of hypoglycemic events and events 
of severe, persistent hyperglycemia.  For effective implementation of measures described here, it 
is important that patients, and their caregivers, if applicable, be well-educated about the signs 
and symptoms of hypoglycemia (eg, intense hunger, sweating, tremor, restlessness, irritability, 
depression, headaches, disturbed sleep, or transient neurological disorders) and hyperglycemia 
(eg, severe thirst, dry mouth, frequent micturition, or dry skin).  Patients should be instructed to 

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contact the investigative site in the event of severe hypoglycemia or severe, persistent 
hyperglycemia between study visits.
7.7.5.2.
Management of Increased Hypoglycemia Risk
If a hypoglycemic event occurs, the patient should record in the study diary the BG level 
measured during the episode and prior to administration of treatment (if taken), as well as 
associated symptoms and treatment administered.  Site personnel will enter this information into
the hypoglycemia eCRF at each visit.  Patients should be trained about signs and symptoms of 
hypoglycemia and how to manage hypoglycemia. Patients should first seek acute medical or 
emergency care if needed, and inform the investigative site as soon as possible after an event of 
severe hypoglycemia has occurred that required assistance to administer corrective treatment.
Investigators should use definitions and criteria provided in Section 9.2.2.1 to diagnose 
hypoglycemia.  In each case of suspected or confirmed hypoglycemia, it is important that details 
for each event be recorded on the eCRF as completely and accurately as possible, including 
information on the date, time, BG value, symptoms, and the nature and outcome of any 
interventions.  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.  
In this study, increased risk of hypoglycemia is defined as having a single episode of severe 
hypoglycemia or having more than 1 episode of documented symptomatic hypoglycemia (<3.0 
mmol/L) within a 1-week period at any time during the Treatment Period.
In cases where a patient experiences hypoglycemia as described above, to confirm the increased 
risk, the study sites must ensure that the patient has been fully compliant with the assigned 
therapeutic regimen and also that there is no evidence of other possible causes of hypoglycemia 
(eg, omission of meal, unexpected increase in exercise).
Patients fulfilling the definition of increased risk of hypoglycemia should first decrease the 
insulin glargine dose, followed by discontinuation of insulin glargine, if needed.  If increased 
risk of hypoglycemia persists despite discontinuation of insulin glargine, then dose reduction or 
discontinuation of OAMs should be considered.  No adjustment of the dulaglutide dose should 
be made.
7.7.5.3.
Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period
Investigators will be trained on the application of criteria for deciding when and how to intervene 
in patients who do not reach glycemic targets.  An additional therapeutic intervention should be 
considered in patients who develop severe, persistent hyperglycemia after randomization based 
on the following criteria:
a) During the first 12 weeks postrandomization (up to Visit 12):  An average daily BG >15 
mmol/L (equivalent to HbAlc 11%) [Nathan, et al. 2008] on at least two 4-point SMBG 
profiles over a consecutive 2-week period
OR

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
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L Y 2 1 8 9 2 6 5
b)
Bet wee n Wee k 1 2 a n d Wee k 2 8 ( bet wee n Visit s 1 2 a n d 1 7):  A n a vera ge dail y B G > 1 1 
m m o l/ L (e q ui vale nt t o H b Alc 8. 5% ) o n at least t w o 4 -p oi nt S M B G pr ofiles o ver a 
c o nsec ut i ve 2- wee k perio d
Persi ste nt h yper gl yce mia c o nsi dere d of se vere i nte nsit y b y t he i n vest i gat or s h o ul d be re p orte d o n 
t he A E e C R F w he ne ver a n y o f t he a b o ve criteria are met.  
I n vesti gat ors s h o ul d first c o nfir m t hat t he patie nt is f ull y c o m plia nt wit h t he assi g ne d t hera pe utic 
re gi me n a n d t hat t he y d o n ot ha ve a n ac ute c o n diti o n t hat is raisi n g t heir B G . If c o nfir me d, t he 
i n vesti gat or will i nitiate a n a p pr o priate gl uc ose-l oweri n g i nter ve nt i on (resc ue i nter ve nt i on) 
acc or di n g t o t he g ui da nce o utli ne d i n Sect i on 7. 7. 1 , a n d it will be rec or de d o n t he e C R F 
s pecifie d f or c ollecti n g a nti h y per gl yce mic me dicati ons.  Ot her G L P- 1 rece pt or a g o nist s
(incl u di n g c o m mercial Tr ulicit y) , basal i ns uli ns, a n d di pe pti d yl pe pt i dase -4 ( D P P -4) i n hi bit ors 
are pr o hi bite d me dicat i ons a n d m ust n ot be i ncl u de d i n t he resc ue i nter ve nt i on. Patie nts w h o 
recei ve resc ue i nter ve nti on f or h yper gl yce mia m a na ge me nt s h o uld als o c o nti n ue a d mi nisteri n g 
st u dy dr u g f or t he re m ai ni n g perio d i n t he tri al.
7. 8.
Tr e at m e nt aft er t h e E n d of t h e St u d y
7. 8. 1.
C o nti n u e d A c c e s s
A n a p pr o priate dia betes treat me nt re gi me n will be prescri be d per t he i n vest i gat or’s j u d g me nt 
f oll owi n g t he last st u d y  visit or a n earl y ter mi nati on visit.  H o we ver, d uri n g t he safet y f oll ow- u p 
p eri o d pati e nts ca n n ot be prescri be d G L P -1 rece pt or a g o nists.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:

Patient Decision
o
The patient requests to discontinue investigational product.

Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via the electronic case report form 
(eCRF).
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X 
upper limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
prothrombin time >1.5X ULN 

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

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 drugs would not be medically appropriate;

Acute or chronic pancreatitis;

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;

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
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L Y 2 1 8 9 2 6 5

If a patie nt is dia g n ose d with C -cell h y per plasia or me d ullar y t h yr oid carci n o ma ( M T C) 
after ra n d o mizati on;

A n y ot her T E A E , S A E, or cli nicall y si g nifica nt la b orat or y val ue f or w hic h t he 
i n vesti gat or belie ves t hat per ma ne nt st u d y dr u g disc o nti n uati on is t he a p pr o priate 
meas ure t o be ta ke n;

A n y si g nifica nt st u d y  dr u g-r elate d h y perse nsit i vity reacti o n ;

If a n o n-st u d y G L P-1 rece pt or a g o nist is i nit iate d, a n d t he patie nt ref uses t o disc o nti n ue 
t his me dicati on;

If fe male patie nt bec ome s pre g na nt;

If a patie nt is dia g n ose d wit h T 1 D;

If a n i n vest i gat or, site pers o n nel perf or mi n g assess me nts, or patie nt is u n bli n de d;

If t he i n vest i gat or or s p o ns or deci des t hat t he patie nt s h o ul d be wit h dra w n fr o m st u d y  
dr u g; if t he i n vest i gat or deci des t o per ma ne ntl y disc o nti n ue st u d y treat me nt beca use of 
a n S A E or a cli nicall y si g nifica nt la b orat or y v alue, Lill y  or its desi g nee s h o uld be alerte d 
i m me diat el y.

if t he patient  or t he patie nt’s desi g nee, f or e xa m ple, le gal g uar dia n, re q uests t hat t he 
pati e nt be wit hdra w n fr o m  st u d y dr u g
P ati e nts w h o st o p t he st u d y dr u g per ma ne ntl y will recei ve a n ot her gl uc ose-l oweri n g i nter ve nti o n 
( Sectio n 7. 7. 1 ) a n d will c o nti n ue partici pati n g i n t he trial acc or di n g t o t he pr ot oc ol t o c ollect all 
pl a n ne d efficac y a n d safety meas ure me nts.
P ati e nts disc o nti n ui n g fr om t he i n vest i gati onal pr o d uct pre mat urel y f or a n y  reas o n s h o uld 
c o mplete A E a n d ot her f o ll ow- u p pr oce d ures per Secti o n 2 Sc he d ule o f Act i vities, Secti o n 9. 2
A d verse E ve nt, a n d Secti o n 9. 4 Safet y of  t his pr ot oc ol.
8. 1. 2.
T e m p or ar y Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt
I n certai n sit uati ons after ra n d o mizat i on, t he i n vesti gat or ma y nee d t o te m p oraril y disc o nt i n ue 
(int err u pt) st u d y dr u g (f or e xa m ple, d ue t o a n A E or a cli nicall y si g nifica nt la b orat or y val ue). If 
st u d y dr u g i nterr u ptio n is d ue t o a n A E, t he e ve nt is t o be d oc u m e nte d a n d f o ll owe d acc or di n g t o 
t he pr oce d ures i n Sect i on 9. 2 of  t his pr ot oc ol.  E ver y  eff ort s h o uld be m a de b y t he i n vestigat or t o 
mai ntai n patie nts o n st u d y  dr u g a n d t o restart st u d y dr u g after a n y t e mp or ar y  int err u pti o n, as 
s o o n as it is safe t o d o s o. I n vesti gat ors s h o ul d i nf or m t he S p o ns or t hat st u d y dr u g has bee n 
t e mp oraril y i nterr u pte d.  T he data relate d t o te m p orar y  int err u ptio n of  st ud y  treat me nt will be 
d oc u m e nte d i n s o urce d oc u me nts a n d e ntere d i n t he e C R F.
8. 1. 3.
Di s c o nti n u ati o n of I n a d v ert e ntl y E nr oll e d P ati e nt s
If t he s p o ns or or i n vesti gat or i de ntif y a patient  w h o di d n ot meet e nr oll me nt criteria a n d was 
i na d verte nt l y e nr olle d, t he n t he patie nt s h o ul d be disc o nti n ue d fr om st u d y treat me nt u nless t here 
are e xte n uat i n g circ u msta nces t hat ma ke it me dicall y necessar y f or t he patie nt t o c o nti n ue o n 

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study treatment.  If the investigator and the sponsor CRP agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product.  Safety follow up is as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.  
8.2.
Discontinuation from the Study
Every attempt should be made to keep patients in the trial irrespective of their adherence to 
treatment with study drug in order to minimize the amount of missing data and to enable 
assessment of study objectives as planned by the study protocol.  Early patient discontinuation 
from the study may be warranted in the following situations for ethical or legal reasons:

If a patient is diagnosed with T1D;

If a female patient becomes pregnant;

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;
Patients may also discontinue from the study due to:

Sponsor or investigator decision 
o
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);

Patient decision
o
the patient or the patient’s designee, for example, parents or legal guardian
requests to be withdrawn from the study.
Patients who agree to provide information relevant to any trial endpoint at the end of the study 
are not considered to have discontinued from the study.
A patient who withdraws consent and clearly indicates that there will be no further contact of any 
kind with the site will be considered to have discontinued from the study.
Prior to early study discontinuation, the patient will discontinue study drug and will have end-of-
study procedures (ET visit) performed as shown in the Schedule of Activities (Section 2). 
During the ET visit, the patient will be prescribed an appropriate glucose-lowering regimen and 
glucose self-monitoring plan.  Visit 801 (safety follow-up visit) should be performed 
approximately 4 weeks after the ET visit as the final study visit.  
Patients discontinuing from the study prematurely for any reason should complete adverse event 
and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events),
and Section 9.4 (Safety) of this protocol.

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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.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or are otherwise 
unable to be followed up by the site.

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
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9.
St u d y  As s e s s m e nt s a n d Pr o c e d ur e s
Secti o n 2 prese nts t he Sc he d ule of Act i vities, wit h t he st u d y pr oce d ures a n d t heir ti mi n g 
(incl u di n g n u m ber of da ys f or all o wa ble visit de viati o ns [ visit wi n d o ws]).
A p pe n di x 2 lists t he la b orat or y tests t hat will be perf or me d f or t his st u d y.
U nless ot her wise state d i n t he s u bsect i ons bel o w, all  sa m ples c ollecte d f or s pecifie d la b orat or y 
tests will be destr o ye d wit hi n 6 0 da ys of recei pt of c o nfir me d test res ults.
9. 1.
Effi c a c y A s s e s s m e nt s
9. 1. 1.
Pri m ar y Effi c a c y A s s e s s m e nt s
T he pri mar y  efficac y meas ure will be e val uate d at 2 8 wee ks :

c ha n ge fr o m baseli ne i n H b A 1c.
9. 1. 2.
S e c o n d ar y Effi c a c y A s s e s s m e nt s
T he f o ll owi n g sec o n dar y  efficac y meas ures will be e val uate d at 2 8 wee ks: 

pr o p orti o n of  patient s ac hie vi n g H b A 1c tar get of < 7. 0 % or ≤6. 5 %;

pr o p orti o n of  patie nts ac hie vi n g H b A 1c tar get of  < 7. 0 % a n d wit h o ut wei g ht gai n ( < 0. 1 
k g) a n d wit h o ut d oc u me nte d s y m pt o mat ic h y p o gl yce mia d uri n g t he mai nte na nce peri o d
( Wee k 1 2- 2 8);

pr o p orti o n of  patient s ac hie vi n g H b A 1c tar get of  < 7. 0 % a n d wit h o ut d oc u me nte d 
s y m pt o mat ic h y p o gl yce mia d uri n g t he mai nte na nce peri o d;

pr o p orti o n of  patient s ac hie vi n g H b A 1c tar get of  < 7. 0 % a n d wit h o ut wei g ht gai n ( < 0. 1
k g);

c ha n ges fr om baseli ne i n F S G meas ure d at t he ce ntral la b orat or y ;

c ha n ges fr om baseli ne i n B G fr om dail y S M B G pr ofiles;

c ha n ges fr om baseli ne i n b o d y  wei g ht;

cha n ge s fr om baseli ne i n dail y  mea n i ns uli n glar gi ne d oses .
9. 1. 3.
E x pl or at or y Effi c a c y M e a s ur e s
T he f o ll owi n g e x pl orat or y  efficac y meas ures will be e val uate d:

fre q ue nc y of ins uli n d ose a dj ust me nt s at 2 8 wee ks;

n u m ber of i ns uli n d ose assess me nts per T T T al g orit h m a n d c om p lia nce with t he T T T 
alg ori t h m at 6, 8, a n d 1 2 wee ks.
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.

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9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patient who have entered this study and 
for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patient during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs. Investigators should 
record their assessment of the potential relatedness of each AE to study procedure,
investigational product and study device via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies. 
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

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

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9.2.2. Adverse Event 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 (ET visit or 801).  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 (Section 2).  Site 
personnel will enter this information into the hypoglycemia 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 BG 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) in accordance with the 2020 ADA 
position statement on glycemic targets:
Level 1 hypoglycemia:
Glucose <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 mmol/L): Level 1 hypoglycemia 
can alert a person to take action such as treatment with fast-acting carbohydrates. Providers 
should continue to counsel particpants to treat hypoglycemia at this glucose alert value.
Level 2 hypoglycemia:  
Glucose <54 mg/dL (3.0 mmol/L):  This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence of absence of symptoms of hypoglycemia.
Level 3 hypoglycemia:  
Severe hypoglycemia (in adults): A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia.  For example, 
participants had altered mental status, and could not assist in their own care, or were
semiconscious or unconscious, or experienced coma with or without seizures, and the 
assistance of another person was needed to actively administer carbohydrate, glucagon, or 
other resuscitative actions. Glucose measurements may not be available during such an 
event, but neurological recovery attributable to the restoration of glucose concentration to
normal is considered sufficient evidence that the event was induced by a low glucose 
concentration.

The determination of a hypoglycemic event as an episode of severe 
hypoglycemia, as defined above, is made by the investigator based on the medical 
need of the participant to have required assistance and is not predicated on the 
report of a participant simply having received assistance.

If a hypoglycemic event meets the criteria of severe hypoglycemia, the 
investigator must record the event as serious on the AE CRF and report it to Lilly 
as an SAE.

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N oct ur n al h y p o gl yce mi a :
N oct ur nal h y p o gl yce mia is a h y p o gl yce mia e ve nt (i ncl u di n g se vere h y p o gl yce mia) t hat occ urs 
at ni g ht a n d pres u ma bl y d uri n g slee p.  
T o a v oi d d u plicate re p orti n g, all c o nsec uti ve B G val ues < 3. 9 m m o l/ L occ urri n g wit hi n a 1-h o ur 
peri o d ma y be c o nsi dere d t o be a si n gle h y p o gl yce mic e ve nt ( Wei n ber g et al. 2 0 1 0; Da n ne et al. 
2 0 1 3 ;  A D A . 2 0 2 0 ).  
I n eac h case of s us pecte d or c o nfir me d h y p o gl yce mia, it is i m p orta nt t hat t he e ve nt be pr o perl y 
cate g orize d, t he effect of t he i nter ve nti o n be assesse d, a n d t he fre q ue nc y of h y p o gl yce mia be 
e val uate d.  T he r ole of dietar y c ha n ges a n d p h ysical e xercise ( or a n y ot her c o ntri b ut i n g fact or) i n 
t he de vel o p me nt of a n e ve nt s h o ul d be esta blis he d.  T he patie nt s h o ul d recei ve a d dit i onal 
e d ucati o n, if dee me d a p pr o priate.  Ma na ge me nt of i ncrease d ris k of h y p o gl yce mia is descri be d 
i n S e cti o n 7. 7. 5. 2 a n d Secti o n 8. 1. 1 .  It is i m p orta nt t hat eac h case of s us pecte d or c o nfir me d 
h y p o gl yce mia be pr o perl y  cate g oriz e d wit h res pect t o se verity.  
9. 2. 2. 2.
S e v er e, P er si st e nt H y p er gl y c e mi a
Se vere, persiste nt h y per gl yce mia will be c ollecte d as a n A E d uri n g t he trial t o assess t he ris k of 
e xtre me i m bala nce i n gl yce mic c o ntr ol, as defi ne d i n Secti o n 7. 7. 5. 3 .  Details of 
a nt i h y per gl yce mic me dicati on i nitiate d as resc ue t hera p y f or se vere, persiste nt h yper gl yce mia 
per t hese criteria will be c o llecte d o n t he a nti h y per gl yce mic c o nc omit a nt t hera p y e C R F.
9. 2. 2. 3.
P a n cr e atiti s
Ac ute pa ncreat itis is defi ne d as a n A E of i nterest i n all trials wit h d ula gl ut i de, i ncl u di n g t his trial. 
Ac ute pa ncreat itis is a n ac ute i nfla m mat or y pr ocess of t he pa ncreas t hat ma y als o i n v ol ve 
p eri pa ncreat ic tiss ues a n d/ or re m ote or ga n s yste ms ( Ba n ks a n d Free ma n 2 0 0 6). T he di a g n osis of 
ac ute pa ncreatit is re q uires 2 of t he f oll owi n g 3 feat ures:

a b d o mi nal pai n, c haracterist ic of ac ute pa ncreatitis ( ge nerall y l ocate d i n t he 
e pig astri u m a n d ra di ates t o t he bac k i n a p pr o xi matel y half t he cases [ Ba n ks 
a n d Free ma n 2 0 0 6; K oiz u mi et al. 2 0 0 6 ]; t he pai n is ofte n ass ociate d wit h 
na usea a n d v o mit i n g);

ser u m a m ylase (t otal a n d pa ncreat ic) a n d/ or li pase ≥3 × U L N ;

c haracterist ic fi n di n gs of ac ute pa ncreatitis o n c o m p ute d t o m o gra p h y ( C T);
sca n or ma g netic res o na nce i ma gi n g ( M RI).
If ac ute pa ncreatitis is s us pecte d, a p pr o priate la b orat or y tests (i ncl u di n g le vels of pa ncreatic 
a m ylase a n d li pase) s h o ul d be o btai ne d via t he ce ntral la b orat or y  (a n d locall y, if nee de d). 
I ma gi n g st u dies, s uc h as a b d o mi nal C T sca n wit h or wit h o ut c o n tr ast, M RI, or gall bla d der 
ul tras o u n d, s h o ul d be perf or me d.  If la b orat or y val ues a n d/ or a b d o mi nal i ma gi n g s u p p ort t he 
di a g n osis of ac ute pa ncreat itis, t he patie nt m ust disc o nti n ue t hera p y with i n vesti gati onal 
pr o d uct ,b ut will still c o nti n ue i n t he st u d y o n a not h er gluc ose -l oweri n g re gi me n (see Secti o n 
7. 7. 1 a n d Secti o n 8. 1. 1 f or details o n t he i ntr o d ucti o n of ne w a nti h y per gl yce mic i nter ve nti o ns).  
T he m ost a p pr o pri at e dia betes t hera pe utic re gi me n will be deci de d b y t he i n vest i gat or, base d o n 

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
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L Y 2 1 8 9 2 6 5
t he patie nt’s cli nical stat us.  A re vie w of t he patie nt’s c o nc o mita nt me dicati ons s h o ul d be 
c o n d ucte d t o assess a n y p ote ntial ca usal relat i ons hi p wi t h pa ncreatitis.
Eac h case o f A E of pa ncreat itis m u st be re p orte d. If ty p ical si g ns a n d/ or s y m pt o ms o f 
pa ncreat itis are prese nt an d c o nfir me d b y la b orat or y val ues (li pase or a m ylase [t otal a n d/ or 
pa ncreat ic]) a n d i ma gi n g st u dies, t he e ve nt m ust be re p orte d as a n S A E. F or a p ote ntial case t hat 
d oes n ot m eet all of t hese criteria, it is u p t o t he i n vesti gat or t o deter mi ne t he seri o us ness of t he 
case ( A E or S A E) a n d t he relate d ness o f t he e ve nt t o st u d y dr u g.
E ac h patie nt will ha ve meas ure me nts of pa ncreat ic a m ylase a n d li pase (assesse d at t he ce ntral 
la b orat or y) as s h o w n o n t he Sc he d ule of Acti vities( Secti o n 2 ), t o assess t he effects of t he 
i n vesti gati onal d oses of d ula gl uti de o n pa ncreat ic e nz y me le vels.  S eri al meas ures of pa ncreat ic 
e nz y mes ha ve li mite d cli nical val ue f or pre dict i n g e pis o des of ac ute pa ncreatit is i n as y m pt o matic 
pati e nts ( Na uc k et al. 2 0 1 7; Stei n ber g et al. 2 0 1 7a; Stei n ber g et al. 2 0 1 7 b).  T h us, f urt her f oll ow-
u p of cases of as y m pt o mat ic pa ncreatic h y pere nz y me mia (li pase a n d/ or pa ncreat ic a m ylase 
≥3 × U L N) is n ot m a n date d, b ut ma y be perf or me d base d o n t he i n vest i gat or’s cli nical j u d ge me nt 
a n d assess me nt of t he patie nt’s o verall cli nical c o n dit i on .  
All s us pecte d cases of  ac ute or c hr o nic pa ncreatitis will be a dj u dicate d b y  a n i n de pe n de nt 
c o m mittee of e x pert p h ysicia ns. O nl y cases of pa ncreatic h y pere nz y me mia t hat u n der g o 
a d ditio nal  di a g n ostic fol l ow- u p a n d/ or are acc o m pa nie d b y s y m pt o ms s u g gest i ve of pa ncreatitis 
will be s u b mitte d f or a dj u dicat i on. I n a d diti on, A Es of se vere or seri o us a b d o mi nal pai n o f 
u n k n o w n et i ol og y  will als o be s u b mitte d t o t he a dj u dicati on c o m mit tee t o assess f or p ossi ble 
pa ncreat itis or ot her pa ncreatic di sease. Rele va nt data fr o m patie nts wit h ac ute or c hr o nic 
pa ncreat itis a n d t hos e wi t h se vere or seri o us a b d o mi nal pai n will  be e ntere d i nt o a s pecificall y 
desi g ne d e C R F pa ge b y st u d y  site or Lill y st aff. T he a dj u dicat i on c o m mittee re prese ntati ve will 
e nter t he res ults of a dj u dicat i on i n a c orres p o n di n g e C R F pa ge.
9. 2. 2. 4.
C- C ell H y p er pl a si a a n d C -C ell N e o pl a s m s
I n di vi d uals wit h pers o nal or famil y hist or y  of certai n t h yr oi d or n o nt h yr oi d e n d ocri ne 
a b n or malities or certai n pree xist i n g la b orat or y a n d ge netic c haracteristics will be e xcl u de d fr om 
t he st u d y (see Sectio n 6. 2 ).  Patie nts wit h a pers o nal or fa mil y hist or y  of M T C or pers o nal 
hist or y  of M E N 2 s y n dr o me, or w h o ha ve ser u m calcit o ni n ≥2 0 p g/ m L at st u d y  e ntr y as 
deter mi ne d b y t he ce ntral la b orat or y  will be e xcl u de d.  T he assess me nt of t h y r oid safet y d uri n g 
t he trial will i ncl u de re p orti n g of t h yr oid treat m e nt -e mer ge nt a d verse e ve nts ( T E A Es) a n d 
meas ure me nts of calcit o ni n acc or di n g t o t he Sc he d ule of Act i vities (Secti o n 2 ).  T he p ur p ose of 
calcit o ni n meas ure me nts is t o assess t he p ote ntial of d ula gl uti de t o affect t h yr oi d C-cell f u ncti o n, 
w hic h ma y  in dicate de vel o p me nt of C -cell h y per plasia a n d ne o plas m s.  
P ati e nts w h o de vel o p ser u m calcit o ni n i ncreases ≥5 0 % of t he scree ni n g val ue A N D a n a bs o l ute 
val ue ≥2 0 p g/ m L a n d < 3 5 p g/ m L at Visit 1 7 ( Wee k 2 8 ) will be as ke d t o re peat t he meas ure me nt 
wi t hi n 1 mo n t h.  If t his re peat val ue is i ncreasi n g (≥1 0 % i ncrease) , t he patie nt will be e nc o ura ge d 
t o u n der g o a d diti onal e n d ocri ne assess me nt a n d l o n ger -t er m fol l ow -u p b y a n e n d ocri n o l ogist t o 
e xcl u de a seri o us a d verse effect o n t he gla n d.  

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Patients with an increase in serum calcitonin ≥50% of screening value AND an absolute value 
≥35 pg/mL at Visit 17 (Week 28) will be recommended to immediately undergo additional 
endocrine assessments and longer term follow-up by an endocrinologist.
For patients who require additional endocrine assessment because of increased calcitonin 
concentration per criteria provided in this section, data from the follow-up assessment will be 
collected in the specific section of the eCRF.
9.2.2.5.
Cardiovascular Events
Vital signs (PR, SBP, DBP) will be monitored throughout the study, and 12-lead 
electrocardiograms (ECGs) will be monitored at screening and Visit 17 (Week 28). Any 
clinically relevant finding from vital signs and ECGs obtained before the first dosing of study 
drug that results in a diagnosis should be recorded in eCRF as a preexisting condition and 
medical history. Any clinically relevant finding from vital signs and ECGs that occurs after the 
first dosing of study drug and results in a diagnosis should be recorded as an AE in eCRF. CV 
events will be analyzed using preferred terms and abnormal ECG result.
Deaths will be monitored throughout the study. Relevant data from patients who experienced 
death will be entered into a specifically designed eCRF page by study site.
9.2.2.6.
Allergic/Hypersensitivity Reactions
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 the eCRF for any AEs or SAEs deemed related to study drug by 
the investigator.  Injection site reactions will be collected on an eCRF separate from the 
hypersensitivity reaction eCRF.  Study drug should be temporarily interrupted in any individual 
suspected of having a severe or serious allergic reaction to study drug (Section 8.1.2).  Study 
drug may be restarted when/if it is safe to do so, in the opinion of the investigator.  It is 
recommended that patients who experience a systemic hypersensitivity reaction be treated per 
the local standard of care.  In the case of generalized urticaria or anaphylaxis, additional blood 
samples might be collected per investigator’s judgement to diagnose and treat the event at local 
hospital.
If study drug is permanently discontinued, the patient will receive another glucose-lowering 
treatment, judged by the investigator to be appropriate based on the patient’s clinical status, and 
will continue in the trial to collect all planed efficacy and safety measurements (see Sections 
7.7.1 and 8.1.1).
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.

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9.3.
Treatment of Overdose
Study drug overdose will be reported as an AE. In the event of overdose, refer to the IB and/or 
Product Labels.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, single 12-lead ECG will be conducted at screening and at week 28 per the 
Schedule of Activities (Section 2).  The patient must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.  Electrocardiograms 
must be recorded before collecting any blood for safety tests.  Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the investigational site.
Electrocardiograms will 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, to determine whether the patient meets entry criteria and for immediate 
patient management, should any clinically relevant findings be identified.  Any clinically 
relevant findings from ECGs obtained before the first dose of study drug that result in a 
diagnosis should be reported as a preexisting condition and medical history.  
After enrollment, if a clinically significant finding is identified from the additional ECGs 
conducted at the discretion of the investigator (including but not limited to changes in QT/QTc 
interval from baseline), the investigator will determine if the patient can continue on study drug.  
The investigator or qualified designee is responsible for determining if any change in patient 
management is needed and must document his/her review of the ECG printed at the time of 
collection.  Any clinically relevant 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 eCRF.
9.4.2. Vital Signs
Sitting BP and PR will be measured using standardized equipment provided by the Sponsor 
according to the Schedule of Activities (Section 2).  Vital sign measurements should be taken 
before obtaining an ECG tracing and before collection of blood samples for laboratory testing, at 
visits where required (see Schedule of Activities Section 2). The patient should be allowed to sit 
quietly for 5 minutes before vital sign measurements.  An appropriately sized cuff (cuff bladder 
encircling at least 80% of the arm) should be used to ensure the accuracy of BP measurements.  
The arm used for the BP measurement should be supported at heart level.  At Visit 1 (screening), 
to determine which arm should be used to collect BP and PR throughout the study. BP and PR
will be measured once in each arm and the arm that had the higher BP should be used to collect 
all 2 measurements of both BP and PR at all study visits.  For each parameter (PR, SBP/diastolic 
blood pressure [DBP]), 2 measurements will be taken using the same arm; the recordings should 

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be taken at least 1 minute apart.  Each measurement of sitting PR and BP is to be recorded in the 
eCRF.  Any AE related to changes in BP and PR should be reported.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product(s) should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.4. Body Weight, Height, and Body Mass Index
Body weight will be measured at prespecified time points (see Schedule of Activities, Section 2).  
Each patient’s weight should be measured according to a standardized protocol.  Body mass 
index will be computed from the patient’s weight and height.
9.4.5. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
Specific safety measures are included in the protocol to ensure appropriate monitoring of 
pancreatic (Section 9.2.2.3), thyroid (Section 9.2.2.4), and liver safety (Section 9.4.5.1).  
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring board (an advisory group for this study 
formed to protect the integrity of data; refer to Interim Analyses section (Section 10.3.8) can 
conduct additional analyses of the safety data.
9.4.5.1.
Hepatic Safety Monitoring
Close Hepatic Monitoring
Laboratory tests (Appendix 4), including ALT, AST, ALP, TBL, direct bilirubin (D. Bil), gamma-
glutamyltransferase (GGT), and creatine kinase (CK), should be repeated within 48 to 72 hours 
to confirm the abnormality and to determine if it is increasing or decreasing, if one or more of 
these conditions occur:
If a participant with baseline 
results of ... 
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN
ALP <1.5x ULN
ALP ≥2x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for patients with 
Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline

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TBL ≥1.5x ULN
TBL ≥2x baseline (except for patients with 
Gilbert’s syndrome)
Abbreviations:  ALT = alanine aminotransferase;  AST = aspartate aminotransferase; ALP = alkaline phosphatase;  
ULN= upper limit of normal;  TBL = total bilirubin
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive Hepatic Evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:
If a participant with baseline 
results of... 
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN with hepatic signs/symptoms*, or
ALT or AST ≥5x ULN
ALP <1.5x ULN
ALP ≥3x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline with hepatic signs/symptoms*, or
ALT or AST ≥3x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥1.5x baseline (except for patients with Gilbert’s 
syndrome) 
Abbreviations:  ALT = alanine aminotransferase;  AST = aspartate aminotransferase; ALP = alkaline phosphatase;  
ULN= upper limit of normal;  TBL = total bilirubin
Note: * Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, 
rash, and/or eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 

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Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and serum phosphatidylethanol.  Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.  
Additional hepatic data collection (hepatic safety CRF) in study 
participants who have abnormal liver tests during the study
Additional hepatic safety data collection in hepatic safety case report forms (CRF) should be 
performed in study participants who meet 1 or more of the following 5 conditions:
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline ALT 
<1.5x ULN)

In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x 
baseline on 2 or more consecutive tests
2. Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome)

In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL 
≥2x baseline
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline ALP 
<1.5x ULN)

In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x 
baseline on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the two consecutive blood tests should be at least 2 days.
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Biomarkers
Not applicable.

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9.9.
Health Outcome
The 3 questionnaires listed below will be completed by the patients per the Schedule of 
Activities (Section 2); these are considered exploratory objectives of the study.  The 
questionnaires will be given to the patient by the investigator or site personnel and self-
completed by the patient during the visit.  The investigator or site personnel will be responsible 
for checking for missing responses before the patient leaves the site.  The questionnaires 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 visit 
procedures.
9.9.1. EuroQol 5-dimension 5-level (EQ-5D-5L)
Generic HR-QoL will be assessed using the EQ-5D-5L (EQ-5D; EuroQoL Group 2015).  The 
EQ-5D-5L is a standardized 5-item instrument for use as a measure of health outcome.  It 
provides a simple descriptive profile and a single index value for health status that can be used in 
the clinical and economic evaluation of health care as well as population health surveys.  The 
EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3251 possible health states.  In addition to the 
health profile, a single health state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension.  This index value ranges between less than 0 
(where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1
(perfect health).  In addition, the EQ Visual Analog Scale records the respondent’s self-rated 
health status on a vertical graduated (0 to 100) visual analog scale.  In conjunction with the 
health state data, it provides a composite picture of the respondent’s health status.  
The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015).
9.9.2. Impact of Weight on Self-Perception (IW-SP)
The IW-SP questionnaire contains 3 items that assess how often 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).  Items are scored on a 5-point numeric rating scale, where 5 
= never and 1 = always.  Overall score is calculated by summing the scores of the 3 items and 
dividing by the number of items (3).  Overall score ranges from 1 to 5.  Transformed overall 
score is obtained by linearly transforming the raw overall score to a 0 to 100 scale.  Higher 
overall score and higher transformed score are indicative of better self-perception.
The IW-SP will be completed by the patients at Visits 3 (Week 0), 12 (Week 12), 17 (Week 28), 
and ET per the Schedule of Activities (Section 2).

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9.9.3. Medication Delivery Device Assessment Battery (MDDAB)
The MDDAB was developed for use in Study H9X-MC-GBDZ (GBDZ) to evaluate patient 
perceptions regarding use and specific features of the SUP.  Modules of the MDDAB that are 
relevant to the current study and appropriate for administration to an injection-experienced 
population will be administered:

Module 1, SUP ease of use:  The ease of use module comprises 12 items evaluating overall 
ease of using the SUP device and ease of using specific SUP device features.  Patients will 
be instructed to complete this module thinking about their weekly injection device (ie, the 
SUP) only.  The module will be administered at Visits 8 (Week 6), 17 (Week 28), and ET, as 
per the Schedule of Activities (Section 2).  

Module 2, SUP device features:  The device features module comprises 13 items evaluating 
the degree to which patients like or dislike specific features of the SUP device.  Patients will 
be instructed to complete this module thinking about their weekly injection device (ie, the 
SUP) only.  The module will be administered at Visits 8 (Week 6), 17 (Week 28), or ET, as 
per the Schedule of Activities (Section 2).  

Module 3a, SUP experience:  The SUP experience module (a) comprises 5 items evaluating 
patient experience with the SUP device; specifically assessing convenience, satisfaction, 
pain, and confidence.  Patients will be instructed to complete this module thinking about 
their weekly injection device (ie, the SUP) only.  Module 3a will be administered at Visit 8 
(Week 6) only, per the Schedule of Activities (Section 2).

Module 3b, SUP experience:  The SUP experience module (b) comprises 8 items, 
collectively evaluating patient experience with the SUP device.  Module 3b includes the 
same 5 items as Module 3a plus items pertaining to willingness to continue using the device 
and willingness to recommend the device to someone else.  Patients will be instructed to 
complete this module thinking about their weekly injection device (ie, the SUP) only.  
Module 3b will be administered at Visit 17 (Week 28) or ET only, per the Schedule of 
Activities (Section 2).

Module 4, Glargine delivery device experience:  The glargine delivery device experience 
module is similar to SUP experience module 3b, differing only in its instructions to the 
patient.  This version will instruct patients to complete the questions according to their 
experience with the daily (ie, glargine) device.  Module 4 will be administered at Visit 17 
(Week 28) or ET only, as per the Schedule of Activities (Section 2). 
At Visit 17 (Week 28) or the ET visit, patient completion of modules 3b and 4 will be arranged 
to minimize bias; additional details will be provided in the SAP.

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10. Statistical Considerations
10.1. Sample Size Determination
A total of approximately 290 patients (145 per group) will be randomized to have approximately 
246 completers (123 per group) to show dulaglutide as add-on to titrated insulin glargine is
superior to placebo as add-on to titrated insulin glargine with 90% power assuming a treatment 
difference of 0.5% in HbA1c reduction, standard deviation (SD)=1.2%, dropout rate of 15%, and 
2-sided alpha of 0.05.  The screen failure rate is estimated as 40%.  Approximately 483 patients 
will be screened.
10.2. Populations for Analyses
Table GBGO.6 defines the populations to be used for analyses.
Table GBGO.6.
Populations for Analyses
Population
Description
Entered
All patients who sign informed consent
Randomized
All patients who are randomized to a treatment arm
Nonrandomized
All patients entered, but not randomized to a treatment arm
Intent-to-treat (ITT)
All patients randomized who take ≥1 dose of study medication for assigned 
treatment arm
Completers
All patients in the ITT population who complete the treatment period (that is, 
do not discontinue early from the study).  Data after initiation of rescue therapy 
will be censored for the efficacy analyses.

Note:  There is no requirement that completers have to be on study 
drug the entire study.  
Per-Protocol (PP)
All patients in ITT and who also meet the following criteria:

Have no protocol deviations expected to impact the primary endpoint 
for HbA1c;

Complete the treatment period (28 week [Visit 17]) for primary 
endpoint (that is, do not discontinue from the study drug early)
Abbreviations: HbA1c = hemoglobin A1c.
Note:  The full list will be defined in the Trial issue management plan..
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 will be conducted as deemed appropriate.
Unless otherwise specified, listings will include all randomized patients.  Both efficacy and 
safety analyses will be conducted using the intention to treat (ITT) population. Unless otherwise 

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specified, efficacy data from patients who started rescue therapy or discontinued study treatment 
prematurely will be censored from the point of initiating rescue treatment or premature 
discontinuation onwards. Selected analyses will also be conducted using the PP and Completers 
populations.  The PP and Completers populations are subsets of the ITT population.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and CIs will be calculated at 95%, 2-sided.  All tests of interactions between treatment 
groups and other factors will be conducted at a 2-sided alpha level of 0.10.  
The baseline will be at the randomization visit (Visit 3).  If baseline data are missing, the last 
nonmissing measurement taken prior to Visit 3 will be used.
The primary and key secondary continuous efficacy measures will be analyzed with mixed-
model repeated measures (MMRM) using restricted maximum likelihood (REML) (Section
10.3.3.1).  The model will include factors for treatment, OAM usage (metformin alone, acarbose 
alone, metformin and acarbose), visit, and treatment-by-visit as fixed effects, baseline as a 
covariate, and patient as random effect.  An unstructured covariance structure will be used to 
model the within-patient variability.  If this model fails to converge, the following covariance 
structures will be tested in order:

Toeplitz with heterogeneity

Autoregressive with heterogeneity, by visit

Compound symmetry with heterogeneous variances, by visit 

Toeplitz

Autoregressive

Compound symmetry without heterogeneous variances, by visit
The first covariance structure that converges will be used.
The proportion of patients achieving the target HbA1c of <7.0% will be analyzed using a 
longitudinal logistic regression with repeated measurements (Section 10.3.3.2).
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and change from baseline measurements.  Least-
squares mean (LS mean) and standard errors derived from the model will also be displayed for 
the change from baseline measurements.  Treatment comparisons will be displayed showing the 
treatment difference LS mean and the 95% CIs for the treatment differences along with the p-
values for the treatment comparisons.
For categorical measures, summary statistics will include sample size, frequency, and proportion.  
Fisher’s exact tests will be used for treatment comparisons .
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study.

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Frequency counts and proportion of all patients entered, randomized/enrolled, completing, 
discontinuing from the study and/or study drug early will be presented for each of the treatment 
groups.  The reasons for discontinuation from the study and/or study drug will be summarized by 
treatment group.  A summary of discontinuations will also be presented by visit.
The overall comparison of proportions of patients who discontinued between the treatment 
groups will be performed using a Fisher’s exact test.
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be summarized by treatment arms.  For 
continuous measures, summary statistics will include sample size, mean, median, maximum, 
minimum, and SDs along with an analysis of variance (ANOVA) to compare the means of the 2 
treatment groups .  For categorical measures, summary statistics will include sample size, 
frequency, and percent.  Frequencies will be analyzed using a Fisher’s exact test.
10.3.2.3. Concomitant Therapy
Concomitant medications, including previous therapy for diabetes, will be summarized by 
treatment groups.  Proportion of certain categories of concomitant medications will be analyzed 
using a Fisher’s exact test.
10.3.2.4. Treatment Compliance
Treatment compliance defined as taking at least 75% of required injections of study drug during 
specified study periods (see Section 7.6).  Overall compliance is defined as being at least 75% 
compliant with study drug for at least 75% of the visits.  The investigator will advise the patient 
that injections should be given weekly at approximately the same time of the day, on the same 
day of the week.  Compliance will be summarized by treatment arm, by visit and overall.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary outcome is the difference in HbA1c change from baseline between treatment groups 
based on the ITT population at the planned end of the treatment period of 28 weeks.  The 
analysis model will be a MMRM for HbA1c change from baseline to 28 weeks (Visit 17) in the 
ITT population with treatment, OAM use, visit and treatment-by-visit as fixed effects, baseline 
HbA1c as a covariate, and patient as a random effect.  
The analysis model, MMRM, will be repeated using the PP and Completers populations.  If the 
conclusion differs from that of the ITT population, the data and analyses will be further 
investigated.  
10.3.3.2. Secondary Analyses
The key secondary objectives include single endpoint (HbA1c of <7.0% or ≤6.5% at 28 weeks);
triple endpoint (HbA1c <7% and with no weight gain [<0.1 kg] at 28 weeks and without
documented symptomatic hypoglycemia [<3.0 mmol/L] during the miantenance period [Weeks 
12-28]); double endpoint (HbA1c <7% at 28 weeks and without documented symptomatic 
hypoglycemia [<3.0 mmol/L] during the miantenance period [Weeks 12-28]); and double 

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endpoint (HbA1c <7% and with no weight gain [<0.1 kg] at 28 weeks).  These endpoints will be 
analyzed using longitudinal logistic regression with repeated measurements.  The model will 
include independent variables of treatment, OAM usage (metformin alone, acarbose alone, 
metformin and acarbose), visit, and treatment-by-visit as fixed effects and baseline HbA1c as 
covariates.
The key secondary continuous efficacy measures (change from baseline in body weight and 
FBG) will be analyzed using MMRM.  The MMRM model will include independent variables of 
treatment, OAM usage (metformin alone, acarbose alone, metformin and acarbose), baseline
HbA1c stratum (<8.5% vs. ≥8.5%), visit, and treatment-by-visit as fixed effects and baseline 
dependent variable as covariates.
For analysis of the other continuous secondary efficacy measures (change from baseline in BG, 
insulin dose), MMRM will be performed using the ITT population.  The MMRM models will 
include the model terms given for the previously described primary analysis model.  There will 
be no multiplicity adjustment for pairwise comparisons.
10.3.3.3. Tertiary/Exploratory Analyses
The number of insulin dose assessments per the TTT algorithm, compliance with the TTT 
algorithm (number of assessments performed correctly, number of assessments that required 
dose change, number of assessments for which the outcomes were correctly followed by the 
patient, and reason the outcomes of assessments were not followed by the patient) and frequency 
of insulin dose adjustments will be analyzed using an ANOVA model, including treatment, 
OAM usage (metformin alone, acarbose alone, metformin and acarbose), and baseline HbA1c 
stratum.
The other objectives include triple endpoint (HbA1c <7% and no weight gain [<0.1 kg] at 28 
weeks, and no documented symptomatic hypoglycemia [BG <3.9 mmol/L] during the 
maintenance period); double endpoint (HbA1c <7% at 28 weeks and no documented 
symptomatic hypoglycemia [BG <3.9 mmol/L] during the maintenance period); Proportion of 
patients achieving HbA1c target <7.0% and without weight gain (<0.1 kg) at 28 weeks.
Furthermore, we will conduct some additional efficacy analysis without censoring the data after 
rescue therapy or premature treatment discontinuation (whichever occurs first). Missing 
endpoints will be imputed by jumping to the reference method. Measurements include actual 
HbA1c, body weight and FSG and frequency counts and percentage of patients achieving the 
HbA1c target of <7.0% and changes in these measures from baseline. We will analyze HbA1c, 
body weight and FSG by ANCOVA. Percentages of patients achieving the target of HbA1c 
<7.0% will be analyzed using longitudinal logistic regression with repeated measurements.
10.3.4. Safety Analyses
The safety analysis will include analysis of AEs, SAEs, hypoglycemic and hyperglycemic 
episodes, vital signs, electrocardiogram and laboratory analyses.  Unless otherwise specified, the 
ITT population will be used for analyses of safety measures.

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10.3.4.1. Study Drug Exposure
Exposure to each study treatment will be calculated for each patient and summarized by 
treatment group.
10.3.4.2. Adverse Events
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported in preferred term and system organ class (SOC).  Selected 
notable AEs of interest may be reported using high-level terms.  All AEs and treatment-emergent 
adverse events (TEAEs), defined as post-baseline events that are new events or preexisting 
conditions that worsened in severity after randomization, will be listed by patient and visit.  
Information on treatment, actual term, preferred term, severity, seriousness, and relationship to 
study drug will also be reported.
Summary statistics will be provided for TEAEs, SAEs, and study and study drug 
discontinuations due to AEs or death during the treatment period.  Counts and proportions of 
patients experiencing AEs will be reported for each treatment group, and Fisher’s exact tests will 
be used to compare the treatment groups.
Summaries (if appropriate) of AESI defined in Section 9.2.2 will be generated.
10.3.4.3. Hypoglycemic Episodes
Section 9.2.2.1 contains definitions of categories of hypoglycemia. A listing of individual 
hypoglycemic episodes by patient will be presented.  Summary reports will include both 
incidence and rates of hypoglycemia for the ITT population (with post-rescue data censored).  
Categories of hypoglycemia for analysis include “documented”, “documented symptomatic”, 
“severe hypoglycemia”, and “nocturnal”.
Hypoglycemic episodes will be analyzed using 2 hypoglycemic thresholds:  Level 1 (glucose 
alert level, <3.9 mmol/L [70 mg/dL] and ≥3.0 mmol/L [54 mg/dL]) and Level 2 (clinically 
significant hypoglycemia level, <3.0 mmol/L [54 mg/dL]).  Other categories, including the 
categories above defined with different glucose thresholds, may also be included in these 
analyses when deemed appropriate.
The incidence of hypoglycemic episodes will be summarized by frequencies and proportion for 
each treatment group, by visit as well as overall.  Treatment differences in the incidence of 
hypoglycemic episodes will be assessed using Fisher’s exact tests.  Treatment differences in rates 
of hypoglycemic episodes (episodes/patient/30 days; episodes/patient/year) will be analyzed 
using a generalized linear mixed-effects model assuming negative binomial distribution.  The 
model will include treatment, OAM usage (metformin alone, acarbose alone, metformin and 
acarbose), baseline HbA1c stratum (<8.5% vs. ≥8.5%), visit, treatment-by-visit interaction, and 
baseline hypoglycemia rate.  The logarithm of days between visits will be included as an offset 
to account for possible unequal duration between visits and between patients.  
10.3.4.4. Severe, Persistent Hyperglycemia
Listings and summaries (if appropriate) will be provided for patients with at least one event of 
severe, persistent hyperglycemia.

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Time to initiation of rescue therapy due to severe, persistent hyperglycemia will be analyzed 
using the semiparametric proportional hazard Cox model with treatment, and OAM use as fixed 
effects and baseline HbA1c as a fixed covariate.  The proportions of patients initiating rescue 
therapy due to severe, persistent hyperglycemia will be analyzed using Fisher’s exact tests.  
10.3.4.5. Vital Signs
The average value of the 2 sitting vital sign measurements will be used for analyses.  
Descriptive statistic for the actual measurements and changes from baseline for SBP, DBP and 
PR will be presented by treatment and visit on the ITT population. 
10.3.4.6. Electrocardiogram
Descriptive statistics for the absolute measurements, changes from baseline, and clinically 
relevant changes for selected ECG parameters will be defined in the SAP.
10.3.4.7. Laboratory Analyses
Laboratory measurements will be listed by patient and visit.  An additional listing will be 
presented for laboratory measurements that are outside the normal range.
Laboratory measurements will also be summarized.  For continuous (numeric) laboratory 
analytes, the change from baseline to endpoint will be analyzed using an ANOVA on the rank-
transformed data, with treatment as fixed effects.  Last observation carried forward will be used 
to impute missing post-baseline values.
For subjective (qualitative) laboratory analytes, counts and proportions of patients with normal 
and abnormal values will be analyzed using Fisher’s exact tests.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.6. Evaluation of Immunogenicity
Not applicable.
10.3.7. Other Analyses
10.3.7.1. Health Economics
Continuous measures from the patient reported outcomes (PRO) instruments will be analyzed 
using the ANCOVA model specified in Section 10.3.1, using on-treatment without rescue data.
Categorical measures from the PRO instruments will be summarized for each treatment.
10.3.7.2. Subgroup Analyses
Subgroup analyses of treatment interaction with important factors may be conducted for the 
primary endpoint of HbA1c. The model for the primary analysis will be an MMRM utilized by 
adding addtional factors of subgroup, subgroup by treatment, subgroup by visit and treatment by 
subgroup by visit when accessing the treatment by subgroup interaction.  If the subgroup is one 
of the stratification variables, then the subgroup will only be included once in the model.

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The following are candidate subgroups that might be analyzed.  This list is not necessarily all-
inclusive:

Sex

Baseline age group (<65 years, ≥65 years)

Duration of diabetes at baseline (<median duration and ≥median duration)

BMI at baseline (<median and ≥median))

Baseline HbA1c (<8.5%, ≥8.5%)

Baseline fasting glucose (by quartile)

OAM usage (metformin alone, acarbose alone, metformin and acarbose), if more than 
25% of the total patients 
10.3.8. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.

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Garratt AM, Schmidt L, Fitzpatrick R. Patient-assessed health outcome measures for diabetes: a 
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patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014; 2(11):885-893.
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Pfalzgraf AR, Nau DP. The relationship of diabetes symptoms and health-related quality of life. 
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(AWARD-9). Diabetes Obes Metab. 2017;19(7):1024-1031
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using a basal-bolus regimen in a randomized, controlled clinical study in patients with a type 2 
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target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 
diabetic patients. Diabetes Care. 2003;26(11):3080-3086.
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hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with 
human NPH insulin in patients with type 2 diabetes. Diabetes Care. 2005;28(4):950-955.
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SL, Stewart MW, Leiter LA; Harmony 6 Study Group. Advancing basal insulin replacement in 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
American Diabetes Association
adjudication 
committee
An external committee whose purpose is to evaluate study data and decide whether a 
study endpoint or other criterion has been met.
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.
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BG
blood glucose
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BMI
body mass index
BP
blood pressure
CI
confidence interval
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease-Epidemiology

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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.
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.
CSR
clinical study report
CT
computed tomography
CV
cardiovascular
D.Bil
direct bilirubin
DBP
diastolic blood pressure
DPP-4
dipeptidyl peptidase-4
EASD
European Association for the Study of Diabetes
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 trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D-5L
EuroQol 5-dimension questionnaire
ERB
Ethics Review Board
ET
early termination
fasting
Abstaining from food and drink (except water) for approximately 8 hours (typically, 
overnight), no significant physical activity and non administration of glucose-lowering 
agents during this period
FBG
fasting blood glucose
FDA
Food and Drug Administration
FSG
fasting serum glucose
FSH
follicle-stimulating hormone
GAD
glutamic acid decarboxylase

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GCP
good clinical practice
GGT
gamma glutamyl transferase
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
hemoglobin A1c
IB
Investigator’s Brochure
ICA
islet cell antibodies
ICF
informed consent form
ICH
International Conference on Harmonisation
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the complete reporting database is created/locked for the 
primary endpoint.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the 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.
IW-SP
Impact of Weight on Self-Perceptions Questionnaire
IWRS
interactive web-response system
LS mean
least-squares mean
MDDAB 
Medication Delivery Device Assessment Battery
MedDRA
Medical Dictionary for Regulatory Activities
MEN
multiple endocrine neoplasia 
MI
myocardial infarction
MMRM
mixed-model repeated measures
MRI
magnetic resonance imaging

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MTC
medullary thyroid carcinoma
NAFLD
nonalcoholic fatty liver disease  
NOAEL
no-observed-adverse-effect level
NPH
neutral protamine Hagedorn
OAM
oral antihyperglycemic medication
OTC
over-the-counter
PD
pharmacodynamic
PK
pharmacokinetics
PP
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.
PR
pulse rate
PRO
patient reported outcome
QD
once daily
QW
once weekly
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
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
SUP
single-use pen
SGLT2
sodium-glucose co-transporter 2
SMBG
self-monitored plasma glucose
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
T1D
type 1 diabetes
T2D
type 2 diabetes 

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TBL
total bilirubin level
TE
treatment-emergent
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.
TTT
treat-to-target
ULN
upper limit of normal
USPI
United States Prescribing Information
VAS
Visual Analog Scale

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Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Testsa,c
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Gamma-glutamyl transferase (GGT)
Eosinophils
Blood urea nitrogen (BUN)
Basophils
Creatinine
Platelets
Creatine kinase (creatine phosphokinase; CPK) d
Uric acid
Urinalysis
Calcium
Albumin/creatinine ratio (urine)b
Glucose
Albumin
Endocrine
Calcitonin
eGFR (calculated by CKD-EPI equation)
Lipid Panel
Fasting glucose
Total cholesterol
LDLg
Pancreas (Exocrine)
HDL
Serum amylase, total and pancreatic
VLDL
Serum lipase
Triglycerides
HbA1c
Pregnancy test serum and urinee
Follicle-stimulating hormonef
Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; CK-MB = creatine kinase-MB; eGFR = 
estimated glomerular filtration rate; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein cholesterol; 
LDL = low-density lipoprotein cholesterol; RBC = red blood cells; WBC = white blood cells; VLDL = very low 
density lipoprotein cholesterol.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Urinary albumin and creatinine are measured; the ratio is calculated.
c
Additional blood samples may be collected based on the investigator’s judgment.
d
CK-MB is to be assayed if the creatine kinase result is >1000 IU/L.
e
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential; a 
urine pregnancy test must be performed at Visit 3.  Urine pregnancy tests may also be performed at the 
investigator’s discretion during the study.  A local laboratory may be used for urine pregnancy tests.
f
Follicle-stimulating hormone test performed at Visit 1 for potential postmenopausal women age 45 years or 
above with an intact uterus, not on hormone therapy or oral contraceptives, and who have had spontaneous 
amenorrhea for more than 6 months and less than 12 months and estradiol levels consistent with a 
postmenopausal state (FSH≥40 mIU/mL and estradiol <30 pg/mL).

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g  This value will be calculated.  If triglycerides >400 mg/dL, then direct LDL will be assayed.

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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 patient may 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 
Brochure (IB) and updates during the course of the study

informed consent form 

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, cardiology, nephrology, internal medicine, 
family medicine, general medicine, or any other specialty physician who has experience treating 
Type 2 Diabetes with clinical research experience will participate as investigators in this clinical 
trial.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
A qualified investigator will serve as the CSR coordinating investigator.  If this investigator is 
unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.

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Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the eCRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
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 eCRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the eCRF.
Additionally, clinical outcome assessment (COA) data (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 

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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.
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 H9X-MC-GBGO is described in the Clinical Research 
Agreement or Master Clinical Trial Agreement.

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Appendix 4.
Liver Safety: Suggested Actions and 
Follow-Up Assessments
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 9.4.5.1 for guidance on 
appropriate test selection.

For testing selected, analysis is required to be completed by the Lilly designated central laboratory except for 
those testings that are denoted as local below.

Local testing may be performed in addition to central testing when required for immediate patient 
management.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry  
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adducts c
Platelets
Alkaline Phosphatase Isoenzymes c
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper c
Ethyl Alcohol (EtOH)
Prothrombin Time, international normalized ratio 
(PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
    HAV Total Antibody
Immunoglobulin IgM (Quantitative)
    HAV IgM Antibody
Phosphatidylethanol (PEth) c
Hepatis B Virus (HBV) Testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug Screen
    Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG) c
    Hepatitis B core total antibody (Anti-HBc)
Other Serology

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    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA)
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a
    HBV DNA d
Anti-actin antibody c, b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody
    HCV RNA d
    EBV DNA d
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNA d
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA d
    HSV (Type 1 and 2) DNA c, d
Microbiology c
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
    Blood
    Urine
a
Not required if anti-actin antibody is tested.
b
Not required if anti-smooth muscle antibody (ASMA) is tested.
c
Assayed ONLY by investigator-designated local laboratory if available; no central testing available.
d
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.

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

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Appendix 6.
Classification of Contraceptive Methods
Highly Effective Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle).  
Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception

Vasectomy – for men in clinical trials
Effective Methods of Contraception (must use combination of 2 methods):

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide

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Appendix 7.
Protocol Amendment H9X-MC-GBGO(a)
Summary A Randomized, Double-Blind Trial Comparing 
the Effect of the Addition of Dulaglutide 1.5 mg versus 
the Addition of Placebo to Titrated Basal Insulin on 
Glycemic Control in Chinese Patients with Type 2 
Diabetes
Overview
Protocol H9X-MC-GBGO A Randomized, Double-Blind Trial Comparing the Effect of the 
Addition of Dulaglutide 1.5 mg versus the Addition of Placebo to Titrated Basal Insulin on 
Glycemic Control in Chinese Patients with Type 2 Diabetes has been amended.  The new 
protocol is indicated by amendment (a) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table. Minor typographical corrections not affecting the protocol content are not 
summarized in this appendix. 
Amendment Summary for Protocol H9X-MC-GBGO(a)
Section # and Name
Description of Change
Brief Rationale
Section 1. Synopsis
In the “Efficacy Analyses” part, the 
wording for analysis of body 
weight change was revised mainly 
by deleting "actual 
value/measurement” and “actual 
values”. 
The deletion was due to that the 
actual value or measurement is not 
a secondary endpoint.
Section 2. Schedule of Activities 
In Table GBGO.1., “Dispense study 
diary, instruct in use” was crossed
at Visit 17 with a new footnote 
added mentioning “Safety data to 
be captured after discontinuation of 
study drug during safety follow-up 
period.”
This new footnote is to explain why 
study diary needs to be dispensed at 
Visit 17.
Section 2. Schedule of Activities
In Table GBGO.1., the superscript
mentioning assessment of the 
patient’s compliance with insulin 
dose adjustment per TTT algorithm 
for “Laboratory tests” was deleted.
The superscript did not fit to 
“Laboratory tests”.
Section 2. Schedule of Activities
Section 5.1. Overall Design
Section 9.4.2. Vital Signs
The “heart rate” or “HR” was 
replaced by “pulse rate” or “PR”.
Per protocol, pulse rate instead of 
heart rate will be measured in the 
study.

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Section 4. Objectives and 
Endpoints 
For the fourth point in the 
exploratory efficacy part, “and 
without documented symptomatic 
hypoglycemia (BG ≤3.9 mmol/L) 
during the maintenance period 
(Weeks 12-28)” was deleted.
This semi-sentence was wrongly 
added here. Only the proportion of 
patients achieving HbA1c target of 
<7.0% and without weight gain 
(<0.1 kg) at 28 weeks will be 
investigated as planned. 
Section 5.1. Overall Design
In the 3rd paragraph, “mean” was 
deleted from the “mean FBG ≥5.6 
mmol/L” and wording was revised.
Since median FBG or mean FBG 
will be used for eligibility 
assessment, which depends on the 
number of FBG values collected 
prior to Visit 3 (Section 7.2.2.2.1), 
using “mean” is not accurate. 
Section 5.1. Overall Design
In the 3rd paragraph, the wording 
was revised to redefine the stability 
and range of metformin and 
acarbose dose
The previous description did not 
specifically define dose stability for 
metformin and acarbose, and the 
dose range was not accurate. 
Section 5.1. Overall Design
In the “Lead-in” part, “at the 
discretion of the investigator” was 
added to specify who determines 
the insulin dose adjustment 
regarding patient safety. 
The previous expression did not 
clarify explicitly who should be the 
one that determines insulin dose 
adjustment. 
Section 5.1. Overall Design
In the “Randomization” part, the 
wording for emphasizing that 
insulin dose assessment and 
adjustment should be done at least 3 
days before Visit 3 was revised
without changing the content
The previous expression is hard to 
be understood. 
Section 5.1. Overall Design
In the “Stabilization Period” and 
“Titration Period” parts, the buffer 
time presented in the brackets for 
Visits 6, 8 and 10 were revised 
from “7 days” to “4 days”.
The previous buffer time “7 days” 
was incorrect. As shown in Section 
2. Schedule of Activities, the 
correct buffer time should be 4 
days. 
Section 5.1. Overall Design
Section 7.2.2.2. Insulin Glargine
In the “Stabilization Period”, “not 
later than 7 days after the first 
dosing of study drug” was deleted 
for describing decrease in insulin 
glargine dose for patients with 
baseline HbA1c ≤8.0%.  Likewise, 
“(within 7 days)” was deleted in 
Section 7.2.2.2.
The deletions of “not later than 7 
days” and “within 7 days” were
suggested by the reviewer arguing 
that “it is difficult to see the 
rationale for the 7 day time window 
given, as the screening HbA1c can 
be used to adjust insulin dose and a 
second HbA1c measurement at 
randomization after only 2 weeks 
from the screening value does not 
really seem reasonable.”
Section 5.1. Overall Design
In the title for the titration period, 
“Weeks 5 to 28” in the bracket was 
revised to “Weeks 4 to 28”.
According to study period, Visit 6 
will take place at Week 4. The 
previous number 5 was incorrect. 

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Section 5.1 Overall Design
For “Titration Period”, the sentence 
“Any patient meeting criteria for 
severe, persistent hyperglycemia 
after 12 weeks of unrestricted 
insulin glargine dose adjustments 
will discontinue study drug and the 
study (see Section 7.7.5.3 for 
details)” was deleted.  
The contenct was in conflict with 
that in Section 7.7.5.3. 
Section 5.1. Overall Design
In the “Safety Follow-up (801)
Visit” part, the safety follow-up 
visit for patients who complete the 
treatment period will take place 
around 4 weeks after last visit 
instead of the previously written 
“after their last dose”. 
The last injection of study drug will 
be at Week 27. According to study 
design, the 4-week interval should 
be the one between the last visit and
safety follow-up visit. 
Section 5.4. Scientific Rationale for 
Study Design
Section 5.5. Justification for Dose
The TTT algorithm was adapted 
from Davies et al. (2005) instead of 
Riddle et al. (2003).
After evaluating comprehensive 
factors, such as the clinical practice
in China, insulin treatment 
consensus, the probability of 
achieving primary endpoint/study 
results, the previous study 
experience, and whether the 
algorithm is validated, the TTT 
algorithm similar as the one used in 
I4L-GH-ABET study, which 
referred to AT. LANTUS study, 
will be applied in this protocol after 
internal alignment, with 
modification to have a minimal 
increase in insulin for FBG 
>5.6mmol/L.
Section 6.1. Inclusion Criteria
Criterion 4 was revised with 
redefining the dose stability and 
range of metformin and/or 
acarbose.
The previous wording of Criterion 
4 was inaccurate. 
Section 6.1. Inclusion Criteria
Criterion 11[a] was revised with 
switching the positions of urine 
pregnancy test and serum 
pregnancy test.
The previous Criterion 11[a] was 
inconsistent with Section 2
regarding the sequence of 
pregnancy tests.
Section 6.1. Inclusion Criteria
A new inclusion criterion was 
added as Criterion [40] to include 
the requirement for male 
contraception. 
The criterion was to make the
contraception inclusion criteria 
more complete. 
Section 6.2. Exclusion Criteria
Criterion 15 was revised to exclude 
the patients with a history of severe 
hypoglycemia from the study.
This is a team decision. The 
revised criterion is in consistency 
with the one in GPHO protocol. 

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Section 6.2. Exclusion Criteria
Criterion 18 was revised to include 
patients with nonalcoholic fatty 
liver disease (NAFLD) into the 
study. 
This is a team decision. Since in 
China many T2DM patients have 
NAFLD, the previous criterion will 
exclude many potentially eligible 
patients. 
Section 6.2. Exclusion Criteria
For Criterion 27, the wording for 
remission from a clinically 
significant malignancy was revised. 
The rewording according to internal 
alignment aimed to eliminate 
misunderstanding.
Section 7.1.1. Packaging and 
Labelling
“prefilled pens” was revised to 
“single-use pens”. 
The full name of “SUPs” should be 
single-use pens instead of prefilled 
pens.  
Section 7.2. Method of Treatment 
Assignment
Section 10.3.3.2. Secondary 
Analyses
Section 10.3.4.3. Hypoglycemic 
Episodes
Section 10.3.7.2. Subgroup 
Analyses
In terms of stratification by HbA1c 
at Visit 1 (screening), patients will 
be stratified to the groups with 
HbA1c <8.5% and ≥8.5% instead 
of with  HbA1c ≤8.5% and >8.5%. 
Stratification method by HbA1c 
was revised to be consistent with 
the one in GBGL, GBDK and 
GBCG protocols.
Section 7.2.2.2.1. Insulin Glargine 
Dose Titration Algorithm 
For Table GBGO.4., “Median or 
Average BG before breakfast” will 
be used for titration of evening dose 
instead of only “Average BG”. “at 
discretion of the investigator” was
deleted. A note “Insulin glargine 
dose adjustment will be discussed 
with the patients and determined by 
the investigator before Week 8 as 
preparation and training for 
implementation of the patient self-
titration according to the TTT 
algorithm after Week 8 (Section 
5.1)” was added below the table.
Per protocol, median or average 
FBG will be used for insulin dose 
titration. Also, the decision of the 
titration after week 8 will be made 
and implemented by patients 
themselves. “at discretion of 
investigator” may cause 
misunderstanding that the insulin 
titration would still be decided by 
the investigator. A note added may 
better clarify who is the decision-
maker for insulin dose titration at 
each stage.
Section 7.6. Treatment Compliance
The assessment dates for treatment 
compliance were revised. And the 
visits that require insulin dose 
assessment and adjustment were 
revised to “from randomization to 
Visit 17”. 
The dates were incorrect and 
inconsistent with those in Section 2.
Section 7.7. Concomitant Therapy
In table GBGO.5., “Y” was 
replaced with “N” for durgs with 
weight loss indication and systemic 
glucocorticoid therapy during 
safety follow-up period. 
According to internal alignment,  
the two drug classes will be 
prohibited during safety follow-up 
period considering that these could 
affect the safety data of study 
drugs. 

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Section 7.7. Concomitant Therapy
In table GBGO.5., the footnote “c” 
for systemic glucocorticoid therapy 
was divided into 2 footnotes “c”
and “d”. A new one “d” with 
“within 4 weeks prior to Visit 1 or 
between Visits 1 and 3” was added 
for “Excluded” during 
screening/lead-in. In footnote “c”, 
the explanation for “Chronic 
systemic glucocorticoid therapy” 
was deleted. 
According to internal reviewers, the 
explanation for “Chronic systemic 
glucocorticoid therapy” was 
incorrect and unnecessary. The 
content of the previous footnote “c” 
does not fully fit for “systemic 
glucocorticoid therapy”.
Section 7.7. Concomitant Therapy
In table GBGO.5., a new footnote 
“e” was added for “Insulins”, 
explaining that the use of insulin 
glargine is allowed during 
screening/lead-in period. Also, the 
text “for acute therapy, rescue 
therapy and therapy during safety 
follow-up period, use of other basal 
insulins will not be allowed in both 
treatment groups” was moved from 
footnote “a” to “e”. 
Insulin glargine is one study drug. 
According to study design, insulin 
glargine is allowed during 
screening/lead-in period. And the 
text being moved from footnote “a”  
to “e” described the use of insulins 
instead of “acute therapy”, which 
was not proper staying in “a”. 
Section 7.7. Concomitant Therapy
In table GBGO.5., for the previous 
footnote “e” (now “g”), “below” 
was replaced with “no more than” 
for describing the upper limit of the 
dose range. 
This previous wording was 
inaccurate.
Section 7.7.1. Antihyperglycemia 
Medications
Anti-hyperglycemic medications 
except study drug, metformin 
and/or acarbose will be also 
allowed during safety follow-up 
period. 
This revision is based on the study 
design.
Section 7.7.3. Systemic 
Glucocorticoids
The wording for the use of chronic 
systemic glucocorticoid therapy 
was revised, making the content 
consistent to the corresponding 
exclusion criterion. 
According to study design, the 
chronic systemic glucocorticoid 
therapy (excluding topical, 
intraocular, intranasal, intra-
articular, or inhaled preparations) is 
exclusionary if being in use or has 
been used during the 4-week period 
before screening or between Visits 
1 and 3. 
Section 7.7.5.1. Standards of 
Medical Care
In the second paragraph, the 
positions of signs and symptoms of 
hyperglycemia and hypoglycemia 
were switched with hypoglycemia 
being the first followed by 
hyperglycemia.
No changes to the content were 
made. The revision was only in the 
consideration of the consistency of 
the text structure. 

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Section 7.7.5.2. Management of 
Increased Hypoglycemia Risk
The wording about management of 
hypoglycemic event was revised to 
clarify that patients should first 
seek acute medical or emergency 
care if needed instead of calling the 
investigative site first. 
The revision is to clarify the 
management of increased 
hypoglycemic events in 
consideration of patient safety. 
Section 7.7.5.2. Management of 
Increased Hypoglycemia Risk
“3.0 mmol/L” was replaced with 
“<3.0 mmol/L” for definition of 
documented symptomatic 
hypoglycemia in the context. 
The blood glucose should be in a 
range for defining documented 
symptomatic hypoglycemia. 
Section 8.1.1. Permanent 
Discontinuation from Study 
Treatment
The item “If a patient requires a 
new intervention due to severe, 
persistent hyperglycemia” was 
deleted from the circumstances 
where patients will be discontinued 
from study treatment. 
This circumstance does not belong 
to those where patients will be 
discontinued from study treatment 
according to study design, and this 
expression is in conflict with last 
sentence in Section 7.7.5.3. 
Section 9.2.2.1 Hypoglycemia
Definitions and criteria for 
hypoglycemia were revised 
according to Lilly Diabetes 
Hypoglycemia Workgroup “White 
Paper on the Classification and 
Data Capture of Hypoglycemia 
Events” (version 5, April 22, 2020).
Also, the paragraph about data 
recording in eCRF below the 
revised definitions and criteria for 
hypoglycemia was deleted. 
The revision for the definitions and 
criteria for hypoglycemia was due 
to the template update. The 
paragraph was deleted since the 
content has been described in the 
beginning of this section. 
Section 9.2.2.5. Cardiovascular 
Events
The “investigator reported terms” 
used for the analysis of CV events 
was replaced with “preferred 
terms”.  The wording was revised 
with the deletion of “data on any 
new CV event will be prospectively 
collected using a CV event eCRF”. 
Instead, the text about recording of 
any clinically significant finding 
from vital signs or ECG into eCRF 
was added. Also, a new paragraph 
regarding monitoring and recording 
of deaths was added. 
Since investigators often use 
different terms or different 
spellings for the same CV event, it 
makes sense to summarize AEs by 
preferred terms. The remaining
revisions were made so as to keep 
consistency with Section 2. 
Schedule of Activities and the list 
of incidences of adverse event of 
special interest in Synopsis.
Section 9.4.1. Eletrocardiograms
In the third paragraph, a text “from 
the additional ECGs conducted at 
the discretion of the investigator” 
was added.
This addition was only to better 
clarify that the ECG from which 
clinical finding is identified is not 
the ECG at week 28.
Section 9.4.5.1.3. Additional 
hepatic data collection (hepatic 
safety CRF) in study participants 
who have abnormal liver tests 
during the study
The language of additional hepatic 
data collection was revised 
according to “hepatic language non-
oncology studies v1.3”.
The hepatic language should be 
used.

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Section 10.2. Populations for 
Analyses
In table GBGO.6., “at least 75% 
compliant with study drug for at 
least 75% of the visit” was deleted 
for the criteria of “Per-Protocol” 
population. 
The reason is that the patients with 
at least 75% compliant with study 
drug for at least 75% of the visit are 
already included in the patients 
without protocol violation 
mentioned in the first point. 
Section 10.3.1. General Statistical 
Considerations
The efficacy data from the patients 
with premature treatment 
discontinuation was added for being 
censored. 
According to our statistician, this 
change aimed to clarify the 
statistical analysis in more detail.
Section 10.3.1. General Statistical 
Considerations
Section 10.3.3.1. Primary Analyses
Section 10.3.3.2. Secondary 
Analyses
Only MMRM will be used for
analyzing primary and key 
secondary continueous efficacy 
measures. ANCOVA (with LOCF)
was no longer used. 
The ANCOVA (with LOCF) model 
could produce biased results. 
Section 10.3.3.2. Secondary 
Analyses
Section 10.3.4.3. Hypoglycemic 
Episodes
In the second paragraph,  
“screening HbA1c stratum” was 
changed to “baseline HbAc1 
stratum” for models. 
Models use baseline HbA1c (Visit 
3) instead of screening HbA1c 
(Visit 1)
Section 10.3.3.3. 
Tertiary/Exploratory Analyses
Additional text about additional 
efficacy analysis without censoring 
the data after rescue therapy or 
premature treatment discontinuation 
was added.
This was revised based on the 
feedback form China’s Center for 
Drug Evaluation on 
pre-investigational new drug
application.
Section 10.3.4. Safety Analyses
“electrocardiogram” was added 
between “vital signs” and 
“laboratory analyses”.
As mentioned in Section 10.3.4.6. 
Electrocardiogram, 
electrocardiogram will be included 
in safety analyses. 
Section 10.3.4.3. Hypoglycemic 
Episodes
“≥3.0 mmol/L [54 mg/dL]” was 
added for defining glucose alert 
level together with “<3.9 mmol/L 
[70 mg/dL]”.
The previous definition is 
inaccurate as defined in Section 
9.2.2.1 Hypoglycemia
Section 11. References
References Ahmann A, et al. and 
Buse JB, et al. were deleted, the 
position of reference Rosenstock J, 
et al. was adjusted, and reference 
[ADA] was added.
References Ahmann A, et al. and 
Buse JB, et al. were repeatedly 
added.  The reference Rosenstock J, 
et al. was wrongly positioned.  The 
reference [ADA] was added due to 
hypoglycemia template update. 

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Appendix 1. Abbreviations and 
Definitions
The abbreviations “CEC”, “DMC”, 
“HR”, “LOCF”, “MAR”, 
“MNAR”, “PMM”, “QTcF”, 
“SDP”, and “SmPC” were deleted.  
“ADA”, “adjudication committee”, 
“CK”, “D.Bil”, “EASD”, “EQ-5D-
5L”, “FSH”, “GAD”, “ICA”, 
“MDDAB”, “MEN”, “NAFLD”, 
“NOAEL”, “NPH”, and “SUP” 
were added.  “mellitus” was deleted 
for the abbreviation “T2D”.  The 
full name of “USPI” was revised to 
“United States prescribing 
information”. 
The deletions, additions, and 
revisions of these abbreviations 
were based on the document 
content.  
Appendix 2. Clinical Laboratory 
Tests
“blood” was added into the footnote 
“c”.  And the superscript “c” was 
added at “Clinical Laboratory 
Tests” and removed from 
“Calcitonin” and “Pancreas 
(Exocrine)”. In footnote “g”, 
“>400 ng/mL” was changed to 
“>400 mg/dL”.
This changes related to footnote 
and superscript “c” were to better 
comply with China’s local 
requirements on blood sample 
collections. The unit change was to 
fix an error.
Appendix 4. Liver Safety: 
Suggested Actions and Follow-Up 
Assessment (Previously named as: 
Hepatic Monitoring Tests for
Treatment Emergent Abnormality)
The new template was applied.  
And the superscript “c” was added 
for the tests “Acetaminophen 
Protein Adducts”, “Alkaline 
Phosphatase Isoenzymes”,
“Copper”, “Phosphatidylethanol 
(PEth)”, “Ethyl glucuronide (EtG)”, 
“Anti-actin antibody”, and “HSV 
(Type 1 and 2) DNA”.  For the 
sentence at beginning mentioning 
the analysis of the selected testing 
is required to be completed by Lilly 
central laboratory, “microbiology” 
was replaced by “those tests that are 
denoted as local below”. 
The new version of the template 
was released by global for the 
hepatic monitoring.  And these tests 
at which the superscript “c” was 
added were unavailable in the Lilly 
designated central laboratory after 
confirmation.
Appendix 6. Classification of 
Contraceptive Methods
The text mentioning that men 
should use  contraceptive methods 
was deleted. 
The deleted text is in conflict with 
the newly added Criterion [40] 
mentioning that no male 
contraception is required except in 
compliance with specific local 
government study requirements.
For the global revisions as shown below, their corresponding instances were not identified 
specifically with strikethrough/underscore in the following Revised Protocol Sections:

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 9 8
L Y 2 1 8 9 2 6 5

Acc or di n g t o Lill y Dia betes H y p o gl yce mia W or k gr o u p “ W hite Pa per o n t he Classificat i on 
a n d Data Ca pt ure of H y p o gl yce mia E ve nts” ( versi o n 5, A pril 2 2, 2 0 2 0), t he bl o o d gl uc ose 
≤3. 9 m m o l/ L f or t he defi niti on of le vel 1 h y p o gl yc e mia was re vise d t o < 3. 9 m m o l/ L 
t hro u g h o ut t he pr ot oc ol. 

F or statistical a nal yses, a Fi s her’s e xact test rat her t ha n a C hi-s q uare test is i nte n de d f or 
bi nar y  o ut c o mes. T heref ore, t he C hi -s q uare test was eit her delete d or re place d wit h Fis her’s 
e xact test. 

Si nce t he patie nts will sta y i n t he st u d y des pite t he occ urre nce of se vere, persiste nt 
h y per gl yce mia, t he i nci de nce of i nit iati o n of resc ure t hera p y instea d of i nci de nce of patie nts 
di sc o nti n ui n g t he st u d y d ue t o se vere, persiste nt h y per gl yce mia is o ne of t he safety 
e n d p o i nts. Als o, ti me t o i nitiati on of resc ue t hera p y a n d t he pr o p orti o ns of pat ient s i nitiati n g 
resc ue t hera p y d ue t o se vere, persiste nt h yper gl yce mia will be a nal yze d. T he a nal yses f or 
ti me t o st u d y disc o nti n uati on a n d pr o p orti o ns of patie nts disc o nt i n ui n g t he st u d y d ue t o 
se vere, persiste nt h y per gl yce mia are n o l o n ger a p plica ble. 
R e vi s e d Pr ot o c ol S e cti o n s
N ote:
D el et i ons ha ve bee n i de nt ifie d b y striket hr o u g hs .
A d dit i ons ha ve bee n i de ntifie d b y  t he use of u n dersc ore .
T he n u m beri n g s yste m use d f or i ncl usi on a n d e xcl usi o n criteria pr o vi des a u ni q ue n u m ber f or 
eac h crit erio n a n d all o ws f or efficie nc y i n data c ollecti o n.
I n case a n a me n d me nt t o t he pr ot oc ol a d ds a criteri o n, t hat criteri o n will recei ve t he ne xt 
a vaila ble n u m ber, re gar dless of w het her it is a n i ncl usi on or e xcl usi o n cri t erio n.
1. S y n o p si s
Efficac y A nal yses:
T he pri mar y  eE val uat i on of act ual val ue/ meas ure me nt a n d c ha n ge fr o m baseli ne f or b o d y  
w ei g ht will be perf or m e d usi n g M M R M a n d A N C O V A m o dels o n t he i nte nt i on t o treat ( I T T)
p o p ul at i on .  T he a nal yses of ot her sec o n dar y efficac y meas ures t hat are c o nti n u o us varia bles 
(act ual val ues a n d c ha n ges fr om baseli ne) will be perf or me d usi n g M M R M o n t he i nte nt i on t o 
treat (I T T) p o p ulat i on.  

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 9 9
L Y 2 1 8 9 2 6 5
2.
S c h e d ul e of A cti viti e s
T a bl e G B G O. 1.
S c h e d ul e of A cti viti e s
Scree ni n
g/ Le a d I n
Tre at me nt Peri o d
S afet y
F oll o w -U p
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
E T
b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
4
5
6
7
8
1 0
1 2
1 5
1 8
2 1
2 4
2 8
3 2
All o w a ble De vi ati o n ( ± D a ys)
± 7
± 3
0
± 3
± 3
± 4
± 2
± 4
± 2
± 4
± 2
± 7
± 2
± 7
± 2
± 7
± 7
± 7
F asti n g visit c
X
X
X
X
T ele p h o ne visit
X
X
X
X
X
P atie nt E d uc ati o n
Dis pe nse st u d y diar y, i nstr uct i n use
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X m
X
Re vie w a n d tra nsfer t o e C R F/ret ur n 
st u d y diar y
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re mi n d patie nts a b o ut 7 p oi nt S M B G n m
X
X
X
Re vie w/rec or d 7 -p oi nt S M B G val ues
X
X
X  
X o n
Re vie w fasti n g/ 4 -p oi nt B G fr o m 
S M B G p o
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re vie w st u d y dr u g usa ge
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Re vie w i ns uli n d ose a n d a dj ust me nt
per T T T al g orit h m q p
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Dis pe nse st u d y dr u g a n d i njecti o n 
s u p plies
X
X
X
X
O bser ve patie nt i nject d ula gl uti de Q W 
X
Patie nt ret ur ns st u d y dr u g a n d i njecti o n 
s u p plies
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Assess d ula gl uti de c o m plia nce
X
X  
X  
X  
X  
X  
X
Assess c o m plia nce wit h wee kl y i ns uli n 
d ose a dj ust me nt per T T T al g orit h m 
X  
X  
X
X r
q
X r
q
X r
q
X  
X  
X  
X
L a b or at or y testsq
sSer u m pre g na nc y test sr
X

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 1 0 0
L Y 2 1 8 9 2 6 5
Scree ni n
g/ Le a d I n
Tre at me nt Peri o d
S afet y
F oll o w -U p
Visit
1
2
3 a
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
E T
b
8 0 1
Wee k of Tre at me nt
- 3
- 2
0
1
2
4
5
6
7
8
1 0
1 2
1 5
1 8
2 1
2 4
2 8
3 2
All o w a ble De vi ati o n ( ± D a ys)
± 7
± 3
0
± 3
± 3
± 4
± 2
± 4
± 2
± 4
± 2
± 7
± 2
± 7
± 2
± 7
± 7
± 7
F asti n g visit c
X
X
X
X
T ele p h o ne visit
X
X
X
X
X
Uri ne pre g na nc y test ts
X
X  
X  
X
F ollicle -sti m ulati n g h or m o ne testut
X
C he mistr y pa nel
X
X v u
X v u
Ser u m creati ni ne, e G F R ( C K D -E PI) w v
X  
X
X  
X
A b bre viati o ns:  8 0 1 = safet y f oll o w -u p visit; B G = bl o o d gl uc ose; B P = bl o o d press ure; e C R F = electr o nic case re p ort f or m; C V = car di o vasc ular; D = da ys; 
e C R F = electr o nic case re p ort f or m; E Q - 5 D-5 L = E ur o Q ol 5 -di me nsi o n q uesti o n naire; E T = earl y ter mi nati o n ; F S H = f ollicle -sti m ulati n g h or m o ne; G A D = 
gl uta mic aci d decar b o x ylase; H b A 1c = gl ycate d he m o gl o bi n A 1c; H R = heart rate; I C A = islet cell a nti b o dies; I W R S = i nteracti ve we b res p o nse s yste m; I W-
S P = I m pact of Wei g ht o n Self -Perce pti o n Scale; 8 0 1 = safet y f oll o w -u p visit; M D D A B = Me dicati o n Deli ver y De vice Assess me nt Batter y; P R = p ulse rate;
B G = bl o o d gl uc ose; Ra n d = ra n d o mizati o n; S M B G = Self -M o nit ore d Plas ma Gl uc ose; S U P = Si n gle -Use P e n; T T T = treat -t o-tar get.
m
Safet y data t o be ca pt ure d after disc o nti n uati o n of st u d y dr u g d uri n g safet y f oll o w -u p peri o d.
m n. Patie nts will be as ke d t o perf or m t w o 7 -p oi nt S M B G pr ofiles o n t w o n o n c o nsec uti ve da ys, i n t he 2 -wee k peri o d pri or t o Visit 3, as well as pri or t o Visit 1 2 
a n d Visit 1 7.  A 7-p oi nt S M B G c o nsists of meas ure me nts bef ore a n d 2 h o urs after eac h of 3 mai n meals wit hi n t he sa me da y a n d at be dti me.  If 7 -p oi nt 
S M B G is n ot perf or me d, t he n data fr o m t he m ost rece nt n o nc o nsec uti ve 4 -p oi nt S M B G ( 3 bef ore eac h meal a n d o ne at be dti me) pr ofiles ca n be use d.  If m ore 
t ha n 2 S M B G pr ofiles are a vaila ble, t he 2 m ost rece nt pr ofiles o n n o nc o nsec uti ve da ys s h o ul d be use d.  I n t he wee ks t hat t he 7- p oi nt pr ofiles are perf or me d, 
t he 4-p oi nt S M B G pr ofile s will n ot be nee de d.
n o. Re vie w/rec or d 7 -p oi nt S M B G pr ofile(s), o nl y if a p plica ble, base d o n pre vi o us st u d y visit.
o p. Patie nts will be e nc o ura ge d t o c ollect a dail y fasti n g B G a n d a wee kl y 4 -p oi nt S M B G. Missi n g a fasti n g B G meas ure me nt will n ot be c o nsi d ere d a pr ot oc ol 
de viati o n.
p q. I ns uli n d ose assess me nt a n d d ose a dj ust me nt s ho ul d be d o ne at least 3 da ys pri or t o Visit 3 t o e ns ure t he c ollect i o n of at least 3 da ys of F B G f or patie nt 
eli gi bilit y assess me nt pri or t o ra n d o mizati o n .  T he i ns uli n glar gi ne d ose s h o ul d be re d uce d b y 2 0 % at Visit 3 if baseli ne H b A 1c ≤8. 0 %.  F urt her d ose 
a dj ust me nts are t o start at Visit 6 per t he T T T al g orit h m, a n d bef ore t hat o nl y i n certai n sit uati o ns (f or details see Secti o n 5. 1 ).  T he T T T al g orit h m s h o ul d be 
use d f or d ose a dj ust me nts u ntil t he last visit o n ra n d o mize d treat me nt ( Visit 1 7 or E T Visit).  After disc o nti n uati o n of st u d y dr u g, t he i n vesti gat or will deci de 
o n t he m ost a p pr o priate t hera pe utic re gi me n, a n d if a p plica ble, t he m ost a p pr o priate i ns uli n d ose a dj ust me nt sc he d ule.  Refer t o Pr ot oc ol Secti o n 7. 2. 2. 2 f or 
c o m plete i nstr ucti o ns o n i ns uli n d ose a dj ust me nt.
qr. Assess me nt of t he patie nt’s c o m plia nce t o t he T T T al g orit h m will be c ollecte d i n t he e C R F at Visits 8, 1 0, a n d 1 2 f or t he peri o d si nce t he pre vi o us visit.
rs
A ser u m pre g na nc y test will be perf or me d at Visit 1 f or w o me n of c hil d beari n g p ote ntial o nl y.
st. A uri ne pre g na nc y test will be perf or me d at Visit 3, wit h t he res ult a vaila ble pri or t o ra n d o mizati o n a n d first i njecti o n of st u d y dr u g, a n d at a d diti o nal visits as 
s h o w n i n t he sc he d ule, f or w o me n of c hil d beari n g p ote ntial o nl y. A d diti o nal pre g na nc y tests will be perf or me d at t he i n vesti gat or’s discreti o n or if re q uire d 

H9X-MC-GBGO(a) Clinical Protocol
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per local regulations and/or institutional guidelines during the study.  
tu. Follicle-stimulating hormone test will be collected 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).  After Visit 1, additional tests may be performed at the investigator’s discretion during the study.
uv. For those visits when fasting glucose is required, glucose will not be included in the chemistry panel.
vw. Chronic Kidney Disease-Epidemiology (CKD-EPI) equation will be used to estimate the glomerular filtration rate.

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4. Objectives and Endpoints
Objectives
Endpoints
Exploratory
Efficacy:

To compare the addition of dulaglutide 1.5 mg 
QW with the addition of placebo QW to titrated 
basal insulin glargine for exploratory efficacy 
parameters after 28 weeks of treatment in 
patients with T2D.

Frequency of insulin dose adjustments through 
28 weeks; 

Number of insulin dose assessments per TTT 
algorithm and compliance with the TTT 
algorithm at 6, 8, and 12 weeks;

Proportion of patients achieving HbA1c target 
of <7.0% and with no weight gain (<0.1 kg) at 
28 weeks and without documented 
symptomatic hypoglycemia (BG<3.9 mmol/L) 
during the maintenance period (Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% and without weight gain (<0.1 kg) at 
28 weeks and without documented 
symptomatic hypoglycemia (BG ≤ 3.9 
mmol/L) during the maintenance period 
(Weeks 12-28);

Proportion of patients achieving HbA1c target 
of <7.0% at 28 weeks and without documented 
symptomatic hypoglycemia (BG <≤3.9 
mmol/L) during the maintenance period
(Weeks 12-28);
5.1. Overall Design
Patients who meet all inclusion criteria and none of the exclusion criteria will enter a 2-week 
lead-in period.  Only those patients who require further up-titration of the insulin glargine dose 
per TTT algorithm at the end of lead-in period (mean FBG ≥5.6 mmol/L in the from prior week 
before Visit 3randomization ≥5.6 mmol/L) (Visit 3 or randomization visit) will then be 
randomized to 1 of the following treatment groups at Visit 3:  (1) dulaglutide 1.5 mg QW as add-
on to insulin glargine or (2) placebo QW as add-on to insulin glargine.  Insulin glargine will be 
titrated using the treat-to-target (TTT) algorithm (Section 7.2.2.2.1).  Metformin and/or acarbose
dose must be stable kept unchanged for at least 3 months prior to Visit 1, and the dose should be 
within the inclusive range of half maximum to maximum approved daily dose per the locally-
approved label during this periodmust meet requirements for more than or equal to half 
maximum daily dose;. Ppatients will be required to continue pretrial metformin and/or acarbose 
during the lead-in and treatment periods.  Patients will be treated for 28 weeks (a 4-week 
stabilization period followed by a 24-week titration period); after which patients will be required 
to complete a safety follow-up visit (801) approximately 4 weeks later.
Study Period I (Screening and Lead-In)
Lead-in (Visit 2 to Visit 3) 

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
P a g e 1 0 3
L Y 2 1 8 9 2 6 5
D uri n g t he l ea d-i n peri o d, patie nts s h o ul d c o nti n ue t heir prest u d y t hera p y a n d s h o uld n ot c ha n ge 
t he t yp e of  O A Ms use d or t heir d oses i n or der t o all o w relia ble assess me nt of H b A 1c at baseli ne 
( Visit 3).  If patie nts de vel o p a c o n diti on t hat i s a c o ntrai n dicati on f or t he use of O A Ms, t he y will 
be c o nsi dere d i ne li gi ble a n d m ust be di sc o nti n ued fr om t he trial before ra n d o mizat i on.  I ns uli n 
d oses s h o ul d be a dj uste d o nl y f or t he safet y of t he st u d y partici pa ntspatie nts ( occ urre nce of 
h y p o gl yce mia [fasti n g bl o o d gl uc ose ( F B G) < < 3 . 9 m m ol/ L] d ue t o i na de q uate i ns uli n d ose or 
se vere h y per gl yce mia, defi ne d as mea n dail y B G fr o m 4-p oi nt S M B G pr ofile > 1 5 m m o l/ L or 
mea n wee kl y F B G > 1 5 m m o l/ L).  I n t hese sit uati ons, t he i ns uli n d ose will be a dj uste d t he patie nt 
will a dj ust t he d ose per t he T T T al g orit h m at t he discr etio n of  t he i n vesti gat or (see Secti o n 
7. 2. 2. 2. 1 ).  
St u d y Peri o d II ( Tre at me nt Peri o d):
R a n d o miz ati o n ( Visit 3)
At  Visit 3, p at ient  s h o uld arri ve t o t he cli nic i n t he fast i n g state, ; t he fasti n g statew hic h s h o uld 
ha ve laste d at least 8 h o urs, wit h o ut ha vi n g ta ke n a n y d oses of t heir st u d y dr u g, O A Ms a n d 
i ns uli n glar gi ne.  Pr oce d ures at t his visit will be perf or me d as s h o w n i n t he Sc he d ule of 
Act i vitiesSt u d y  Sc he d ule (Secti o n 2 ).  T he q uesti o n naires ( E Q - 5 D-5 L a n d I W -S P) s h o ul d be 
c o mplete d bef ore a n y ot her st u d y  pr oce d ures if t he patie nt is n ot a d versel y affecte d b y t he 
fasti n g c o n diti on or c o m plete d after t he patie nt has s ufficie nt l y rec o vere d fr o m t he prece di n g 
visit pr oce d ures.  
I n vesti gat ors will re vie w t he diar y a n d assess patient  eli gi bility ( Secti o n 6. 1 a n d 6. 2 ).  I ns uli n 
d ose s h o ul d be ke pt u nc ha n ge d f or at  least 3 da ys pri or t o Visit 3, s o as t o ha ve at least 3 dail y 
F B G val ues rea d y f or eli gi bilit y assess me nt at Visit 3.I ns uli n d ose assess me nt a n d i ns uli n d ose 
a djust m e nt s h o uld be d o ne at l east 3 da ys pri or t o Visit 3 t o e ns ure t he c ollect i on of at least 3 
da ys of F B G o n t he c urre nt i ns uli n d ose f or eli gi bilit y assess me nt prior t o ra n d o mizat i on.   
P ati e nts w h o c o nti n ue t o be eli gi ble will be ra n d o mize d i n a 1: 1 rati o t o o ne of  t h e fol l owi n g 
treat me nt gr o u ps:  ( 1) d ula gl ut i de 1. 5 m g Q W  as a d d-o n t o i ns uli n glar gi ne or ( 2) place b o Q W as 
a d d-o n t o i ns uli n glar gi ne, wi t h metfor m i n a n d/ or acar b ose. 
St a biliz ati o n Peri o d ( E n d of Visit 3 t o Visit 6 [ Weeks 0 t o 4])  
I n a d diti on, f or patie nts wit h baseli ne H b A 1c ≤8. 0 %, t he i ns uli n glar gi ne d ose will be decrease d 
b y 2 0 % i m me di at el y after ra n d o mizati on , n ot later t ha n 7 da ys after t he first d osi n g of st u d y 
dr u g , a n d will t he n re mai n u nc ha n ge d d uri n g t he sta bilizati on peri o d t o decrease t he ri s k of 
h y p o gl yce mia.  
T he pl a n ne d visit s for t hi s perio d, Visi ts 4, 5, a n d 6, will ta ke pl ace 1 wee k ( ± 3 da ys), 2 wee ks 
( ± 3 da ys), a n d 4 wee ks ( ±7 4 da ys) after ra n d o mizati o n, res pecti vel y.  St u d y  pr oce d ures will be 
perf or m e d per t he Sc he d ule of Act i vities ( Sectio n 2 ).
Titr ati o n Peri o d ( E n d of Visit 6 t o Visit 1 7 [ Weeks 5 4 t o 2 8])
T he pl a n ne d office visit s d uri n g t his peri o d (e xcl u di n g t he fi nal visit), Visit s 8 t hr o u g h 1 6 , will 
ta ke place at Wee k 6 ( ± 7 4 d a y s), 8 ( ±4 7 da ys), 1 2 ( ± 7 da y s), 1 8 ( ± 7 da ys), a n d 2 4 wee ks ( ± 7 

H9X-MC-GBGO(a) Clinical Protocol
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days) after randomization.  In addition to the office visits, 5 telephone visits will be scheduled 
during this period at Visit 7 (Week 5), Visit 9 (Week 7), Visit 11 (Week 10), Visit 13 (Week 15), 
and Visit 15 (Week 21) will take place at Weeks 5, 7, 10, 15, and 21, respectively.  At each of 
these visits, procedures will include assessments of SMBG, compliance with insulin titration 
algorithm, insulin dose, dulaglutide compliance (will be re-assessed at the office visit), 
hypoglycemic events, concomitant medications, and AEs.  The data obtained at these telephone 
visits will be entered into the eCRFs at the next office visit. 
Between Week 4 and Week 8, the insulin glargine dose adjustment will be discussed with the 
patients and determined by the investigator, and this procedure will be used as preparation and 
training for implementation of the patient self-titration according to the TTT algorithm
(Table GBGO.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 12, patients will be contacted by the 
study site personnel every 2 weeks (either telephone or office visit).  Investigators or study site 
personnel will review the insulin dose adjustment made by the patient at each office visit or 
telephone visit.  From Week 12 , patients will be contacted by the study site personnel every 3-4 
weeks (either telephone or office visit), to enable the site to properly monitor patients’ usage of 
the TTT algorithm.  Investigators may perform additional telephone visits if necessary, or 
perform additional office visits if deemed necessary by the investigator.  Also, more frequent 
insulin dose assessments may be requested by the investigator if clinically appropriate.  Any 
patient meeting criteria for severe, persistent hyperglycemia after 12 weeks of unrestricted 
insulin glargine dose adjustments will discontinue study drug and the study (see Section 7.7.5.3 
for details).
The final office visit, Visit 17, will take place at Week 28 (±7 days).  Study procedures at this 
visit are shown in the Schedule of Activities (Section 2).  The EQ-5D-5L, IW-SP, and MDDAB 
modules 1, 2, 3b, and 4 questionnaires will 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.  A final physical examination will be 
performed, including weight and vital signs (sitting blood pressure [BP] and pulseheart rate 
[PHR]) measurements and electrocardiogram (ECG) testing using the existing equipment at the 
site.  Study drug will be discontinued and an appropriate diabetes treatment regimen will be 
prescribed per the investigator’s judgment.  A patient summary eCRF will be completed.
Study Period III (Safety Follow-Up Period):
Safety Follow-Up (801) Visit 
All patients who complete the treatment period are required to complete Visit 801, a safety 
follow-up visit approximately 4 weeks after last visittheir last dose.  Patients discontinuing the 
study early and performing an early termination (ET) visit will also be asked to perform the 
safety follow-up visit, so that the safety follow-up visit will be their final visit.

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5.4. Scientific Rationale for Study Design
To ensure a valid comparison of the randomized study treatments, it is important that insulin 
glargine is titrated in an optimal way 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 T2D to achieve their therapeutic targets when treated with insulin glargine (DaviesRiddle et 
al. 20053).
5.5. Justification for Dose
The TTT algorithm (Section 7.2.2.2.1), adapted from RiddleDavies et al. (20035), is a broadly 
accepted approach to insulin glargine dose adjustments and will be used in this study to target a 
FBG <5.6 mmol/L.
6.1. Inclusion Criteria
[4] doses of once daily insulin glargine and OAMs must be stable during the 3-month period 
prior to Visit 1.  Insulin glargine dose is considered stable when all doses during this 
period are within the range defined by ±20% of the most commonly used insulin glargine 
dose during this same period. Doses of metformin and/or acarbose are considered stable 
when doses are unchanged during the same period, and the doses should be in the 
inclusive range of the half maximum to maximum approved daily dose per the locally-
approved labelare considered stable if all prescribed doses during this period are more 
than or equal to half maximum approved daily dose during the 3 months before Visit 1;
[11] Otherwise, women of child-bearing potential participating must agree to use one highly 
effective (less than 1% failure rate) method of contraception or use a combination of 
two effective methods of contraception until plasma concentration equals or is lower 
than the [NOAEL for embryo fetal effects]. 
[a] Women of child-bearing potential participating must test negative for pregnancy 
prior to initiation of treatment as indicated by a negative urineserum pregnancy test 
at the screening visit followed by a negative serumurine pregnancy test within 24 
hours prior to exposure. 
[40] No male contraception required except in compliance with specific local government
study requirements.
6.2. Exclusion Criteria
[15] have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 
months prior to Visit 1;
[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 >2.5 
times the upper limit of the reference range, as determined by the central laboratory at 
study entry (Visit 1); patients with NAFLD are eligible for participation in this trial only 
if their ALT level is ≤2.5 times the upper limit of normal (ULN) for the reference range;

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have acute or chronic hepatitis, signs and symptoms of any other liver disease, or 
alanine aminotransferase (ALT) level >2.5 times the upper limit of the reference range, 
as determined by the central laboratory (patients with nonalcoholic fatty liver disease 
are eligible);
   [27] have a history of active or untreated malignancy, or have beenare 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 thanduring the 5 years prior 
to Visit 1;  
7.1.1. Packaging and Labelling
The sponsor will provide dulaglutide and placebo in single-use pensprefilled pens (SUPs), which 
will be dispensed via an Interactive Web Response System (IWRS).  Each SUP will be packaged 
in cartons to be dispensed.  Each carton contains a 4-week supply, as each pen providesis a 
weekly dose.  Injections are to be administered as described in Section 7.2.2.
7.2. Method of Treatment Assignment
Patients will be randomized in a 1:1 ratio to (1) dulaglutide 1.5 mg QW as add-on to insulin 
glargineor (2) placebo QW as add-on to insulin glargine, with metformin and/or acarbose.  
Patients will also be stratified by HbA1c at Visit 1 (screening) (<≤8.5% vs. ≥>8.5%) and OAM 
usage (metformin alone, acarbose alone, metformin and acarbose) at Visit 3 (randomization) to 
achieve between-group comparability and to mitigate against the confounding the effects of the 
treatments with severity of disease or treatment with metformin and/or acarbose.
7.2.2.2. Insulin Glargine
For patients with baseline HbA1c ≤8.0%, the basal insulin dose will be decreased by 20% 
immediately (within 7 days) after randomization and will then remain unchanged during the 
stabilization period.
7.2.2.2.1. Insulin Glargine Dose Titration Algorithm
Table GBGO.4.
Insulin Glargine Treatment-to-Target Algorithm
Median or Average BG Before Breakfast (for Titration of 
Evening Dose)
Increase in Basal Dose (Units)
<70 mg/dL (<3.9 mmol/L)
Decrease to previous lower dose*
70-<100 mg/dL (3.9-5.6 mmol/L)
No adjustment
100-<120 mg/dL (5.6-6.7 mmol/L)
+1 to- +2 U# (at discretion of the investigator)
120-<140 mg/dL (6.7-7.8 mmol/L)
+ 2 U
140-<180 mg/dL (7.8-10.0 mmol/L)
+ 4 U
≥180 mg/dL (>10.0 mmol/L)
+6 to- +8 U# (at discretion of the investigator)
* The patient will be administered with the previous lower dose if he/she has documented hypoglycemia or probable 
symptomatic hypoglycemia.

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# Insulin glargine dose adjustment will be discussed with the patients and determined by the investigator before 
Week 8 as preparation and training for implementation of the patient self-titration according to the treatment-to-
target algorithm after Week 8 (Section 5.1).
Abbreviations:  BG = blood glucose; U = unit(s).
7.6. Treatment Compliance
•
Treatment compliance for once weekly study drug is defined as taking at least 75% of the 
required injections of study drug, 
o
Between Visit 3 (randomization) and Visit 6 (Week 4) 6, and
o
Since the previous visit, assessed at Visits 10 (Week 8), 12 (Week 12), 14  (Week 
18), 16 (Week 24) and 17 (Week 28)
Compliance is assessed by site personnel; this information will be entered in the eCRF.
Compliance with the TTT algorithm will be determined by the following:
• The study site will review and document patients’ use of the insulin glargine TTT algorithm 
for appropriate number of assessments, appropriate assessment of the insulin dose, and 
subsequent dose adjustments at each visit from randomization to Visit 17the last study visit 
(801 or ET).  These data will be entered into the eCRF for the period prior to Visits 8 (Week 
6), 10 (Week 8), and 12 (Week 12).
7.7. Concomitant TherapyTable GBGO.5.
Criteria for Use of Concomitant Medications 
that May Interfere with Efficacy and Safety Assessments
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
NY
Systemic glucocorticoid therapyc
Excludedd except for 
acute therapya
Y
N/A
NY
Antihyperglycemia medications
Other GLP-1 RAs and related
fixed-dose combinations
Excluded
N
N
N
DPP-4 inhibitors and related
fixed-dose combinations
Excluded
N
N
N
Pramlintide
Excluded
N
N
N
SGLT2 inhibitors
Excluded
N
Y
Y
Insulins ea
Excluded
Y
Y
Y
Meglitinides
Excluded
N
Y
Y
Alpha-glucosidase inhibitorsfd
Allowed
N/A
Yge
Y
Sulphonylureas
Excluded
N
Y
Y
Thiazolidinediones
Excluded
N
Y
Y
Metforminfd
Allowed
N/A
Ye
Y

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a
Ac ute t hera p y = treat me nt f or u p t o 1 4 da ys.  F or ac ute t hera p y, resc ue t hera p y a n d t hera p y d uri n g safet y f oll o w -
u p peri o d, u se of ot her basal i ns uli ns will n ot be all o we d i n b ot h treat me nt gr o u p s.
c
C hr o nic s y ste mic gl uc oc ortic oi d t hera p y = treat me nt f or u p t o 1 4 da ys . Fr o m 1 m o nt hs pri or t o Visit 1 or 
bet wee n Visits 1 a n d 3; d D oes n ot a p pl y t o t o pical, i ntra oc ular, i ntra nasal, i ntra -artic ular, or i n hale d pre parati o ns.
d
C hr o nic s y ste mic gl uc oc ortic oi d t hera p y ( > 1 4 da ys) s h o ul d be e xcl u de d wit hi n 4 wee ks pri o r t o Visit 1 or 
bet wee n Visits 1 a n d 3.
e
Use of i ns uli n glar gli ne is all o we d d uri n g scree ni n g/lea d -i n peri o d.  F or ac ute t hera p y, resc ue t hera p y a n d 
t hera p y d uri n g safet y f oll o w-u p peri o d, u se of ot her basal i ns uli ns will n ot be all o we d i n b ot h treat me n t gr o u p s.
f d S witc hi n g metf or mi n or acar b ose ma n ufact urers is all o we d as l o n g as t he d osa ge is t he sa me.  C ha n gi n g t o a 
metf or mi n f or m ulati o n wit h a differe nt acti o n pr ofile (f or e xa m ple, fr o m s h ort -acti n g t o l o n g -acti n g metf or mi n) 
is n ot per mitte d.
ge F or  resc ue t hera p y, metf or mi n or acar b ose d ose ca n be i ncrease d if t he d ose is bel o w n o m ore t ha n ma xi m u m 
a p pr o ve d d ose per c o u ntr y-s pecific la bel a n d is well t olerate d.
7. 7 . 1. A nti h y p er gl y c e mi a M e di c ati o n s
A nt i-h y per gl yce mic me dicat i ons, ot her t ha n st u d y dr u g, metfor m i n a n d/ or acar b ose, are n ot 
all o we d at a n y time d uri n g t he st u d y , e xce pt t hose as all o we d f or use d as resc ue t hera p y, a n d/ or 
use d after earl y st u d y dr u g disc o nti n uati on or d uri n g safet y f oll ow- u p peri o d , or i ns uli ns f or 
s h ort-t er m i ns uli n use.  Resc ue t hera p y  wit h ot her gluc ose -l oweri n g a ge nts, i ncl u di n g i ns uli n, 
ma y be me dicall y i n dicate d i n certai n sit uat i ons after ra n d o mizat i on d ue t o se vere, persiste nt 
h y per gl yce mia or earl y  disc o nti n uatio n of  st u d y treat me nt.  T hese sit uat i ons are descri be d i n 
Secti o n 7. 7. 5. 3 a n d Secti o n 8. 1. 1 , res pecti vel y.  If a n y s uc h sit uati on occ urs, t he patie nts ma y  be 
treate d wit h a n y l ocall y-a p pr o ve d gl uc ose -l oweri n g a ge nts.  Ot her G L P -1 R As, a n ot her basal 
i ns uli n, or D P P-4 i n hi bit ors, fi xe d -d ose c o m bi nat i o n wit h c om p o ne nt of G L P -1 rece pt or a g o ni sts 
or D P P -4 i n hi bit or , a n d pra mli nt i de are pr o hi bite d me dicat i ons a n d are n ot all o we d as resc ue 
t hera pies.  
If a n y ne w a nt i-h y per gl yce mic me dicati o n is i nit iate d after ra n d o mizati o n at Visit 3 a n d pri or t o 
Vi sit 17 (e n d of Treat me nt Peri o d), ot her t ha n st u d y dr u g, resc ue t hera p y, p ost dr u gs use d after 
earl y st u d y dr u g disc o nti n uati on or d uri n g safet y f oll o w-u p peri o d , or i ns uli ns f or s h ort-t er m use 
of  ins uli n f or me dical e mer ge ncies, t he patie nt will be re q uire d t o i m me diatel y disc o nti n ue t he 
me dicat i on a n d t he a p pr o priate st u d y  de viati on re p ort will be ge nerate d.  A n y s uc h vi o lati on of 
t he pr ot oc ol t hat lasts > 1 4 c o nsec ut i ve da ys will e xcl u de t he patie nt fr o m t he Per-Pr ot oc ol ( P P) 
P o p ul at i on f or a nal yses.
7. 7. 3. S y st e mi c Gl u c o c orti c oi d s
C hr o nic s yste mic gl uc oc ortic o i d t hera p y (> 1 4 c o nsec ut i ve da ys; e xcl u di n g t o pical, i ntra oc ular, 
i ntra nasal, i ntra-artic ular, or i n hale d pre parat i ons) is e xcl usi o nar y  if be i n g i n use or has bee n 
use d > 1 4 c o nsec ut i ve da ys d uri n g t he 4 -wee k peri o d bef ore st u d y  e ntr y or bet wee n st u d y e ntr y 
a n d ra n d o mizati o n at Visit 3.  If gl uc oc ortic o i d t hera p y is nee de d f or m ore t ha n 1 4 c o nsec ut i ve 
da ys d uri n g t he treat me nt peri o d, t he n patie nt s will n ot be i ncl u de d i n t he P P a nal ysis.
7 . 7. 5. 1. St a n d ar d s of M e di c al C ar e
T his sect i on pr o vi des g ui da nce o n ma na ge me nt of e pis o des of h y p o gl yce mic e ve nts a n d e ve nts 
of  se vere, persiste nt h yper gl yce mia.  F or effect i ve i m ple me ntati o n of meas ures descri be d here, it 

H 9 X -M C -G B G O( a) Cli ni c al Pr ot o c ol
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is i m p orta nt t hat patie nts, a n d t heir care gi vers, if a p plica ble, be well -e d ucate d a b o ut t he si g ns 
a n d s y m pt o ms of h y p o gl yce mia (e g, i nte nse h u n ger, s weati n g, tre m or, restless ness, irrita bilit y,  
de pressi o n, hea dac hes, dist ur be d slee p, or tra nsie nt ne ur ol o gical dis or ders) a n d h y per gl yce mia 
(e g, se vere t hirst, dr y mo ut h, f r eq ue nt mict uri tio n, or dr y  s ki n) a n d h y p o gl yce mia (e g, i nte nse 
h u n ger, s weat i n g, tre m or, restless ness, irrita bility,  de pressio n , hea dac hes, dist ur be d slee p, or 
tra nsie nt ne ur olo gi c al dis or ders).  Patie nts s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gati ve site i n 
t he e ve nt of se vere h y p o gl yce mia se vere, persiste nt h yper gl yce mia or se vere, persiste nt 
h y per gl yce mia se vere h y p o gl yce mia bet wee n st u d y  visits.
7. 7. 5. 2. M a n a g e m e nt of I n cr e a s e d H y p o gl y c e mi a Ri s k
If a h y p o gl yce mic e ve nt occ urs, t he patie nt s h o ul d rec or d i n t he st u d y diar y t he B G le vel 
meas ure d d uri n g t he e pis o de a n d pri or t o a d mi nistrati o n of treat me nt (if ta ke n), as well as 
ass ociate d s y m pt o ms a n d treat me nt a d mi nistere d.  Site pers o n nel will e nter t his i nf or mat i on i nto 
t he h y p o gl yce mia e C R F at eac h visit.  Pati e nts s h o uld be i nstr ucte d t o call t he i n vest i gati ve site 
as s o o n as p ossi ble if t he y e x p erie nce a h y p o gl yce mic e ve nt t hat re q uires assista nce t o a d mi nister 
treat me nt. Patie nts s h o ul d be trai ne d a b o ut si g ns a n d s y m pt o ms of h y p o gl yce mia a n d h o w t o 
ma na ge h y p o gl yce mia.  Patie nts s h o ul d first see k ac ute me dical or e mer ge nc y care if nee de d, 
a n d i nf or m t he i n vest i gati ve site as s o o n as p ossi ble after a n e ve nt of se vere h y p o gl yce mia has
occ urre d t hat re q uires assista nce t o a d mi nister c orrecti ve treat me nt .
I n t his st u d y, i ncrease d ris k of h y p o gl yce mia is defi ne d as ha vi n g a si n gle e pis o de of se vere 
h y p o gl yce mia or ha vi n g m ore t ha n 1 e pis o de of d oc u me nte d s y m pt o mat ic h y p o gl yce mia ( < 3. 0 
m m o l/ L) wit hi n a 1-wee k peri o d at a n y  ti me d uri n g t he Treat me nt Peri o d.
8. 1. 1. P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt

A n y si g nifica nt st u d y  dr u g-r elate d h y perse nsit i vity reacti o n ;

If a patie nt re q uires a ne w i nter ve nti on d ue t o se vere, persiste nt h y per gl yce mia ;

If a n o n-st u d y G L P-1 rece pt or a g o nist is i nit iate d, a n d t he patie nt ref uses t o disc o nt i n ue 
t his me dicati on;
9. 2. 2. 1. H y p o gl y c e mi a 
I n vesti gat ors s h o ul d use t he f oll owi n g defi nit i ons a n d criteria w he n dia g n osi n g a n d cate g orizi n g 
a n e pis o de c o nsi dere d t o be relate d t o h yp o gl yce mia (t he B G val ues i n t his sect i on refer t o val ues 
deter mi ne d b y a la b orat or y  or I nter natio nal Fe derati o n of  Cli nical C he mistr y a n d La b orat or y 
Me dici ne plas ma -e q ui vale nt gl uc ose meters a n d stri ps) i n acc or da nce wit h t he 2 0 1 7 2 0 2 0 A D A 
p osi tio n state m e nt o n gl yce mic tar gets:
Le vel 1 h y p o gl yce mi a:
Gl uc ose < 7 0 m g/ d L ( 3. 9 m m ol/ L) a n d ≥ 5 4 m g/ d L ( 3. 0 m m ol/ L):   Le vel 1 h y p o gl yce mia 
ca n alert a pers o n t o ta ke acti o n s uc h as treat me nt wit h fast -acti n g car b o h y drates. Pr o vi ders 
s h o ul d c o nti n ue t o c o u nsel partic pa nts t o treat h y p o gl yce mia at t his gl uc ose alert val ue.
Le vel 2 h y p o gl yce mi a:  

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Glucose <54 mg/dL (3.0 mmol/L):  This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence of absence of symptoms of hypoglycemia. 
Level 3 hypoglycemia:  
Severe hypoglycemia (in adults):  A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia.  For example, 
participants had altered mental status, and could not assist in their own care, or were
semiconscious or unconscious, or experienced coma with or without seizures, and the 
assistance of another person was needed to actively administer carbohydrate, glucagon, or 
other resuscitative actions. Glucose measurements may not be available during such an 
event, but neurological recovery attributable to the restoration of glucose concentration to
normal is considered sufficient evidence that the event was induced by a low glucose 
concentration.

The determination of a hypoglycemic event as an episode of severe 
hypoglycemia, as defined above, is made by the investigator based on the medical 
need of the participant to have required assistance and is not predicated on the 
report of a participant simply having received assistance.

If a hypoglycemic event meets the criteria of severe hypoglycemia, the 
investigator must record the event as serious on the AE CRF and report it to Lilly 
as an SAE.
Nocturnal hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep.  
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has 
a BG level of ≤3.9 mmol/L.

Documented asymptomatic hypoglycemia is defined as any event not accompanied 
by typical symptoms of hypoglycemia, but with a measured BG ≤3.9 mmol/L.

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured BG ≤3.9 mmol/L.
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has 
a BG level of <3.0 mmol/L.

Documented asymptomatic hypoglycemia is defined as any event not accompanied 
by typical symptoms of hypoglycemia, but with a measured BG <3.0 mmol/L.

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
D oc u me nte d u ns pecifie d h y p o gl yce mi a is defi ned as a n y  e ve nt wit h n o i nf or mat i on 
a b o ut s y m pt o ms of h y p o gl yce mia a vaila ble, b ut wit h a meas ure d B G < 3. 0 m m ol/ L .
Severe hy p o glyce mi a ( Level 3):

Se vere h y p o gl yce mi a is defi ne d as a n e pis o de wit h se vere c o g niti ve i m pair me nt,
re q uirin g t he assista nce of a n ot her pers o n t o acti vel y  a d mi nister car b o h y drate, 
gl uca g o n, or ot her res uscitati ve act i ons.  T hese e pis o des ma y  be ass ociate d wit h 
s ufficie nt ne ur o gl yc o pe nia t o i n d uce seiz ure or c o ma.  Bl o o d gl uc ose meas ure me nts 
ma y n ot be a vaila ble d uri n g s uc h a n e ve nt, b ut ne ur ol o gical rec o ver y attri b uta ble t o 
t he rest orati o n of B G t o n or mal is c o nsi dere d s ufficie nt e vi de nce t hat t he e ve nt was 
i n d uce d b y a lo w B G c o nce ntrati o n.
Ot h er hy p o glyce mi a c ate g ories:

N oct ur n al h y p o gl yce mi a is defi ne d as a n y h y p o gl yce mic e ve nt t hat occ urs bet wee n 
be dt i me a n d wa ki n g.

Rel ati ve h y p o gl yce mi a is defi ne d as a n y s y m pt o matic e ve nt d uri n g w hic h t he pers o n re p orts 
a n y of t he t ypi c al  s y m pt o ms of h y p o gl yce mia a n d i nter prets t h ose as i n dicati ve of 
h y p o gl yce mia, b ut a meas ure d B G c o nce ntrati o n > 3. 9 m m ol/ L is c ollecte d.

Pr o b a ble s y m pt o m atic h y p o gl yce mi a is defi ne d as s y m pt o ms of h y p o gl yce mia b ut B G 
meas ure me nt was n ot re p orte d.
All re p orte d cases of h y p o gl yce mia will be re p orte d o n t he h y p o gl yce mia e C R F.  If a 
h y p o gl yce mic e ve nt meets t he criteria of se vere, it als o nee ds t o be rec or de d o n t he A E e C R F as
serio us a n d re p orte d t o Lill y as a n S A E.
T o a v oi d d u plicate re p orti n g, all c o nsec uti ve B G val ues < ≤3. 9 m m o l/ L occ urri n g wit hi n a 1-h o ur 
peri o d ma y be c o nsi dere d t o be a si n gle h y p o gl yce mic e ve nt ( Wei n ber g et al. 2 0 1 0; Da n ne et al. 
2 0 1 3 , A D A . 2 0 2 0).  
9. 2. 2 . 5. C ar di o v a s c ul ar E v e nt s
Vi t al si g ns ( P R, S B P, D B P) will be m onit ore d t hr o u g h o ut t he st u d y , a n d 1 2-lea d 
electr ocar dio gr a m s ( E C Gs) will be m onit ore d at scree ni n g a n d Visit 1 7 ( Wee k 2 8). A n y 
cli nicall y rele va nt fi n di n g fr o m vit al si g ns a n d E C Gs o btai ne d bef ore t he first d osi n g of st u d y 
dr u g t hat res ults i n a dia g n osis s h o ul d be rec or de d i n e C R F as a pree xist i n g c o n diti on a n d 
me dical hist or y .  A n y cli nicall y rele va nt fi n di n g fr o m vital si g ns a n d E C Gs t hat occ urs after t he 
first d osi n g of st u d y dr u g a n d res ults i n a dia g n osis s h o uld be rec or de d as a n A E i n e C R F.   
I nf or mat i on o n C V ris k fact ors will be c o llecte d o n a n e C R F at Visit 3 ( baseli ne).  I n a d diti on t o 
m o nit ori n g of vital si g ns ( P R, S B P, D B P) a n d 1 2 -lea d electr ocar di o gra ms ( E C Gs) t hr o u g h o ut t he 
stu d y, data o n a n y ne w C V e ve nt will be pr os pecti vel y c o llecte d usi n g a C V e ve nt e C R F. C V 
e ve nts will be a nal yze d usi n g pr ef erre d i n vesti gat or re p orte d t er ms a n d a b n or mal E C G res ult.
Deat hs will be m o nit ore d t hr o u g h o ut t he st u d y . Rel e va nt data fr o m patie nts w h o e x perie nce d 
deat h will be e ntere d i nt o a s pecificall y  desi g ne d e C R F pa ge b y st u d y sit e.

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9.4.1. Electrocardiograms
After enrollment, if a clinically significant finding is identified from the additional ECGs 
conducted at the discretion of the investigator (including but not limited to changes in QT/QTc 
interval from baseline), the investigator will determine if the patient can continue on study drug.  
9.4.2. Vital SignsSitting BP and heart rate (PHR) will be measured using standardized 
equipment provided by the Sponsor according to the Schedule of 
Activities (Section 2).  Vital sign measurements should be taken before 
obtaining an ECG tracing and before collection of blood samples for 
laboratory testing, at visits where required (see Schedule of Activities 
Section 2).  The participant should be allowed to sit quietly for 5 minutes 
before vital sign measurements.  An appropriately sized cuff (cuff 
bladder encircling at least 80% of the arm) should be used to ensure the 
accuracy of BP measurements.  The arm used for the BP measurement 
should be supported at heart level.  At Visit 1 (screening), to determine 
which arm should be used to collect BP and PHR throughout the study. 
BP and PHR will be measured once in each arm and the arm that had the 
higher BP should be used to collect all 2 measurements of both BP and 
PHR at all study visits.  For each parameter (HPR, SBP/diastolic blood 
pressure [DBP]), 2 measurements will be taken using the same arm; the 
recordings should be taken at least 1 minute apart.  Each measurement of 
sitting HPR and BP is to be recorded in the eCRF.  Any AE related to 
changes in BP and HPR should be reported.
9.4.5.1.3. Additional hepatic data collection (hepatic safety CRF) in study
participants who have abnormal liver tests during the studyHepatic 
Safety Data Collection 
Additional hepatic safety data collection in hepatic safety case report forms (CRF) should be 
performed in study participants who meet 1 or more of the following 5 conditions:
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline ALT 
<1.5x ULN)

In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x 
baseline on 2 or more consecutive tests
2. Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome)

In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL 
≥2x baseline
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline ALP 
<1.5x ULN)

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
In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x 
baseline on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of study drug due to a hepatic even
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests if 
baseline ALT <1.5x ULN;  In participants with baseline ALT ≥1.5x ULN, the 
threshold is ALT ≥3x baseline on 2 or more consecutive tests;
2. Elevated TBL to ≥ 2x ULN if baseline TBL <1.5x ULN (except for cases of known 
Gilbert’s syndrome); In participants with baseline TBL ≥1.5x ULN, the threshold 
should be TBL ≥2x baseline;
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests if 
baseline ALP <1.5x ULN;  In participants with baseline ALP ≥1.5x ULN, the 
threshold is ALP ≥2x baseline on 2 or more consecutive blood tests;
4. Hepatic event considered to be a SAE;
5. Discontinuation of study drug due to a hepatic event.
Note: the interval between the two consecutive blood tests should be at least 2 days.
10.2. Populations for Analyses <<GBDI protocol section 12.2.1.1>>
Table GBGO.7.
Populations for Analyses
Population
Description
Per-Protocol (PP)
All patients in ITT and who also meet the following criteria:

Have no protocol deviations expected to impact the primary endpoint 
for HbA1c (see below);

Complete the treatment period (28 week [Visit 17]) for primary 
endpoint (that is, do not discontinue from the study drug early); 

At least 75% compliant with study drug for at least 75% of the visits.
10.3.1. General Statistical Considerations
Unless otherwise specified, listings will include all randomized patients.  Both efficacy and 
safety analyses will be conducted using the intention to treat (ITT) population. Unless otherwise 
specified, eEfficacy data from patients who started rescue therapy or discontinued study 
treatment prematurelyand remain in the study will be censored from the point of initiating rescue 
treatment or premature discontinuation onwards. Selected analyses will also be conducted using 
the PP and Completers populations.  The PP and Completers populations are subsets of the ITT 
population.
Two analysis models will be used for Tthe primary and key secondary continuous efficacy 
measures.  The primary analysis will be analyzed with mixed-model repeated measures 
(MMRM) analysis using restricted maximum likelihood (REML) (Section 10.3.3.1).
The secondary analysis for the primary and key secondary continuous endpoints will be analysis 
of covariance (ANCOVA) (Section 10.3.3.1 and 10.3.3.2).  Missing endpoints will be imputed 
with the last (postbaseline) observation carried forward (LOCF).  The proportion of patients 

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achieving the target HbA1c of <7.0% will be analyzed using a longitudinal logistic regression 
with repeated measurements (Section 10.3.3.2).
10.3.3.1. Primary Analyses
The primary outcome is the difference in HbA1c change from baseline between treatment groups 
based on the ITT population at the planned end of the treatment period of 28 weeks.  The 
primary analysis model will be a MMRM for HbA1c change from baseline to 28 weeks (Visit 
17) in the ITT population with treatment, OAM use, visit and treatment-by-visit as fixed effects, 
baseline HbA1c as a covariate, and patient as a random effect.  
The primary analysis model, MMRM, will be repeated using the PP and Completers populations.  
If the conclusion differs from that of the ITT population, the data and analyses will be further 
investigated.  
The secondary analysis model will be an ANCOVA for HbA1c change from baseline to 
endpoint, with missing endpoints imputed with the LOCF using post-baseline data only.
10.3.3.2. Secondary Analyses
The key secondary continuous efficacy measures (change from baseline in body weight and 
FBG) will be analyzed using both models, the MMRM and the ANCOVA with LOCF models.  
The MMRM model will include independent variables of treatment, OAM usage (metformin 
alone, acarbose alone, metformin and acarbose), baselinescreening HbA1c stratum (<≤8.5% vs. 
≥>8.5%), visit, and treatment-by-visit as fixed effects and baseline dependent variable as 
covariates. The ANCOVA model will include independent variables of treatment, OAM usage 
(metformin alone, acarbose alone, metformin and acarbose), screening HbA1c stratum (≤8.5% 
vs. >8.5%) as fixed effects and baseline dependent variable as covariates.
10.3.3.3. Tertiary/Exploratory Analyses
The other objectives include triple endpoint (HbA1c <7% and no weight gain [<0.1 kg] at 28 
weeks, and no documented symptomatic hypoglycemia [BG <≤3.9 mmol/L] during the 
maintenance period); double endpoint (HbA1c <7% at 28 weeks and no documented 
symptomatic hypoglycemia [BG <≤3.9 mmol/L] during the maintenance period); Proportion of 
patients achieving HbA1c target <7.0% and without weight gain (<0.1 kg) at 28 weeks.
Furthermore, we will conduct some additional efficacy analysis without censoring the data after 
rescue therapy or premature treatment discontinuation (whichever occurs first). Missing 
endpoints will be imputed by jumping to the reference method. Measurements include actual 
HbA1c, body weight and FSG and frequency counts and percentage of patients achieving the 
HbA1c target of <7.0% and changes in these measures from baseline. We will analyze HbA1c, 
body weight and FSG by ANCOVA. Percentages of patients achieving the target of HbA1c 
<7.0% will be analyzed using longitudinal logistic regression with repeated measurements.

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10.3.4. Safety Analyses
The safety analysis will include analysis of AEs, SAEs, hypoglycemic and hyperglycemic 
episodes, vital signs, electrocardiogram and laboratory analystes.  Unless otherwise specified, the 
ITT population will be used for analyses of safety measures.
10.3.4.3. Hypoglycemic Episodes
Hypoglycemic episodes will be analyzed using 2 hypoglycemic thresholds:  Level 1 (glucose 
alert level, <3.9 mmol/L [3.9 mmol/L70 mg/dL] and ≥ 3.0 mmol/L [54 mg/dL]) and Level 2 
(clinically significant hypoglycemia level, <3.0 mmol/L [3.0 mmol/L 54 mg/dL]).  Other
categories, including the categories above defined with different glucose thresholds, may also be 
included in these analyses when deemed appropriate.
The incidence of hypoglycemic episodes will be summarized by frequencies and proportion for 
each treatment group, by visit as well as overall.  Treatment differences in the incidence of 
hypoglycemic episodes will be assessed using Fisher’s exact tests or Chi-square test.  Treatment 
differences in rates of hypoglycemic episodes (episodes/patient/30 days; episodes/patient/year) 
will be analyzed using a generalized linear mixed-effects model assuming negative binomial 
distribution.  The model will include treatment, OAM usage (metformin alone, acarbose alone, 
metformin and acarbose), baselinescreening HbA1c stratum (<≤8.5% vs. ≥>8.5%), visit, 
treatment-by-visit interaction, and baseline hypoglycemia rate.  The logarithm of days between 
visits will be included as an offset to account for possible unequal duration between visits and 
between patients.  
10.3.7.2. Subgroup Analyses
•
Baseline HbA1c (≤<8.5%, >≥8.5%)
11. References
[ADA] American Diabetes Association. Glycemic targets: Standards of medical care in diabetes-   
2020.  Diabetes Care 2020 Jan; 43(Supplement 1):S66–S76.
[ADA] American Diabetes Association. 2019, Pharmacologic Approaches to Glycemic 
Treatment: Standards of Medical Care in Diabetes—-2019. Diabetes Care 2019 Jan; 
42(Supplement 1): S90-S102. 
Rosenstock J, Fonseca VA, Fross JL, Ratner RE, Ahren B, Chow FC, Yang F, Miller D, Johnson 
SL, Stewart MW, Leiter LA; Harmony 6 Study Group. Advancing basal insulin replacement in 
type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of 
adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin 
lispro. Diabetes Care. 2014;37(8):2317-2325.
Rosenstock J, Shenouda SK, Bergenstal RM, et al. Baseline factors associated with glycemic
control and weight loss when exenatide twice daily is added to optimized insulin glargine in 
patients with type 2 diabetes. Diabetes Care. 2012;35(5):955‐958.
Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC, 2015.

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Weinberg ME, Bacchetti P, Rushakoff RJ. Frequent repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582.
Yki-Järvinen H, Kauppinen-Mäkelin R, Tiikkainen M, Vähätalo M, Virtamo H, Nikkilä K, 
Tulokas T, Hulme S, Hardy K, McNulty S, Hänninen J, Levänen H, Lahdenperä S, Lehtonen 
R, Ryysy L. Insulin glargine or NPH combined with metformin in type 2 diabetes: the 
LANMET study. Diabetologia. 2006;49(3):442-451.
Ahmann A, Rodbard HW, Rosenstock J, et al. Efficacy and safety of liraglutide versus placebo 
added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: 
a randomized, placebo‐controlled trial. Diabetes Obes Metab. 2015;17(11):1056‐1064 .
Buse JB, Bergenstal RM, Glass LC, et al. Use of twice‐daily exenatide in basal insulin‐treated 
patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 
2011;154(2):103‐112.
Rosenstock J, Shenouda SK, Bergenstal RM, et al. Baseline factors associated with glycemic 
control and weight loss when exenatide twice daily is added to optimized insulin glargine in 
patients with type 2 diabetes. Diabetes Care. 2012;35(5):955‐958.
Appendix 1. Abbreviations and Definitions
ADA
American Diabetes Association
adjudication 
committee
An external committee whose purpose is to evaluate study data and decide whether a 
study endpoint or other criterion has been met.
CEC
Clinical Endpoint Committee
CK
creatine kinase
D.Bil
direct bilirubin
DMC
Data Monitoring Committee
EASD
European Association for the Study of Diabetes
EQ-5D-5L
EuroQol 5-dimension questionnaire
FDAFBG
fasting blood glucoseFood and Drug Administration
FBG FDA
fasting blood glucoseFood and Drug Administration
FSH
follicle-stimulating hormone
GAD
glutamic acid decarboxylase
HR
heart rate
ICA
islet cell antibodies

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LOCF
last observation carried forward
MAR
missing at random
MDDAB 
Medication Delivery Device Assessment Battery
MEN
multiple endocrine neoplasia 
MNAR
missing not at random
NAFLD
nonalcoholic fatty liver disease  
NOAEL
no-observed-adverse-effect level
NPH
neutral protamine Hagedorn
PMM
pattern-mixture model
QTcF
QT corrected for heart rate using Fridericia’s formula
SDPSUP
single-dose use pen
SmPC
Summary of Product Characteristics
T2D
type 2 diabetes mellitus
USPI
United States Prescribing InformationPackage Insert
Appendix 2. Clinical Laboratory Tests
Clinical Laboratory Testsa,c
Calcitoninc
Pancreas (Exocrine)c
c Additional blood samples may be collected based on the investigator’s judgment.
g This value will be calculated.  If triglycerides >400 ng/mLmg/dL, then direct LDL will be 
assayed.

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Appendix 4. Liver Safety: Suggested Actions and Follow-Up AssessmentsHepatic 
Monitoring Tests for Treatment-Emergent Abnormality
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 9.4.5.1 for 
guidance on appropriate test selection.

For testing selected, analysis is required to be completed by the Lilly designated central 
laboratory except for those testings that are denoted as local below.

Local testing may be performed in addition to central testing when required for immediate 
patient management.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells) 
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry  
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adductsc
Platelets
Alkaline Phosphatase Isoenzymesc
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copperc
Ethyl Alcohol (EtOH)
Prothrombin Time, international normalized ratio 
(PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
    HAV Total Antibody
Immunoglobulin IgM (Quantitative)
    HAV IgM Antibody
Phosphatidylethanol (PEth) c
Hepatis B Virus (HBV) Testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug Screen
    Hepatitis B surface antibody (Anti-HBs) 
Ethyl glucuronide (EtG) c
    Hepatitis B core total antibody (Anti-HBc)
Other Serology
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA)

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    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a
    HBV DNA d
Anti-actin antibody c, b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody
    HCV RNA d
    EBV DNA d
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNA d
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA d
    HSV (Type 1 and 2) DNA c, d
Microbiology c
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
    Blood
    Urine
a
Not required if anti-actin antibody is tested.
b
Not required if anti-smooth muscle antibody (ASMA) is tested.
c
Assayed ONLY by investigator-designated local laboratory if available; no central testing available.
d
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.

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Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.
Appendix 6. Classification of Contraceptive Methods
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.

Leo Document ID = 64c5c8ad-f1ed-4922-9abc-808bbfb94fd3
Approver: 
Approval Date & Time: 29-Jul-2020 08:37:21 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 30-Jul-2020 13:20:58 GMT
Signature meaning: Approved
PPD
PPD