A 24-week Multicenter, Open-label, Single-arm Study to Evaluate Safety in Patients With Type 2 Diabetes Mellitus in India Treated With Dulaglutide
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company

Protocol H9X-IN-GBGR
A 24-week Multicenter, Open-label, Single-arm Study to Evaluate Safety in Patients With Type 2 
Diabetes Mellitus in India Treated With Dulaglutide
NCT05659537
Approval Date: 19-Jun-2023

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Title Page  
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. 
Protocol Title: 
A 24-week multicenter, open-label, single-arm study to evaluate safety in patients with type 2 
diabetes mellitus in India treated with dulaglutide. 
Protocol Number: H9X-IN-GBGR 
Amendment Number: H9X-IN-GBGR (b) 
Compound: Dulaglutide (LY2189265) 
Brief Title: 
A study to investigate adverse and serious adverse events with dulaglutide in participants with 
type 2 diabetes mellitus in India. 
Study Phase: 4 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: 
Plot No. 92, Institutional Area, Sector 32, Gurugram, Haryana 122001, India 
Regulatory Agency Identifier Number: Not applicable 
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below. 
 
 
 
Document ID: VV-CLIN-117803 
 
 
 
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Medical Monitor Name and Contact Information will be provided separately.  
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Initial Protocol 
02-Jun-2022 
Amendment (b) 
The amendment is considered to be non-substantial because it is not likely to have a significant 
impact on the  
● safety or the rights of the study participants 
● reliability and robustness of the data generated in the clinical study, and 
● the quality or safety of any investigational medicinal product used in the study. 
Overall rationale for the amendment 
Protocol H9X-IN-GBGR titled “A 24-week multicenter, open-label, single-arm study to evaluate 
safety in patients with type 2 diabetes mellitus in India treated with dulaglutide” has been 
amended. The new protocol is indicated by Amendment (b) 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: 
Section Number and Name 
Description of 
Change 
Brief Rationale 
Section 1.3 Schedule of Activities 
Marked X for AEs in 
Screening column 
 
Corrected the error. 
Added “temperature” in 
Vital signs 
 
Corrected the error. 
Removed “insulin dose 
(if the patient is taking 
insulin)” in Diary 
compliance check 
Patient Diary does not have a provision of 
capturing Insulin Dose.  
Insulin dose can be captured in source 
document (eCRF) 
Section 2.1 Study Rationale 
Deleted “combination 
therapy” for 0.75mg in 
Study Rationale. 
0.75 mg is not recommended as a 
combination therapy in the label - it is only 
approved as a monotherapy- since 0.75 mg 
dose is approved, one can maintain the 
patient on this if the patient is not able to 
tolerate 1.5 mg for some reason or as is 
common practice, one can start on 0.75 mg 
and build up the dose to 1.5 mg. 
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Section Number and Name 
Description of 
Change 
Brief Rationale 
Figure 6.1 
For GI Side effects, - 
Yes, superscript “a” was 
added to clarify. 
Corrected the error. 
Section 6.5 Dose modification 
Updated language by 
adding “permitted only 
once”. 
There could be a titration in the initial part 
of the study as explained in the dispensing 
scenarios which usually covers the first 4-6 
weeks in the study. Thereafter and once 
this happens, this titration is not allowed 
beyond that period. 
Section 6.8 Concomitant therapy 
Replaced the 
hypoglycemia word to 
“hyperglycemia” 
The chances of developing hypoglycemia 
with dulaglutide per se is less. However, if 
there is an occasional hypoglycemia in a 
patient following dulaglutide start, the 
concomitant dose of SU and or insulin 
should be modified as per the PI 
discretion. 
Section 7.1.3 Temporary 
Discontinuation 
   
 
Updated the language to 
“allowed once” and 
added that “Study drug 
discontinuation decision 
will be taken post the 
titration in the initial 4-6 
weeks of the study” 
Corrected the error. 
Study drug discontinuation decision will 
be taken post the titration in the initial 4-6 
weeks of the study. 
Section 8.2.5. Hepatic Monitoring 
For additional hepatic 
data collection, “hepatic 
safety CRF” and 
“collection in the hepatic 
safety in” was deleted. 
There is no eCRF page for hepatic safety. 
All central lab data are received through 
medical listing and not being captured in 
eCRF. 
Section 8.3.1 Timing and Mechanism 
for Collecting Events 
SAE CRF was corrected 
to SAE paper form in the 
table 
Corrected the error. 
Section 9.3 Analyses Sets 
For enrolled participant 
analysis set, Description 
was updated to include 
“screen positive” 
To be consistent with SAP. 
Section 10.3.4 Recording and Follow-
Up of AE and/or SAE and Product 
Complaints 
“Facsimile transmission 
of SAE paper form” was 
updated to “E-mail 
transmission of SAE 
paper form”. 
 
“SAE CRF pages” was 
corrected to “SAE paper 
form” 
Corrected the error. 
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Table of Contents  
Section 
Page  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................13 
2. 
Introduction ...................................................................................................................18 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................18 
2.3. 
Benefit/Risk Assessment ................................................................................................19 
2.3.1. 
Risk Assessment .............................................................................................................19 
2.3.2. 
Benefit Assessment .........................................................................................................19 
2.3.3. 
Overall Benefit/Risk Conclusion ....................................................................................19 
3. 
Objectives and Endpoints ............................................................................................20 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.2. 
Scientific Rationale for Study Design ............................................................................22 
4.3. 
Justification for Dose ......................................................................................................22 
4.4. 
End of Study Definition ..................................................................................................22 
5. 
Study Population ...........................................................................................................23 
5.1. 
Inclusion Criteria ............................................................................................................23 
5.2. 
Exclusion Criteria ...........................................................................................................23 
5.3. 
Lifestyle Considerations .................................................................................................24 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................24 
5.4. 
Screen Failures ................................................................................................................25 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................25 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................26 
6.1. 
Study Intervention(s) Administered................................................................................26 
6.1.1. 
Rescue Medicine .............................................................................................................31 
6.1.2. 
Background Therapy or Standard of Care ......................................................................31 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................31 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................31 
6.4. 
Study Intervention Compliance ......................................................................................31 
6.5. 
Dose Modification ..........................................................................................................32 
6.6. 
Continued Access to Study Intervention After the End of the 
Study ...............................................................................................................................32 
6.7. 
Treatment of Overdose ...................................................................................................32 
6.8. 
Concomitant Therapy .....................................................................................................32 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34 
7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................34 
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7.1.2. 
Hypersensitivity Reactions .............................................................................................36 
7.1.3. 
Temporary Discontinuation ............................................................................................36 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................37 
7.3. 
Lost to Follow-Up ...........................................................................................................37 
8. 
Study Assessments and Procedures.............................................................................38 
8.1. 
Efficacy Assessments .....................................................................................................38 
8.2. 
Safety Assessments .........................................................................................................38 
8.2.1. 
Physical Examinations ....................................................................................................38 
8.2.2. 
Vital Signs .......................................................................................................................39 
8.2.3. 
Electrocardiograms .........................................................................................................39 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................39 
8.2.5. 
Hepatic Monitoring .........................................................................................................40 
8.2.6. 
Pregnancy Testing ...........................................................................................................42 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................42 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................43 
8.3.2. 
Pregnancy ........................................................................................................................45 
8.3.3. 
Systemic Hypersensitivity Reactions ..............................................................................46 
8.3.4. 
Injection-Site Reactions ..................................................................................................46 
8.3.5. 
Hypoglycemia .................................................................................................................46 
8.3.6. 
Adverse Events of Special Interest .................................................................................47 
8.4. 
Pharmacokinetics ............................................................................................................48 
8.5. 
Pharmacodynamics .........................................................................................................48 
8.6. 
Genetics ..........................................................................................................................48 
8.7. 
Biomarkers ......................................................................................................................48 
8.8. 
Immunogenicity Assessments.........................................................................................48 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................48 
9. 
Statistical Considerations .............................................................................................49 
9.1. 
Statistical Hypotheses .....................................................................................................49 
9.2. 
Statistical Methodology ..................................................................................................49 
9.3. 
Analyses Sets ..................................................................................................................49 
9.4. 
Statistical Analyses .........................................................................................................49 
9.4.1. 
General Considerations ...................................................................................................49 
9.4.2. 
Primary Endpoints Analysis ...........................................................................................51 
9.4.3. 
Secondary Endpoints Analysis .......................................................................................52 
9.4.4. 
Exploratory Endpoints Analysis .....................................................................................52 
9.4.5. 
Other Safety Analyses.....................................................................................................53 
9.4.6. 
Other Analyses ................................................................................................................53 
9.5. 
Interim Analysis ..............................................................................................................54 
9.6. 
Sample Size Determination ............................................................................................54 
10. 
Supporting Documentation and Operational Considerations ..................................55 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................55 
10.1.1. Regulatory and Ethical Considerations ...........................................................................55 
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10.1.2. Financial Disclosure........................................................................................................55 
10.1.3. Informed Consent Process ..............................................................................................56 
10.1.4. Data Protection................................................................................................................56 
10.1.5. Dissemination of Clinical Study Data.............................................................................56 
10.1.6. Data Quality Assurance ..................................................................................................56 
10.1.7. Source Documents ..........................................................................................................58 
10.1.8. Study and Site Start and Closure ....................................................................................58 
10.1.9. Publication Policy ...........................................................................................................59 
10.1.10. Investigator Information .................................................................................................59 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................60 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting ...........................................................................................................62 
10.3.1. Definition of AE .............................................................................................................62 
10.3.2. Definition of SAE ...........................................................................................................63 
10.3.3. Definition of Product Complaints ...................................................................................64 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................65 
10.3.5. Reporting of SAEs ..........................................................................................................66 
10.3.6. Regulatory Reporting Requirements ...............................................................................67 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................68 
10.4.1. Definitions.......................................................................................................................68 
10.4.2. Contraception Guidance..................................................................................................68 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments ....................................................................................................................71 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................73 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................77 
11. 
References ......................................................................................................................81 
 
 
 
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Table of Contents 
Figure 
Page 
Figure 6.1. 
IP dispensing scenarios – Scenario 1 (top panel), Scenario 2 (middle panel), and 
Scenario 3 (bottom panel). ............................................................................................................ 30 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
A 24-week multicenter, open-label, single-arm study to evaluate safety in patients with type 2 
diabetes mellitus in India treated with dulaglutide. 
Brief Title: 
A study to investigate adverse and serious adverse events with dulaglutide in participants with 
type 2 diabetes mellitus in India. 
Regulatory Agency Identifier Number: Not applicable 
Rationale: 
Once weekly dulaglutide was approved on 23 December 2014 by CDSCO. As per the approved 
label in India, once-weekly 1.5 mg dulaglutide is recommended as a combination therapy in 
patients with T2DM in addition to the ongoing OHAs and/or insulin. In select cases, for 
example, in patients with metformin intolerance, 0.75 mg dulaglutide is recommended as 
monotherapy. The CDSCO had stipulated a Phase 4 study to document the experience of the 
local population with T2DM from India as a clause toward marketing authorization for 
dulaglutide in India. A Phase 4 observational study to assess the safety including AEs and SAEs 
with dulaglutide in patients with T2DM India is currently ongoing. This Phase 4 clinical study, 
over and above the observational study, is being proposed to fulfill this marketing authorization 
clause. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Assess the safety profile of 1.5 and 0.75 mg 
dulaglutide in patients with T2DM in India 
Incidence of AEs (deaths, SAEs, TEAEs, and 
hypoglycemia, including severe hypoglycemia) 
 
Proportion of patients reporting AEs and SAEs 
between baseline and Week 24 
 
Incidence of GI AEs 
Secondary 
Change in HbA1c for pooled doses of dulaglutide 
Mean change in HbA1c from baseline to Week 24 
Exploratory 
Change in body weight 
Mean change in body weight from baseline to Week 24 
Change in FBG 
Mean change in FBG from baseline to Week 24  
Change in vital signs 
Change in systolic blood pressure, diastolic blood 
pressure, and pulse rate from baseline to Week 24 
Overall Design 
This is a Phase 4, single-arm study to study the safety of dulaglutide in patients with T2DM in 
India who are on stable doses of oral antihyperglycemic medications with or without stable doses 
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of basal or premix insulin for the last 3 months prior to screening. The efficacy profile of 
dulaglutide will be measured as a secondary endpoint. 
Brief Summary: 
The purpose of this study is to assess the safety profile of 1.5 and 0.75 mg dulaglutide in patients 
with T2DM in India. 
The study includes a 
 Screening Visit 
 2-week lead-in period 
 24-week treatment period, and 
 follow-up period 4 weeks after the last treatment. 
Study Population: 
In general, participants may take part in the study if they 
 are 18 years of age or older, at the time of signing the informed consent 
 reside in India 
 have a diagnosis of T2DM of at least 1-year duration currently treated with stable doses 
of oral antihyperglycemic medications with or without stable doses of basal or premix 
insulin for the last 3 months prior to screening. Premix insulin is allowed up to twice 
daily in the screening period to be taken up further. Doses of other OHAs will be 
optimized as per investigator’s discretion. Patients on thrice-daily premix insulin or full 
basal bolus insulin (insulin regimen 3-4 times daily) therapy are excluded from the study 
 have HbA1c ≥7.5% and ≤11.5%, both inclusive, at screening, and 
 have BMI ≥23 kg/m2. 
In general, participants may not take part in the study if they have 
 a diagnosis of T1DM or latent autoimmune diabetes, or specific type of diabetes other 
than T2DM 
 been treated with antihyperglycemic medication like GLP-1 RA or have a prior history of 
any contraindication to GLP-1 RA therapy within 3 months prior to screening, or 
 eGFR <15 ml/min/1.73m2. 
Number of Participants: 
An estimated 250 participants will be screened, and assuming a 20% screen failure rate, an 
estimated 200 participants will be initiated on IP. Assuming a 20% dropout rate by the end of the 
study period, approximately 160 patients at the end of the study would allow for an adequate 
description of AEs and other safety outcomes. This is required to fulfill the market authorization 
clause.  
Intervention Groups and Duration: 
This table lists the intervention used in this clinical study. 
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Intervention Name 
Dulaglutide 
Dosage Levels 
0.75 or 1.5 mg 
Route of 
Administration 
Subcutaneous injection 
Frequency of 
Administration 
Once weekly 
 
The following circumstances are permitted: 
1. Treatment will be started with dulaglutide 1.5 mg as combination therapy or dulaglutide 
0.75 mg as combination therapy or monotherapy. For patients who report GI AEs after 
starting treatment with 1.5 mg dulaglutide, the investigator may reduce the dose to 
0.75 mg based on symptoms reported by patients. Treatment will be continued with 
0.75 mg for 2 to 3 weeks. Thereafter, the 1.5-mg dose will be reintroduced. 
2. As per common practice in India, treatment may be started with 0.75 mg dulaglutide as a 
combination therapy in select cases (Wasir et al. 2018). The dose may be up titrated to 
1.5 mg after a period of 2 to 4 weeks in consultation with the medical monitor. 
Ethical Considerations of Benefit/Risk: 
Considering the clinical data to date and measures taken to minimize risk for the participants in 
this study, the potential risks identified in association with dulaglutide are justified by the 
anticipated benefits that may be afforded to persons with T2DM. 
Data Monitoring Committee: No 
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1.2. 
Schema  
 
 
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1.3. 
Schedule of Activities (SoA)  
Screening 
Treatment Period 
Follow-Up 
Comments 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
801 
  
Weeks from Start of 
Treatment 
-2 
0 
4 
8 
12 
16 
20 
24 
28 
  
Visit Interval 
Tolerance (days) 
±3 
— 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
  
Visit Detail 
F 
F 
T 
T 
F 
T 
T 
F 
T 
T=telehealth visit 
F=fasting visit 
Informed consent 
X 
The ICF must be signed by 
patients or their caregivers 
before any -protocol specific 
tests or procedures are 
performed. See 
Section 10.1.3 for additional 
details. 
Inclusion or exclusion 
criteria, review, and 
confirm 
X 
X 
 
 
 
 
 
 
 
The Investigator will confirm 
inclusion and exclusion 
criteria prior to enrollment 
and administration of first 
dose of study intervention. 
Demographics 
X 
Includes ethnicity (where 
permissible), year of birth, 
gender, and race 
Preexisting conditions 
and medical history, 
including relevant 
surgical history  
X 
  
  
  
  
  
Collect all ongoing 
conditions and relevant past 
surgical and medical history 
Prespecified medical 
history (indication and 
history of interest) 
X  
  
  
  
  
  
  
Prior treatments for 
indication 
X  
  
  
  
  
  
 
 
 
  
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Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
  
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs are any events that occur 
after signing the informed 
consent. 
These will also include any 
AE reported after the first 
dose of dulaglutide. 
Hypoglycemia events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment based on 
participant history and diary 
entries 
Physical Evaluation 
Height 
X 
 
 
 
 
 
 
 
 
Participant should remove 
shoes. 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
Includes temperature, blood 
pressure, and pulse rate. 
Measure 3 times, using the 
same arm, after participant 
has been sitting at least 5 min 
and before ECG tracing and 
collection of blood samples 
for laboratory testing. Of the 
3 measurements, the blood 
pressure and pulse rate 
values observed during the 
third and final measurements 
will be entered in the eCRF. 
Additional vital signs may be 
measured as necessary at 
investigator’s discretion. 
Physical examination 
X 
 
 
 
 
 
 
 
 
This includes examination 
for any sensory loss, motor 
neuropathy, and retinopathy. 
Additional physical 
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examinations may be 
completed as necessary at 
investigator’s discretion. 
12-lead ECG (local) 
X 
 
 
 
 
 
 
 
 
Participants should be supine 
for approximately 5-10 min 
before ECG collections and 
remain supine but awake 
during the ECG collection.  
ECGs may be repeated at the 
investigator’s discretion at 
any visit. 
Diabetes counseling, 
training, and education 
 
X 
 
 
X 
 
 
X 
 
Includes SMBG and 
hypoglycemia (see 
Section 5.3). 
After Visit 2, conduct as 
needed. 
Provide training on 
paper diary and 
glucometer 
 
X 
 
 
X 
 
 
 
 
After Visit 2, conduct as 
needed. 
Refer to Section 4.1. 
 
Participant Diary and Blood Glucose Meter 
Dispense paper diary 
and glucometer 
 
X 
 
 
X 
 
 
 
 
Dispense supplies as needed. 
Re-dispense paper diary at 
Visit 5. 
Diary compliance check 
 
X 
X 
X 
X 
X 
X 
X 
 
Review entries of BG and  
dulaglutide.  If participant is 
not compliant, study 
personnel will re-educate the 
participant on study 
requirements for continued 
study participation. 
Collect information from 
study diary 
 
X 
X 
X 
X 
X 
X 
X 
 
Includes SMBG results, 
hypoglycemic events, , date, 
and exact time of every study 
drug injection. 
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Laboratory Tests and Sample Collections 
Hematology 
X 
X 
 
 
X 
 
 
X 
 
 
HbA1c 
X 
X 
 
 
X 
 
 
X 
 
 
Clinical chemistry 
X 
X 
 
 
X 
 
 
X 
 
 
FBG 
 
 X 
 
 
X 
 
 
X 
 
 
Lipid panel 
 
X 
 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
X 
 
 
 
 
 
 
 
For only WOCBP 
Urine pregnancy (local) 
 
X 
 
 
 
 
 
 
 
The test will be done only for 
WOCBP. The result must be 
available prior to first dose of 
intervention.  
Perform additional 
pregnancy tests if a 
menstrual period is missed, if 
there is clinical suspicion of 
pregnancy, or as required by 
local law or regulation. 
Follicle-stimulating 
hormone 
X 
 
 
 
 
 
 
 
 
Perform as needed to confirm 
postmenopausal status in 
women. Definition in 
Section 10.4. 
eGFR (CKD-EPI) 
X 
X 
 
 
 
 
 
X 
 
 
Urinary 
albumin/creatinine ratio 
 
X 
 
 
 
 
 
X 
 
 
Dosing-Related Activities 
Dosing and injection 
training 
 
X 
 
 
X 
 
 
 
 
After Visit 2, conduct as 
needed. 
Distribute study drug 
 
X 
 
 
X 
 
 
 
 
 
IMP administration 
 
Once weekly 
 
The first dose will be 
administered under medical 
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Abbreviations: BG = blood glucose; CKD-EPI = chronic kidney disease-epidemiology; ECG = electrocardiogram; eGFR = estimated glomerular filtration 
rate; ICF = informed consent form; IMP = investigational medicinal product; SMBG = self-monitored blood glucose; WOCBP = women of childbearing 
potential.  
supervision by the 
investigator or designee at 
the clinical site. Subsequent 
doses will be self-
administered by participants 
at home. 
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2. 
Introduction  
Dulaglutide (LY2189265; Eli Lilly and Company [Lilly], Indianapolis, IN, USA) is a long-acting 
GLP-1 RA that was approved on 23 December 2014 by CDSCO for the treatment of adults with 
T2DM. 
2.1. 
Study Rationale  
Once-weekly dulaglutide was approved on 23 December 2014 by CDSCO. As per the approved 
label in India, once-weekly 1.5 mg dulaglutide is recommended as a combination therapy in 
patients with T2DM in addition to the ongoing OHAs and/or insulin. In select cases, for 
example, in patients with metformin intolerance, 0.75 mg dulaglutide is recommended as 
monotherapy. The CDSCO had stipulated a Phase 4 study to document the experience of the 
local population with T2DM from India as a clause toward marketing authorization for 
dulaglutide in India. A Phase 4 observational study to assess the safety including AEs and SAEs 
with dulaglutide in patients with T2DM India is currently ongoing. This Phase 4 clinical study, 
over and above the observational study, is being proposed to fulfill this marketing authorization 
clause.  
2.2. 
Background  
Of the current population burdened with T2DM, 60% are Asians (Hu 2011). As of 2021, India 
has an estimated 74 million people with diabetes, the second largest number for any individual 
country in the world. The projected growth of patients with diabetes between 2021 and 2045 in 
India is one of the highest in the world. By 2045, approximately 125 million people in India are 
projected to be suffering from diabetes (IDF Diabetes Atlas [https://diabetesatlas.org/]). T2D is 
the most common type of diabetes, accounting for over 90% of all diabetes cases. There is a 
paucity of data on the current state of T2DM glycemic control in India. The recently concluded 
India Diabetes Study has highlighted the need for optimum cardiovascular risk control in 
recently diagnosed T2DM in India, along with the need for optimum glycemic control. GLP-1 
RA along with sodium-glucose co-transporter-2 inhibitors are being increasingly used in patients 
with T2DM in India for optimal glycemic control along with additional benefits of weight loss 
and cardiovascular event prevention. Dulaglutide, which is a once-weekly GLP-1 RA, is 
available in India since the last 5 years and is being used as combination therapy in patients with 
T2DM and in select cases (for example, metformin-intolerant patients) as monotherapy as well. 
The efficacy and safety of dulaglutide have been well established in the AWARD program, 
which has shown powerful and sustained HbA1c reduction for up to 2 years, and in the 
cardiovascular outcome study, which has shown reduction in outcomes in patients with T2D both 
with cardiovascular disease and those with risk factors. Dulaglutide is well tolerated with 
predominant side effects being GI in nature and dominated by nausea, vomiting, and diarrhea. 
Some patients have also complained of abdominal pain, loss of appetite, dyspepsia, and 
constipation. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of dulaglutide is 
provided in the IB. 
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2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dulaglutide may be found in the IB and patient information leaflet. 
2.3.1. 
Risk Assessment  
The AE profile with dulaglutide has been mainly GI in nature, with nausea, diarrhea, and 
vomiting being the most common AEs. 
The measures taken in the present proposed study are sufficient to ensure the safety of the 
participants in this study, and the risks due to AEs are outweighed by the potential benefits seen 
with the molecule. 
2.3.2. Benefit Assessment  
The AWARD program, which included 10 completed placebo- and/or active-controlled Phase 3 
studies of more than 5800 patients with T2DM, has shown powerful and sustained HbA1c 
reduction in patients with T2DM with additional benefits of weight loss. The REWIND study 
showed that dulaglutide improves cardiovascular outcomes in patients with T2DM with 
established cardiovascular disease or with risk factors, and no new safety concerns were reported 
(Gerstein et al. 2019). Additionally, real-world studies in India of more than 700 patients in 
patients with T2D showed that dulaglutide reduced HbA1c and reduced weight as a secondary 
benefit. Mild-to-moderate GI AEs were reported, which is at par with what is seen with 
GLP-1 RAs (Ghosal and Sinha 2018; Robinson et al. 2020; Srivastava et al. 2018).  
2.3.3. Overall Benefit/Risk Conclusion  
Taking into account the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with dulaglutide are justified by the anticipated 
benefits that may be afforded to participants with T2DM. 
 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
Assess the safety profile of 1.5 and 0.75 mg 
dulaglutide in patients with T2DM in India  
Incidence of AEs (deaths, SAEs, TEAEs, and 
hypoglycemia, including severe hypoglycemia) 
 
Proportion of patients reporting AEs and SAEs 
between baseline and Week 24 
 
Incidence of GI AEs 
Secondary 
Change in HbA1c for pooled doses of dulaglutide 
Mean change in HbA1c from baseline to Week 24 
Exploratory 
Change in body weight 
Mean change in body weight from baseline to Week 24 
Change in FBG 
Mean change in FBG from baseline to Week 24  
Change in vital signs 
Change in systolic blood pressure, diastolic blood 
pressure, and pulse rate from baseline to Week 24 
 
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4. 
Study Design  
4.1. 
Overall Design  
This is a Phase 4, single-arm study to study the safety of dulaglutide in patients with T2DM in 
India who are on stable doses of oral antihyperglycemic medications with or without stable doses 
of basal or premix insulin for the last 3 months prior to screening. The efficacy profile of 
dulaglutide will be measured as a secondary endpoint. 
The study consists of a 
screening visit 
2-week lead-in period 
24-week treatment period, and 
safety follow-up visit.  
 
Screening and lead-in 
Visit 1: Screening 
Interested participants will sign the appropriate informed consent document(s) prior to initiating 
any procedures. 
The investigator will review medical history, symptoms, risk factors, and other inclusion and 
exclusion criteria prior to any diagnostic procedures. If the participant is eligible after this 
review, the site will perform the diagnostic procedures to confirm eligibility. 
Treatment period 
Visit 2 
Participants will receive their glucometer and first paper diary . 
Participants will receive training on 
 
diabetes self-monitoring and management 
 
study glucometer 
 
paper diaries, and 
 
study requirements.  
All participants will be treated with once weekly dulaglutide throughout the treatment period, as 
described in Section 6.1.  
Visit 3 through Visit 8 and safety follow-up Visit 801  
Study personnel will collect the first paper diary and dispense a second paper diary at Visit 5. 
Study personnel and participants will complete all visit procedures described in the SoA. 
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4.2. 
Scientific Rationale for Study Design  
Primary endpoint 
The primary measurement is the incidence of AEs, a widely used measure to study safety 
profiles. 
Overall design 
Dulaglutide is approved in India for the treatment of T2DM. Dulaglutide, like other GLP-1 RAs 
that are available in India, is an established mode of therapy for T2DM. The aim of this study is 
to investigate the AEs and SAEs that may occur when patients with T2DM take dulaglutide. 
Hence, a comparator group has not been considered for this study.  
The most common side effects with dulaglutide are GI in nature and mainly comprise of nausea, 
vomiting, and/or diarrhea. These usually occur early during therapy, are mostly mild to moderate 
in nature, and are self-limiting over the next 2 to 4 weeks after therapy initiation. A Phase 1 
study with dulaglutide in elderly patients with T2DM from has shown reduction of FBG and 
postprandial glucose with the first dose of dulaglutide. Statistically significant HbA1c reduction 
and weight loss as a secondary benefit have been seen with dulaglutide compared to placebo 
within 12 weeks of start of therapy in the AWARD studies and various published real-world 
experiences. Hence, the proposed treatment duration of 24 weeks in this study is a reasonable 
timeframe to observe the effects of dulaglutide both from an AE and efficacy perspective. The 
follow-up visit after the last dose is designed to capture any safety data that may occur after the 
drug is stopped. 
4.3. 
Justification for Dose  
Dulaglutide will be recommended as per the approved label in India. Once-weekly 1.5 mg 
dulaglutide is recommended as a combination therapy with ongoing OHAs and/or insulin. In 
select cases, for example, in patients with metformin intolerance, 0.75 mg dulaglutide is 
recommended as monotherapy or combination therapy, and this will be at the investigator’s 
discretion. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit. 
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5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. The intended study population is adult patients 
who have been diagnosed with T2DM for at least 1 year. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Participants are 18 years of age or older, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants have a diagnosis of T2DM for at least 1 year, currently treated with stable 
doses of oral antihyperglycemic medications with or without stable doses of basal or 
premix insulin for the last 3 months prior to screening. Premix insulin is allowed up to 
twice daily in the screening period to be taken up further. Doses of other OHAs will be 
optimized as per investigator’s discretion. Patients on thrice-daily premix insulin or full 
basal bolus insulin (insulin regimen, 3 to 4 times daily) therapy are excluded from the 
study. 
3. Participants have HbA1c ≥7.5% and ≤11.5%, both inclusive, at screening. 
Weight/BMI 
4. Participants have BMI ≥23 kg/m2. 
Sex and Contraceptive/Barrier Requirements 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
5. Male study participants: No male contraception is required except in compliance with 
specific local government study requirements. Female study participants: For the 
contraception requirements of this protocol, see Section 10.4. 
Informed Consent 
6. Participants are capable of giving signed informed consent as described in Appendix 1, 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
Other Inclusions 
7.  Residents of India 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
 
 
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Medical Conditions 
8. Participants have a diagnosis of T1DM or latent autoimmune diabetes, or specific type of 
diabetes other than T2DM (for example, monogenic diabetes, diseases of the exocrine 
pancreas, or drug-induced or chemical-induced diabetes). 
9. Participants have eGFR <15 mL/min/1.73 m2. 
10. Participants have a prior history of intolerance to GLP-1 RA or ultrasonographical or 
radiological (CT/MRI) evidence or a history of acute or chronic pancreatitis. 
11. Participants have a prior history of decompensated liver disease with or without evidence 
of ascites. SGPT/SGOT/amylase ≥3 × ULN at baseline.  
12. Participants have a history of medullary thyroid cancer or multiple endocrine neoplasia 
syndrome type 2 in the patient or in the family.  
13. Participants have an active or untreated malignancy, except for successfully treated basal 
or squamous cell carcinoma. 
Prior/Concomitant Therapy 
14. Participants have been treated with antihyperglycemic medication like GLP-1 RA alone 
or in combination or have a prior history of any contraindication to GLP-1 RA therapy 
within 3 months prior to screening. 
15. Participants have been treated with dipeptidyl peptidase-4 inhibitors within 4 weeks prior 
to screening. 
Other Exclusions 
16. Participants have known hypersensitivity or allergy to dulaglutide or its excipients. 
17. Participants are on systemic steroids for any period of more than 14 days.  
18. Participants have severe GI disease, including severe gastroparesis. 
19. Participants have T2DM along with morbid obesity and being considered for bariatric 
surgery  
20. Participants are persons of childbearing potential who 
 
are pregnant or intend to become pregnant 
 
are lactating/breastfeeding (including the use of a breast pump) 
 
are unwilling to remain abstinent or use birth control, or 
 
test positive for pregnancy at the time of screening. 
5.3. 
Lifestyle Considerations  
5.3.1. 
Meals and Dietary Restrictions  
Diabetes management counseling 
Qualified study personnel will provide diabetes management counseling, which will include 
instructions on diet and exercise and education about the signs, symptoms, and treatment of 
hypoglycemia, should it occur. Diabetes self-management counseling should be reviewed 
throughout the study, as needed. 
 
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Dietary and exercise considerations 
Study participants should generally follow a healthy meal plan and continue their usual exercise 
habits throughout the course of the study.  
Dietary and exercise restrictions 
Study participants should not initiate an intensive diet or 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. 
Blood donation 
Study participants should not donate blood or blood products during the study or for 4 weeks 
following their last study visit. 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently assigned to dulaglutide. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes 
 demography 
 screen failure details 
 eligibility criteria, and 
 any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after 4 weeks from the date of screen failure after discussion with the medical 
monitor from the Lilly team. Rescreened participants should be assigned a new participant 
number for every screening or rescreening event. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable for this study. All entry criteria must be met within the specified 
intervals in the SoA. 
 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to or used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
This table lists the intervention used in this clinical study. 
Intervention Name 
Dulaglutide 
Dosage Levels 
0.75 or 1.5 mg 
Route of 
Administration 
Subcutaneous injection 
Frequency of 
Administration 
Once weekly 
The following circumstances are permitted: 
1. Treatment will be started with dulaglutide 1.5 mg as combination therapy or dulaglutide 
0.75 mg as combination therapy or monotherapy. For patients who report GI AEs after 
starting treatment with 1.5 mg dulaglutide, the investigator may reduce the dose to 
0.75 mg based on symptoms reported by patients. Treatment will be continued with 
0.75 mg for 2 to 3 weeks. Thereafter, the 1.5-mg dose will be reintroduced. 
2. As per common practice in India, treatment may be started with 0.75 mg dulaglutide as 
combination therapy in select cases. The dose may be up titrated to 1.5 mg after a period 
of 2 to 4 weeks in consultation with the medical monitor. 
IP dispensing scenarios 
IP dispensing will be done at Visit 2 for first 3 months of therapy and again at Visit 5 for next 3 
months of therapy. 
The various IP dispensing scenarios are shown in Figure 6.1. 
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Abbreviations: F2F = face to face; GI = gastrointestinal; IP = investigational product; QW = once weekly; T = telephonic.  
b 
Refer to the process in Panel 1 for scenario. Note:  
1 pack of dulaglutide contains 2 pens. 
Note: Patient followed up every 4 weeks on a remote basis till V4/ V8 (F2F) or V801 which is end of study visit (T). 
Note: All efforts must be taken by the investigator to ensure that patients comply to therapy. 
Note: All pens that are not used must be returned to the site at Visit 5 when the patient comes back for repeat F2F visit.  
Note: Dulaglutide is provided as a combination with either other antihyperglycemic medications or in combination with insulin 
(basal, basal plus or premixes up to twice daily insulin regimen) 
 
Figure 6.1. 
IP dispensing scenarios – Scenario 1 (top panel), Scenario 2 (middle panel), and Scenario 3 (bottom panel).  
 
 
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Packaging and labeling 
Study interventions will be supplied by Lilly in accordance with current good manufacturing 
practice. Study interventions will be labeled as appropriate for country requirements. 
6.1.1. 
Rescue Medicine  
Although the use of rescue medications is allowable at any time during the study, the use of 
rescue medications should be delayed, if possible, for at least the 4 weeks following the first 
administration of study intervention. The date and time of rescue medication administration, as 
well as the name and dosage regimen of the rescue medication, must be recorded. 
6.1.2. 
Background Therapy or Standard of Care  
For most patients with T2DM, standard of care stipulates treatment with OHAs and/or insulin. In 
this study, participants will be treated once weekly with dulaglutide 1.5 mg as combination 
therapy or dulaglutide 0.75 mg if used as monotherapy. Dulaglutide 0.75 mg can also be 
considered as a combination therapy dosage in very frail patients as per investigator discretion 
after discussion with the study monitor. 
6.2. 
Preparation, Handling, Storage, and Accountability  
1. The investigator or designee must confirm that appropriate storage conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the investigator and authorized study personnel until these are provided 
to the participants to take home. 
3. The investigator or authorized study personnel is responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
Not applicable. 
6.4. 
Study Intervention Compliance  
The first dose will be administered under medical supervision by the investigator or designee. 
The dose of study intervention and study participant identification will be confirmed prior to the 
time of dosing. The date and time of each dose administered will be recorded in the source 
documents and will be provided to the Sponsor as requested. 
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Subsequent doses will be self-administered by participants at home. Compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning and 
documented in the source documents and CRF.  
6.5. 
Dose Modification  
Dose modifications are permitted only once in the following circumstances. The dose 
modification will be permitted only once within a maximum of 4 to 6 weeks after starting 
treatment with dulaglutide. 
 As per common practice in India, treatment may be started with 0.75 mg of dulaglutide as 
combination therapy. The dose may be up titrated to 1.5 mg after a period of 2 to 4 weeks 
in consultation with the medical monitor. For patients who report GI AEs after starting 
treatment with 1.5 mg dulaglutide, the investigator may reduce the dose to 0.75 mg based 
on symptoms reported by patients. Treatment will be continued with 0.75 mg for 2 to 3 
weeks. Thereafter, the 1.5-mg dose will be reintroduced.  
6.6. 
Continued Access to Study Intervention After the End of the Study  
The Sponsor will not provide participants with any ongoing supplies of study intervention after 
they have completed the study treatment period or permanently discontinued the study 
intervention. 
6.7. 
Treatment of Overdose  
For this study, any dose of dulaglutide greater than 1.5 mg within a 72-hour period will be 
considered an overdose. 
Lilly does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator or treating physician should 
 contact the medical monitor immediately 
 evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced 
 closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention no longer has a clinical effect, and 
 document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
6.8. 
Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with 
 reason for use 
 dates of administration, including start and end dates, and 
 dosage information including dose and frequency for concomitant therapy of special 
interest. 
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The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Centrally acting pre-emetic medications are permitted for use any time during the study. Other 
concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the medical monitor. In cases of hyperglycemia, treatment with insulin or 
OHAs is permitted as per investigator discretion. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits, as 
shown in the SoA. 
Participants who stop dulaglutide permanently may receive another glucose-lowering medication 
at the investigator discretion. The new glucose-lowering medication will be recorded on the 
appropriate CRF. 
A participant should be permanently discontinued from study intervention if the participant 
 becomes pregnant during the study 
 requests to discontinue dulaglutide 
 did not take dulaglutide for more than 4 consecutive weeks or missed more than 4 
consecutive doses of dulaglutide at any time during the study 
 is inadvertently enrolled (this would be decided in consultation with the Sponsor’s 
medical officer), or 
 should permanently discontinue the study intervention for safety reasons, in the opinion 
of the investigator. 
7.1.1. 
Liver Chemistry Stopping Criteria  
Interrupting study drug based on liver test elevations in participants with normal or 
near-normal baseline liver tests 
In study participants with normal or near-normal baseline liver tests (ALT, AST, and ALP <1.5× 
ULN based on the normal limits determined by the testing laboratory), the study drug should be 
interrupted and close hepatic monitoring should be done if 1 or more of these conditions occur. 
Elevation 
Exception 
ALT or AST >8× ULN 
 
ALT or AST >5× ULN for >2 weeks 
 
ALT or AST >3× ULN and either TBL >2× ULN or INR >1.5 
For participants with Gilbert’s syndrome: If 
baseline direct bilirubin is >0.5 mg/dL, then 
doubling of direct bilirubin should be used 
for drug interruption decisions rather than 
TBL >2× ULN. 
ALT or AST >3× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3× ULN, when the source of increased ALP is the liver 
 
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Elevation 
Exception 
ALP >2.5× ULN and TBL >2× ULN  
For participants with Gilbert’s syndrome: If 
baseline direct bilirubin is >0.5 mg/dL, then 
doubling of direct bilirubin should be used 
for drug interruption decisions rather than 
TBL >2× ULN. 
ALP >2.5× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal (as determined by the 
testing laboratory). 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications. 
 
Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT, AST, and ALP ≥1.5× ULN), the 
study drug should be interrupted if 1 or more of these conditions occur. 
Elevation 
Exception 
ALT or AST >4× baseline 
 
ALT or AST >3× baseline for more than 2 weeks 
 
ALT or AST >2× baseline and either TBL >2× ULN or INR >1.5 
For participants with Gilbert’s syndrome: If 
baseline direct bilirubin is >0.5 mg/dL, then 
doubling of direct bilirubin should be used 
for drug interruption decisions rather than 
TBL >2× ULN. 
ALT or AST >2× baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >2.5× baseline, when the source of increased ALP is the liver 
 
ALP >2× baseline and TBL > 2× ULN 
For participants with Gilbert’s syndrome: If 
baseline direct bilirubin is >0.5 mg/dL, then 
doubling of direct bilirubin should be used 
for drug interruption decisions rather than 
TBL >2× ULN. 
ALP >2× baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
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Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal (as determined by the 
testing laboratory). 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications. 
 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited non-drug 
etiology is identified. Otherwise, the study drug should be discontinued. 
7.1.2. 
Hypersensitivity Reactions  
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the Sponsor’s designated medical monitor should be notified. 
If the investigator is uncertain about whether a systemic hypersensitivity reaction has occurred 
and whether discontinuation of study intervention is warranted, the investigator may consult the 
designated medical monitor from the study sponsor team. 
7.1.3. 
Temporary Discontinuation  
Criteria for temporary discontinuation of dulaglutide 
The investigator may temporarily interrupt study treatment due to an AE, clinically significant 
variation in laboratory value, COVID-19 infection, hospital visits, travel, emergency surgery, 
hospitalization, or shortage of study treatment supply. Interruption in study treatment for 4 weeks 
or more will lead to permanent discontinuation of study treatment. 
This will be allowed once at any time during the study. This information should be documented 
by the investigator. The study drug discontinuation decision will be taken post the titration in the 
initial 4-6 weeks of the study. 
Guidance for temporary discontinuation of dulaglutide 
Every effort should be made by the investigator to maintain participants in the study and to 
restart dulaglutide promptly, as soon as it is safe to do so. 
Participants will continue their study visits and follow-up according to the SoA. 
Participants should resume the dose prescribed before the temporary dosing interruption or as 
advised by the investigator. 
Recording temporary discontinuation of dulaglutide 
The dates of dulaglutide interruption and restart must be documented in source documents and 
entered in the CRF. 
Participant noncompliance should not be recorded as interruption of dulaglutide in the CRF. 
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7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study 
 at any time at the participant’s own request 
 at the request of the participant’s designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 if enrolled in any other clinical study involving an IP or enrolled in any other type of 
medical research judged not to be scientifically or medically compatible with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication. In this case, discontinuation from the study occurs prior to introduction 
of the new agent, and 
 if a study participant is diagnosed with any type of diabetes mellitus other than T2D. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and posttreatment follow-up, as shown in the SoA. If the 
participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up  
A participant 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. For participants who fail to return 
for a scheduled visit or were otherwise unable to be followed up by the site, the site personnel or 
designee is expected to make diligent attempts to contact till 4 weeks from the scheduled visit. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all randomly assigned participants, including 
those who did not get IP. Public sources may be searched for vital status information. If vital 
status is determined to be deceased, this will be documented, and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to collect 
vital status information. 
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8. 
Study Assessments and Procedures  
 Study procedures and their timing are summarized in the SoA. 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8.1. 
Efficacy Assessments  
Efficacy will be measured by HbA1c and fasting glucose. See Section 3 for specific efficacy 
endpoints. 
Glucose monitoring 
Participants will receive a sponsor-approved glucometer and related testing supplies for use 
during the study. 
Site personnel will train the participant on correct use of the glucometer for self-monitoring BG 
and reporting of hypoglycemia data in the paper diary. 
 As directed by the investigator, they may use the glucometer 
 whenever hypoglycemia is experienced or suspected 
 when there is awareness of increased risk related to changes in dietary intake, physical 
activity, or inadvertent or atypical insulin dosing 
 when patients take concomitant insulin therapy or sulfonylureas. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
Physical examination at screening 
The complete physical examination will include, at a minimum, assessments of these systems: 
 cardiovascular 
 respiratory 
 GI, and 
 neurological. 
Height and weight will be measured and recorded. 
Additional assessments include 
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 clinical signs and symptoms related to T2D 
 T2D-related illnesses, and 
 injection-site reactions. 
8.2.2. 
Vital Signs  
Blood pressure and pulse rate will be measured as specified in the SoA and as clinically 
indicated. Additional vital signs may be measured during study visits if warranted, as determined 
by the investigator. 
8.2.3. 
Electrocardiograms  
Local and single 12-lead ECG will be obtained as outlined in the SoA.  
ECGs will initially be interpreted by the investigator or qualified designee at the site as soon as 
possible after ECG collection, and ideally, while the participant is still present, to determine 
whether the participant meets entry criteria and for immediate participant management, should 
any clinically relevant findings be identified. 
The investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document their review of the ECG printed at the time of 
evaluation.  
8.2.4. 
Clinical Safety Laboratory Tests  
 See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for 
the timing and frequency. 
 The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those that are 
not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
 All laboratory tests with values considered to be clinically significantly abnormal during 
participation in the study or within 2 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
o If such values do not return to normal or baseline within a period judged 
reasonable by the investigator, the etiology should be identified, and the Sponsor 
should be notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA, standard collection requirements, and 
laboratory manual. 
 If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (for example, SAE, AE, or dose 
modification), then report the information as an AE. 
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8.2.5. 
Hepatic Monitoring  
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests (Section 10.5), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if 1 or more of these 
conditions occur.  
If a participant with baseline results of 
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN 
ALP <1.5× ULN 
ALP ≥2× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥1.5× baseline (except for participants with Gilbert’s 
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
What to do if the abnormal condition persists or worsens 
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for the 
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, 
o heart failure 
o systemic infection 
o hypotension, or 
o seizures 
 recent travel 
 history of concomitant medications, including over-the-counter, herbal, and dietary 
supplements, and 
 history of alcohol drinking and other substance abuse. 
 
Frequency of monitoring 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels. 
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Comprehensive hepatic evaluation 
When to perform a comprehensive evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 1 
or more of these conditions occur: 
If a participant with baseline 
results of 
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN with hepatic signs or symptomsa, or ALT or AST 
≥5× ULN 
ALP <1.5× ULN 
ALP ≥3× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline with hepatic signs or symptomsa, or ALT or 
AST ≥3× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥2× baseline (except for participants with Gilbert’s syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
What a comprehensive evaluation should include 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, 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 computed tomography scan).  
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 
 cytomegalovirus 
 Epstein-Barr virus 
 acetaminophen levels 
 acetaminophen protein adducts 
 urine toxicology screen 
 Wilson’s disease 
 blood alcohol levels 
 urinary ethyl glucuronide, and 
 blood 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 
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 endoscopic retrograde cholangiopancreatography 
 cardiac echocardiogram, or 
 a liver biopsy. 
Additional hepatic data collection  in study participants who have abnormal liver tests 
during the study 
Collect additional hepatic safety data in CRFs if a participant 
 develops a hepatic event considered to be an SAE 
 discontinues study intervention due to a hepatic event, or 
 has changes in laboratory results described in this table 
If a participant with 
baseline results of 
develops the following elevations, 
then 
Elevated serum ALT 
Collect additional hepatic safety data in 
the hepatic safety CRF. 
ALT <1.5× ULN 
ALT to ≥5× ULN on 2 or more 
consecutive blood tests 
ALT ≥1.5× ULN 
ALT ≥3× baseline on 2 or more 
consecutive blood tests 
Elevated TBL 
TBL <1.5× ULN 
TBL ≥2× ULN, except for participants 
with Gilbert’s syndrome 
TBL ≥1.5× ULN 
TBL ≥2× baseline  
Elevated ALP 
ALP <1.5× ULN 
ALP ≥2× ULN on 2 or more consecutive 
blood tests 
ALP ≥1.5× ULN 
ALP ≥2× baseline on 2 or more 
consecutive blood tests 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; CRF = case report form; TBL = total 
bilirubin; ULN = upper limit of normal. 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
See Section 10.5 for hepatic laboratory tests. 
8.2.6. 
Pregnancy Testing  
Pregnancy testing will occur as outlined in the SoA. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected as outlined in Sections 8.3.1 and 8.3.2. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3, Appendix 3: 
 AEs 
 SAEs, and 
 PCs. 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, are considered related to the study intervention or study procedures, or caused the 
participant to discontinue the study intervention or study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits or contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
For PCs, the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Section 10.3. 
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
The last 
safety 
follow-up 
visit 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
The last 
safety 
follow-up 
visit 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
90 days after 
the last dose 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = serious adverse event. 
a SAEs should not be reported unless the investigator deems them to be possibly related to study treatment or study 
participation. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive dulaglutide. 
After learning of pregnancy in the female partner of a study participant, the investigator will 
 obtain a consent to release information from the pregnant female partner directly, and 
 within 24 hours after obtaining this consent, record pregnancy information on the 
appropriate form and submit it to the Sponsor.  
The female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a participant’s 
pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and neonate, and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
 gestational age 
 fetal status (presence or absence of anomalies), or 
 indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
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A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring at ≥20 
weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the Sponsor, as described in protocol Section 8.3.1. While 
the investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
dulaglutide. The participant will follow the standard discontinuation process and continue 
directly to the follow-up phase. The follow up on the pregnancy outcome should continue 
independent of intervention or study discontinuation. 
8.3.3. 
Systemic Hypersensitivity Reactions  
Many drugs, including biologic agents, carry the risk of systemic hypersensitivity reactions. If 
such a reaction occurs, additional data should be provided to the Sponsor in the designated 
CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. Participants who experience a 
systemic hypersensitivity reaction are recommended to be treated per national and international 
guidelines. 
8.3.4. 
Injection-Site Reactions  
Symptoms and signs of a local injection-site reaction may include 
 erythema 
 induration 
 pain 
 pruritus 
 lipodystrophy, and 
 edema. 
If an injection-site reaction is reported by participant or study personnel, additional information 
about this reaction will be collected in the CRF. 
8.3.5. 
Hypoglycemia  
Participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia and how to treat it. Hypoglycemia events entered into the participant paper diary 
will be reviewed by investigators at site visits or over telephone. 
Hypoglycemia classification and definitions 
Level 1 
Glucose <70 mg/dL and ≥54 mg/dL 
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Level 1 hypoglycemia can alert a person to take action such as treatment with fast-acting 
carbohydrates. Providers should continue to counsel participants to treat hypoglycemia at this 
glucose alert value. 
Level 2 
Glucose <54 mg/dL 
Level 2 hypoglycemia is also referred to as documented or BG confirmed hypoglycemia. The 
glucose threshold is clinically relevant regardless of the presence or absence of symptoms of 
hypoglycemia.  
Level 3  
Severe hypoglycemia 
A severe hypoglycemic event is characterized by altered mental or physical status requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions for its treatment. 
The determination of an episode of severe hypoglycemia 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. 
Examples of severe hypoglycemia in adults are 
 altered mental status and the inability to assist in their own care 
 semiconscious or unconscious, or  
 coma with or without seizures. 
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. 
Nocturnal hypoglycemia 
Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, that occurs at 
night and presumably during sleep between midnight and 0600 (6:00 am). 
Reporting of severe hypoglycemic events 
If a hypoglycemic event meets the criterion of severe, the investigator must record the event as 
serious on the SAE paper form and report it to Lilly as an SAE. 
The investigator should also determine if repeated or prolonged episodes of hypoglycemia 
occurred prior to the severe event.  
8.3.6. Adverse Events of Special Interest   
Adverse events of special interest include 
 amylase and lipase ≥3× ULN 
 pancreatitis 
 medullary thyroid cancer or any other solid organ cancer 
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 medullary thyroid C-cell hyperplasia/neoplasm, and 
 GI events including nausea and vomiting. 
If either of these are reported, sites will be prompted to collect additional details. For each event, 
assessment of severity, duration, and investigator’s opinion of relatedness to study drug and 
protocol procedure will be captured. 
8.4. 
Pharmacokinetics  
Pharmacokinetic parameters will not be evaluated in this study. 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters will not be evaluated in this study. 
8.6. 
Genetics  
Genetics will not be evaluated in this study. 
8.7. 
Biomarkers  
Biomarkers will not be evaluated in this study. 
8.8. 
Immunogenicity Assessments  
Immunogenicity assessments will not be performed in this study. 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics  
Health economics or medical resource utilization and health economics parameters will not be 
evaluated in this study 
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9. 
Statistical Considerations  
The SAP will be finalized prior to database lock, and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints, including primary, key secondary, 
and exploratory endpoints. 
9.1. 
Statistical Hypotheses  
Not applicable 
9.2. 
Statistical Methodology  
Descriptive summary statistics will be presented for patient demographics, and AE frequency 
and percentage will be summarized.  
Details are provided in Section 9.4. 
9.3. 
Analyses Sets  
For purposes of analysis, the following populations are defined: 
Participant Analysis Set 
Description 
Enrolled 
 
All participants who sign informed consent form and are screen 
positive 
FAS 
 
All patients who received at least 1 dose of study treatment and have 
at least 1 measurement of HbA1c after study treatment 
Per-protocol set 
All patients in the FAS who meet the following criteria 
 
have no important protocol deviations that could impact the 
assessment of the primary objective (see SAP) 
 
are at least 80% compliant with the study drug in terms of dose taken 
 
have no instance of deviation from persistence with study drug in 
terms of no more than the 15 days gap between 2 consecutive doses 
 
complete the treatment phase (24 weeks) for the primary endpoint 
Safety analysis set 
 
All patients who received at least 1 dose of study treatment 
Abbreviations: FAS = full analysis set; HbA1c = hemoglobin A1c; SAP = statistical analysis plan. 
The FAS is used to analyze endpoints related to the efficacy objectives, and the safety analysis 
set is used to analyze the endpoints and assessments related to safety. 
9.4. 
Statistical Analyses  
9.4.1. General 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 CSR. Additional 
exploratory analyses of the data will be conducted as deemed appropriate. 
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All data will be entered, verified, and archived by a CRO external to Lilly and/or at Lilly. Data 
listings, summaries, and analyses will be performed by a CRO under the guidance and approval 
of statisticians at Lilly. 
Summary statistics will be provided for the observed value, and change from baseline will be 
summarized. 
Unless otherwise specified, listings will include all enrolled patients. Efficacy analyses will be 
conducted using the FAS. 
Similarly, the exploratory measures (change in body weight from baseline and change in FBG 
from baseline) will be evaluated in the FAS population.  
Also, safety analyses will be conducted on the safety population. The exploratory measures of 
vital signs (change in SBP, DBP, and pulse rate from baseline) will be analyzed using the safety 
population). 
Unless otherwise specified, testing effect of dulaglutide on change from baseline will be 
conducted at a 2-sided alpha level of 0.05, and CIs will be calculated at 95%, 2-sided. 
For continuous measures, summary statistics will include number of patients, mean, SD, median, 
minimum, maximum, and interquartile ranges for both the actual and the change from baseline 
measurements. Number of missing values will be specified along with this information.  
For categorical measures, summary statistics will include sample size, frequency, and 
percentages. Number of missing values will be specified along with this information. 
No multiplicity adjustment will be done in this study.  
Change from baseline will only be calculated for patients with both baseline and post baseline 
values as: 
Change from baseline = postbaseline value – baseline value. 
The analysis for other continuous exploratory efficacy and safety measurements and continuous 
laboratory measures at 24 weeks will use the MMRM. It will be used to model change from 
baseline in FBG and any other safety or efficacy endpoints. Missing data will be assumed 
missing at random and will be accommodated by the MMRM. 
The MMRM using restricted maximum likelihood will be done for analyses of change in FBG 
from baseline (note: statistical comparison will not be conducted) during the entire study period. 
The MMRM could be repeated for other safety and efficacy endpoints. 
For FBG, summary statistics will be provided for the observed value and change from baseline 
value based on the MMRM. 
An unstructured covariance structure will be used to model the within-patient variability and 
implicitly adjust for missing data. If this analysis fails to converge, the following covariance 
structures will be tested in order. 
1. Toeplitz with heterogeneity 
2. Autoregressive with heterogeneity, by visit 
3. Compound symmetry with heterogeneous variances, by visit 
4. Toeplitz 
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5. Autoregressive 
6. Compound symmetry without heterogeneous variances, by visit 
The first covariance structure that converges will be used. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. Significance tests will be based on 
least-squares mean using Type III sum of squares. 
If none of the models converge then an analysis of covariance using LOCF imputation with 
similar terms as in the MMRM (except no terms that include visit) will be used in its place. 
The MMRM for each of the endpoints will include the respective baseline score and any 
covariate. 
Baseline insulin use will be included as covariate in the model if convergence is met. Dose will 
be included as a covariate in the models, if appropriate. Details will be included in the SAP. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.4.2. 
Primary Endpoints Analysis  
AEs (deaths, SAEs, TEAEs, and hypoglycemia, including severe hypoglycemia) 
Frequency and percentage of AE occurrence (including deaths, SAEs, TEAEs, hypoglycemia, 
including severe hypoglycemia and GI disorders) will be presented for the study duration using 
safety population. 
The proportion of patients with AEs and SAEs occurring within the duration of the study 
(24 weeks) after being administered dulaglutide 1.5 or 0.75 mg will be presented. 
The proportion of patients with AEs, TEAEs, and SAEs occurring within the duration of the 
study (24 weeks) after being administered dulaglutide 1.5 or 0.75 mg and 95% CIs will be 
estimated based on normal approximation. 
The incidence of AE (death, SAE, and TEAE) will be summarized. The rate per year will be 
assessed using a negative binomial model with the log of the study treatment exposure time as an 
offset variable. 
The incidence of hypoglycemic AEs will be summarized. The number of hypoglycemic events 
per subject over the study period will be analyzed as continuous variables and will be 
summarized (mean, median, SD, SE, minimum, and maximum). 
The rate per year of hypoglycemic events, that is, the number of hypoglycemic events per 
patient-year (365.25 days) will be assessed using a negative binomial model, with baseline 
HbA1c and baseline insulin usage as covariates and the log of the study treatment exposure time 
as an offset variable. 
The incidence of AEs will be calculated based on the number of new AEs out of the total eligible 
population using the following formula: 
Number of new AEs post intervention/Total eligible population *100. 
Exposure-adjusted AE incidence will be presented by the severity and preferred term for the 
primary analysis.  
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It is defined as 
Number of patients with new or worsened AEs during treatment period 
Patient-year exposure/365.25 
Patient-year exposure is counted in days up to the AE (or end of time at risk for subjects without 
AE). 
 
Incidence of gastrointestinal AEs 
The incidence of GI AEs per week will be plotted over time from baseline up to 24 weeks. The 
proportion of subjects with at least 1 GI AE will be plotted from baseline up to Week 24. A plot 
of prevalence by severity (mild, moderate, or severe) for nausea, vomiting, and diarrhea over the 
24-week period will be provided for the rate of GI AEs. 
Three Cox proportional hazard models, each with covariates for baseline HbA1c and baseline 
insulin use, will be used to model the time to the first onset of nausea, vomiting, or diarrhea 
TEAE, respectively. 
9.4.3. 
Secondary Endpoints Analysis  
Change in HbA1c from baseline to 24 weeks of therapy with dulaglutide 1.5 or 0.75 mg 
The change in HbA1c level from baseline to Weeks 12 and 24 for all available data including 
post-rescue medication values will be analyzed using descriptive statistics (mean, median, SD, 
SE, minimum, maximum, and number with missing values). In addition, for the actual value and 
change from baseline, a descriptive analysis using LOCF will be performed, using the baseline or 
12-week value, if the 24-week value is missing or occurred after use of rescue medication. 
For subjects requiring rescue medication (see Section 6.1.1), HbA1c values recorded after the 
first administration of rescue medication will not be considered for analysis, and these values 
will be considered as missing. The MMRM, as described in Section 9.4.1 will be used for 
analysis of the change in HbA1c level from baseline to Weeks 12 and 24. 
If convergence is not met in the MMRM, the change in HbA1c level from baseline to Week 24 
will be analyzed using the general linear model for the FAS population. The general linear model 
will evaluate the change from baseline in HbA1c level as the dependent variable and the baseline 
value of HbA1c as covariate. The LOCF method of missing value imputation will be used. 
FAS population will be used for analysis as per planned treatment. 
The analyses will be repeated for the per-protocol population. 
9.4.4. 
Exploratory Endpoints Analysis  
The actual values and change from baseline will be summarized by descriptive statistics (mean, 
median, SD, SE, minimum, and maximum) by visit for the FAS population and for the 
per-protocol population for the following parameters: 
 body weight 
 FBG 
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 SBP 
 DBP, and 
 pulse rate. 
Details of exploratory analyses will be documented in SAP. 
9.4.5. 
Other Safety Analyses  
Laboratory measurements 
Continuous chemistry and hematology measures will be summarized by descriptive statistics at 
baseline and at different visits (Section 1.3) for the safety population. 
Continuous chemistry and hematology measures will be summarized as change from baseline to 
Week 24 using the general linear model, with the baseline value of the response variable as 
covariate. 
All laboratory measurement analyses will be repeated for the Per Protocol population. 
 
AEs analyses 
AEs will be listed by 
 subject 
 SOC 
 Medical Dictionary for Regulatory Activities® PT 
 severity, and 
 relationship to the study disease, drug, or procedure for all subjects. 
AEs (including injection-site reactions and neoplasms) will be summarized as TEAEs for the 
safety population. TEAEs are defined as events that are newly reported after the first study drug 
treatment or are reported to have worsened in severity after the first study drug treatment. The 
proportion of subjects experiencing each TEAE will be presented by PT, SOC, and treatment 
group. The proportion of subjects experiencing each TEAE that is assessed as possibly related to 
the study disease, drug, or procedures will also be summarized. TEAEs will be summarized by 
PT within SOC and by PT by decreasing frequency. 
All SAEs will be listed by subject and summarized by treatment as counts and percentages. 
Similar analyses will be performed for discontinuations due to AEs. 
All AEs analyses will be repeated for the PPS population. 
9.4.6. 
Other Analyses  
A detailed description of subject disposition will be provided at the end of the study. 
Concomitant medications, including previous therapy for diabetes, will be summarized by 
different categories and concomitant medication treatment group using the safety population. All 
concomitant therapies that were originally mapped using the WHO Drug Dictionary in the 
ClinTrial database will be further classified using Anatomical Therapeutic Chemical codes for 
reporting purposes. 
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Subject compliance with study medication will be assessed at each visit of the treatment period 
and overall. 
Subgroup analysis will be done on the primary, secondary, and exploratory data based on the 
stratification of age (<65 and ≥65), HbA1c (<8.5 and ≥8.5), sex, and BMI category (<27 and 
≥27) if needed. Details will be provided in SAP. 
9.5. 
Interim Analysis  
No interim analyses and/or sample size re-estimation 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. 
9.6. 
Sample Size Determination  
An estimated 250 participants will be screened, and assuming a 20% screen failure rate, an 
estimated 200 participants will be initiated on IP. Assuming a 20% dropout rate by the end of the 
study period, approximately 160 patients at the end of the study would allow for an adequate 
description of AEs and other safety outcomes. This is required to fulfill the market authorization 
clause. 
 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
o consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o applicable ICH GCP guidelines, and 
o applicable laws and regulations. 
 The protocol, protocol amendments, ICF, IB, and other relevant documents (for example, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
 The investigator will be responsible for the following: 
o providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations, and 
o reporting to the Sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity. 
 Investigator sites are compensated for participation in the study as detailed in the CTA. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3. 
Informed Consent Process  
 The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. 
 Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/IEC or study center. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the participant and is kept on file. 
10.1.4. 
Data Protection  
 Participants will be assigned a unique identifier by the Sponsor. Any participant records 
and datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred. 
 The participant must be informed that the participant’s personal study-related data will be 
used by the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent. 
 The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, 
appropriate IRB/IEC members, and inspectors from regulatory authorities. 
 The Sponsor has processes in place to ensure data protection, information security’ and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach. 
10.1.5. 
Dissemination of Clinical Study Data  
Reports 
The Sponsor will disclose a summary of study information, including tabular study results, as per 
local law or guidelines.  
Data 
The Sponsor provides access to all individual participant data collected during the trial, after 
anonymization. 
10.1.6. 
Data Quality Assurance  
 All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (for example, laboratory data). The 
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investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 QTLs will be predefined to identify systematic issues that can impact participant safety 
and/or reliability of study results. These predefined parameters will be monitored during 
the study and important excursions from the QTLs, and remedial actions taken will be 
summarized in the CSR. 
 Monitoring details describing strategy (for example, risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques are provided in the Monitoring Plan. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals (for 
example, CROs). 
 Study monitors will perform ongoing source data verification to confirm that data 
transcribed into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; the safety and rights of participants are being 
protected; and the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the CTA unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
 In addition, the Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by the Sponsor or its representatives and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs. 
Data capture system 
An EDC will be used in this study for the collection of data. The site will maintain a separate 
source for the data entered by the site into the Sponsor-provided EDC system. The investigator is 
responsible for the identification of any data to be considered as source data and for confirming 
that data reported are accurate and complete by signing the CRF. 
Any data, for which paper documentation provided by the subject will serve as the source 
document, will be identified and documented by each site in that site’s study file. Paper 
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documentation provided by the subject may include subject diary. Data from these paper 
documentations will be transcribed to eCRFs at the sites. 
eCRF data will be encoded and stored in a clinical trial database. Data managed by a central 
vendor will be stored electronically in the central vendor’s database system. The investigator will 
have continuous access to the data during the study and until decommissioning of the data 
capture system. Prior to decommissioning, the investigator will receive or access 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 reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the Sponsor data 
warehouse. 
Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
product complaint management system. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor. 
10.1.7. 
Source Documents  
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
 Data that are reported or entered in the CRF and are transcribed from source documents 
must be consistent with the source documents, or the discrepancies must be explained. 
The investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
 Definition of what constitutes source data can be found in Section 10.1.6. 
10.1.8. 
Study and Site Start and Closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
The Sponsor or Sponsor’s designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of the Sponsor. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to 
For study termination: 
 discontinuation of further study intervention development 
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For site termination: 
 failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
 inadequate recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator, and 
 total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.9. 
Publication Policy  
In accordance with the Sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.10. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the Sponsor, 
will participate as investigators in this clinical trial. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table here will be performed by the Lilly-designated laboratory or by the 
local laboratory, as specified in the table. 
Local laboratory results are only required if the central laboratory results are not available in 
time for study intervention administration and/or response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make either a study intervention decision 
or response evaluation, the results must be recorded. 
In circumstances where the Sponsor approves local laboratory testing in lieu of central laboratory 
testing (in the table), the local laboratory must be qualified in accordance with applicable local 
regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
Clinical Laboratory Tests 
Comments 
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (red blood cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs - white blood cells)  
  
Differential 
  
Percent and absolute count of 
  Neutrophils, segmented 
  
  Lymphocytes 
  
  Monocytes 
  
  Eosinophils 
  
  Basophils 
  
Platelets 
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase  
  
Alanine aminotransferase  
  
Aspartate aminotransferase  
  
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Clinical Laboratory Tests 
Comments 
Gamma-glutamyl transferase  
  
Blood urea nitrogen  
 
Creatinine  
  
Uric acid 
  
Total protein 
  
Albumin 
  
Glucose  
Fasting at baseline and Week 24 
Cholesterol  
  
Triglycerides 
  
Lipid Panel 
Assayed by Lilly-designated laboratory  
High-density lipoprotein  
  
Low-density lipoprotein (LDL-C) 
This value will be calculated. If triglycerides >400 mg/dL, 
the direct LDL will be assayed  
Very-low-density lipoprotein (VLDL-C) 
  
Urinalysis 
Assayed by Lilly-designated laboratory 
Specific gravity 
  
pH 
  
Protein 
  
Glucose 
  
Ketones 
  
Bilirubin 
  
Urobilinogen 
  
Blood 
  
Nitrite 
  
Urine leukocyte esterase 
  
Microscopic examination of sediment 
  
Hormones (female) 
  
Serum pregnancy  
Assayed by Lilly-designated laboratory  
Urine pregnancy 
Evaluated locally  
Follicle-stimulating hormone  
Assayed by Lilly-designated laboratory. Performed as 
needed to confirm participant’s postmenopausal status 
Urine Chemistry 
Assayed by Lilly-designated laboratory 
Albumin 
 
Creatinine 
 
Calculations 
Generated by Lilly-designated laboratory 
Estimated glomerular filtration rate (chronic kidney 
disease-epidemiology)  
  
Urinary albumin/creatinine ratio 
  
Additional Testing 
Assayed by Lilly-designated laboratory  
Hemoglobin A1c 
  
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-Up, and 
Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and that does not necessarily have a causal relationship with the 
study intervention. An AE can, therefore, be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This 
definition includes events related to the investigational medical device or comparator 
and events related to the procedures involved except for events in users or other 
persons, which only include events related to investigational devices. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, and vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease) 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. See definitions in Section 10.7. 
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
 
 
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Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
 Medical or surgical procedure (for example, endoscopy and appendectomy): the 
condition that leads to the procedure is the AE 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or 
more of the criteria listed: 
a. Results in death 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to the 
hospital or emergency ward (usually involving at least an overnight stay) for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the 
AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (for example, sprained ankle), which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
 
10.3.3. 
Definition of Product Complaints  
Product Complaint 
A PC is any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness, or performance of a study 
intervention. When the ability to use the study intervention safely is impacted, the following 
are also PCs: 
deficiencies in labeling information, and 
use errors for device or drug-device combination products due to ergonomic design elements 
of the product. 
PCs related to study interventions used in clinical trials are collected to ensure the safety of 
participants, monitor quality, and facilitate process and product improvements. 
Investigators will instruct participants to contact the site as soon as possible if they have a PC 
or problem with the study intervention so that the situation can be assessed. 
An event may meet the definition of both a PC and an AE/SAE. In such cases, it should be 
reported as both a PC and an AE/SAE. 
 
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10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page, and PC 
information is reported on the PC form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the PC form for PCs. 
 There may be instances when copies of medical records for certain cases are requested 
by the Sponsor or designee. In this case, all participant identifiers, except for the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, significantly affects 
clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event, and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
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Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
 The investigator will also consult the IB for dulaglutide and Product Information for 
insulin glargine and insulin lispro in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that they have 
reviewed the AE/SAE and have provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to Sponsor or designee. However, it 
is very important that the investigator always assesses the causality for every event 
before the initial transmission of the SAE data to the Sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include 
o additional laboratory tests or investigations 
o histopathological examinations, or 
o consultation with other healthcare professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
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 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken offline, then the site can report this information on an SAE paper form (see next 
section) or to the Sponsor by telephone. 
 Contacts for SAE reporting can be found in site training documents. 
 
SAE Reporting via Paper Form 
E-mail transmission of the SAE paper form is the preferred method to transmit this 
information to the Sponsor. 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE paper form within the designated reporting time frames. 
Contacts for SAE reporting can be found in site training documents. 
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (for example, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements. 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Females of childbearing potential 
Adult females are considered WOCBP unless they are WNOCBP. 
Females not of childbearing potential 
Females are not considered WOCBP if they 
 do not have a uterus, including having a congenital condition such as Mullerian agenesis 
 are infertile due to surgical sterilization, or 
 are postmenopausal. 
Examples of surgical sterilization include 
 total hysterectomy 
 bilateral salpingo-oophorectomy 
 bilateral salpingectomy, or 
 bilateral oophorectomy. 
 
Postmenopausal state 
The postmenopausal state should be defined as a woman 
 at any age, at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note 
 at least 40 years of age and up to 55 years old with an intact uterus, not on hormone 
therapya, who has had cessation of menses for at least 12 consecutive months without an 
alternative medical cause, AND with follicle-stimulating hormone levels >40 mIU/mL 
 55 years of age or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or 
 at least 55 years of age with a diagnosis of menopause prior to starting hormone 
replacement therapy. 
 
aWomen should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
10.4.2. 
Contraception Guidance  
Guidance for women of childbearing potential 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
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Must… 
Must not… 
agree to either remain 
abstinent or stay in a 
same-sex relationship 
without sexual 
relationships with males 
 
use periodic abstinence methods 
calendar  
ovulation  
symptothermal, or 
post-ovulation  
 
declare abstinence just for the duration of a trial, or 
 
use the withdrawal method 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or NOT in a 
same-sex relationship as their preferred and usual lifestyle, must do the following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative urine and serum 
result at enrollment. See the protocol Schedule of Activities for subsequent pregnancy 
testing requirements. 
Contraception 
Agree to use 1 highly effective method (less than 1% failure rate) of contraception or 
a combination of 2 effective methods of contraception 
These forms of contraception must be used for the duration of the study. 
 
Guidance for all men 
No male contraception is required except in compliance with specific local government study 
requirements. 
 
Examples of different forms of contraception 
 
Methods 
Examples 
Highly effective 
contraception (<1% failure 
rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women weighing <198 pounds or <90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
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Effective contraception 
 
barrier method with use of a spermicide 
o 
male condom with spermicide 
o 
diaphragm with spermicide or cervical sponge, or 
o 
female condom with spermicide 
 
Note: The barrier method must include use of a spermicide (i.e., condom with 
spermicide, diaphragm with spermicide, or female condom with spermicide) to be 
considered effective. 
Ineffective forms of 
contraception whether used 
alone or in any combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical mucus, 
or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments   
Hepatic evaluation testing 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant 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  
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase  
Differential: 
Aspartate aminotransferase  
    Neutrophils, segmented 
Gamma-glutamyl transferase  
    Lymphocytes 
Creatine kinase  
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol  
Prothrombin time, INR  
Haptoglobin 
Serology 
Immunoglobulin A (quantitative) 
Hepatitis A virus testing: 
Immunoglobulin G (quantitative) 
    HAV total antibody 
Immunoglobulin M (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus testing: 
Urine Chemistry 
    Hepatitis B surface antigen  
Drug screen 
    Hepatitis B surface antibody  
Ethyl glucuronide  
    Hepatitis B core total antibody  
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody  
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody a 
    HBV DNAb 
Anti-actin antibodyc 
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Hematology 
Clinical Chemistry 
Hepatis C virus testing: 
Epstein-Barr virus testing: 
    HCV antibody 
    EBV antibody 
    HCV RNAb 
    EBV DNAb 
Hepatitis D virus testing: 
Cytomegalovirus testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus testing: 
    CMV DNAb 
    HEV IgG antibody 
Herpes simplex virus testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody 
    HEV RNAb 
    HSV (Type 1 and 2) DNAb 
Microbiologyd 
Liver kidney microsomal type 1 antibody 
Culture: 
 
    Blood 
 
    Urine 
 
 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 
 
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10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the Sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend onsite visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the Sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local ERBs, regulatory bodies, and any other relevant local authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific requirements in which notification is 
required, for example, upon implementation and suspension of changes. All approvals and 
notifications must be retained in the study records. 
If the Sponsor grants written approval for changes in study conduct, the Sponsor will also 
provide additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations: 
 
 
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Remote visits 
Types of remote visits 
Telemedicine: Telephone- and/or technology-assisted virtual visits are acceptable to complete 
appropriate assessments according to the SoA, if written approval is provided by the Sponsor. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the Sponsor. 
Other alternative locations: Laboratory draws may be done at an alternate location in exceptional 
circumstances, if written approval is provided by the Sponsor. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to onsite visits 
Every effort should be made to enable participants to return to onsite visits as soon as reasonably 
possible, while ensuring the safety of both participants and site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing, except for HbA1c 
and serum glucose testing. Lilly-designated laboratory testing must be retained for HbA1c and 
serum glucose. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Obtain local labs for safety hematology, chemistry, hormone panel, and urinalysis, when 
applicable, per the SoA. Safety labs should be obtained as specified in the SoA. 
All labs will be reviewed by the investigators. Sign and date review of local labs per normal 
process and follow-up with the participant as needed. Results will not be recorded in the CRF. 
Lilly Medical should be informed of any labs that meet criteria for temporary or permanent study 
intervention discontinuation. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal onsite 
visits, the site should work with the Sponsor to determine appropriate actions. These actions may 
include 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
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 arranging delivery of study supplies. 
These requirements must be met before action is taken. 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site, for example, 
participant’s home, the investigator and/or the Sponsor should ensure oversight of the 
shipping process to ensure accountability and product quality, that is, storage 
conditions maintained and intact packaging upon receipt. 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening or the lead-in visits are considered valid for a maximum of 24 days. The following 
rules will be applied for active, non-enrolled participants whose participation in the study must 
be paused due to exceptional circumstances: 
 If screening is paused for less than 24 days from the signing of the ICF to the start of 
treatment, the participant will proceed to the next study visit per the usual SoA, 
provided that the treatment is started within 30 days from first screening. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 24 days from signing of the ICF to the start of 
treatment, the participant must be discontinued because of screening interruption due 
to an exceptional circumstance. This is documented as a screen failure in the 
CRF. The participant can reconsent and be rescreened as a new participant. The 
screening procedures per the usual SoA should be followed, starting at the screening 
visit to ensure participant eligibility by the randomization visit. 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
onsite visits, the windows for visits may be adjusted, upon further guidance from the Sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
 
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Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
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10.7. 
Appendix 7: Abbreviations and Definitions  
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AWARD 
Assessment of Weekly AdministRation of LY2189265 in Diabetes 
BG 
blood glucose 
BMI 
body mass index 
CDSCO 
Central Drugs Standard Control Organisation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CKD-EPI 
chronic kidney disease-epidemiology 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
A printed, optical, or electronic document designed to record all of the protocol-
required information to be reported to the Sponsor for each trial participant. 
CRO 
contract research organization 
CTA 
clinical trial agreement 
Data monitoring 
committee 
A data monitoring committee, or data monitoring board is a group of independent 
scientists who are appointed to monitor the safety and scientific integrity of a human 
research intervention, and to make recommendations to the Sponsor regarding the 
stopping of a study for efficacy, or for harms, or for futility. The composition of the 
committee is dependent upon the scientific skills and knowledge required for 
monitoring the particular study. 
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DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
FAS 
full analysis set 
FBG 
fasting blood glucose 
GCP 
good clinical practice 
GI 
gastrointestinal 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
HbA1c 
hemoglobin A1c 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated ICF. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
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IP 
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. See also “IMP.” 
IRB 
institutional review board 
LOCF 
last observation carried forward 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold 1 or more of 
the 5 “rights” of medication use: the right participant, the right drug, the right dose, the 
right route, and at the right time. 
In addition to the core 5 rights, the following may also represent medication errors:  
 
dose omission associated with an AE or a PC 
 
dispensing or use of expired medication 
 
use of medication past the recommended in-use date 
 
dispensing or use of an improperly stored medication 
 
use of an adulterated dosage form or administration technique inconsistent 
with the medication's labeling (for example, summary of product 
characteristics, IB, local label, and protocol), or 
 
shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MMRM 
mixed model for repeated measures 
OHAs 
oral hypoglycemic agents 
participant 
Equivalent to the CDISC term “subject”: an individual who participates in a clinical 
trial, either as a recipient of an IMP or as a control 
PC 
product complaint 
PPS 
per-protocol set 
The set of data generated by the subset of participant 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. 
PT 
preferred term 
PT-INR 
prothrombin time-international normalized ratio 
QTL 
quality tolerance limit 
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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 
SE 
standard error 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SoA 
schedule of activities 
SOC 
system organ class 
T1DM 
type 1 diabetes mellitus 
T2D 
type 2 diabetes 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
An untoward medical occurrence that emerges during a defined treatment period, 
having been absent pretreatment, or worsens relative to the pretreatment state, and does 
not necessarily have to have a causal relationship with this treatment. 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 
 
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11. 
References  
Gerstein HC, Colhoun HM, Dagenais GR et al. Dulaglutide and cardiovascular outcomes in type 
2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 
2019;394(10193):121-130. https://doi.org/10.1016/S0140-6736(19)31149-3 
Ghosal S, Sinha B. Liraglutide and dulaglutide therapy in addition to SGLT-2 inhibitor and 
metformin treatment in Indian type 2 diabetics: a real world retrospective observational study. 
Clin Diabetes Endocrinol. 2018;4:11. https://doi.org/10.1186/s40842-018-0061-8 
Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care. 
2011;34(6):1249-1257. https://doi.org/10.2337/dc11-0442 
IDF Diabetes Atlas. 2021. https://diabetesatlas.org/. Accessed on 24 April 2022. 
Robinson S, Boye KS, Mody R, et al. Real-world effectiveness of dulaglutide in patients with 
type 2 diabetes mellitus: a literature review. Diabetes Ther. 2020;11:1437-1466. 
https://doi.org/10.1007/s13300-020-00839-5 
Srivastava B, Deepa M, Anjana RM, Siddharth M, Priyasandhya P, Mohan V. Abstract #221 
Combination Therapy with Once Weekly GLP 1 Receptor Agonist Dulaglutide and SGLT2 
Inhibitors in Asian Indians with Type 2 Diabetes. Prediab/Diab mellitus. 2018;24(1):38-39. 
Wasir JS, Mithal A, Agarwal P, Mittal A. Once weekly dulaglutide therapy in type 2 diabetic 
subjects, real-world evidence from a tertiary care diabetes center in India. Indian J Endocrinol 
Metab. 2018;22(6):728-734. https://doi.org/ 10.4103/ijem.IJEM_424_18 
 
Approved on 19 Jun 2023 GMT

Signature Page for VV-CLIN-117803 v1.0
Signature Page for VV-CLIN-117803 v1.0
Approval
Medical Director
19-Jun-2023 11:06:17 GMT+0000
Approved on 19 Jun 2023 GMT
PPD