Clinical trial NCT03482024
Conditions: Renal Insufficiency End Stage Renal Disease
Sponsor: Eli Lilly and Company
Start date: 2018-03-30; Completion date: 2019-08-19
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess how fast tirzepatide gets into the blood stream and how long it takes the body to remove it in participants with impaired kidney function compared to healthy participants.

Detailed description:

Arms: arm 1: Group 1 - Tirzepatide 5 milligrams (mg) administered subcutaneously (SC) to healthy participants with normal renal function. arm 2: Group 2 - Tirzepatide 5mg administered SC to participants with mild renal impairment. arm 3: Group 3 - Tirzepatide 5mg administered SC to participants with moderate renal impairment. arm 4: Group 4 - Tirzepatide 5mg administered SC to participants with severe renal impairment. arm 5: Group 5 - Tirzepatide 5mg administered SC to participants with ESRD.
Interventions: intervention 1: Tirzepatide
Intervention descriptions: intervention 1: Administered SC.

Protocol documents:
Prot_000.pdf: 
Protocol I8F-MC-GPGG(b) 
 
Title: Pharmacokinetics of LY3298176 Following Administration to Subjects with Impaired Renal 
Function 
 
NCTID: NCT03482024 
 
Approval Date: 03-May-2019 


I8F-MC-GPGG(b) Clinical Pharmacology Protocol
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LY3298176
Protocol I8F-MC-GPGG(b)
Pharmacokinetics of LY3298176 Following Administration 
to Subjects with Impaired Renal Function
Confidential Information
The information contained in this protocol 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 
LY3298176, 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.  
LY3298176
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
15 January 2018
Amendment (a) Electronically Signed and Approved by Lilly:  08 June 2018
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.  
Approval Date: 03-May-2019 GMT


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Table of Contents
Pharmacokinetics of LY3298176 Following Administration to 
Subjects with Impaired Renal Function
Section
Page
Protocol I8F-MC-GPGG(b) Pharmacokinetics of LY3298176 Following 
Administration to Subjects with Impaired Renal Function...................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................15
4.
Objectives and Endpoints..................................................................................................16
5.
Study Design.....................................................................................................................17
5.1.
Overall Design .............................................................................................................17
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................21
6.1.
Inclusion Criteria..........................................................................................................21
6.1.1.
Inclusion Criteria for All Subjects ........................................................................21
6.1.2.
Additional Inclusion Criteria for Control Subjects................................................22
6.1.3.
Additional Inclusion Criteria for Subjects with Mild to 
Severe Renal Impairment or ESRD ......................................................................23
6.1.4.
Additional Inclusion Criteria for Subjects with T2DM and 
Renal Impairment or ESRD..................................................................................23
6.2.
Exclusion Criteria ........................................................................................................23
6.2.1.
Exclusion Criteria for All Subjects.......................................................................23
6.2.2.
Additional Exclusion Criteria for Subjects with Mild to 
Severe Renal Impairment or ESRD ......................................................................25
6.2.3.
Additional Exclusion Criteria for Subjects with T2DM and 
Renal Impairment or ESRD..................................................................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26


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6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................26
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Selection and Timing of Doses.............................................................................28
7.3.
Blinding .......................................................................................................................29
7.4.
Dose Modification........................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................29
7.8.
Treatment after the End of the Study............................................................................30
8.
Discontinuation Criteria ....................................................................................................31
8.1.
Discontinuation from Study Treatment.........................................................................31
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................31
8.2.
Discontinuation from the Study....................................................................................31
8.3.
Subjects Lost to Follow-up...........................................................................................32
9.
Study Assessments and Procedures ...................................................................................33
9.1.
Efficacy Assessments...................................................................................................33
9.2.
Adverse Events ............................................................................................................33
9.2.1.
Serious Adverse Events........................................................................................34
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................34
9.2.2.
Complaint Handling.............................................................................................35
9.3.
Treatment of Overdose.................................................................................................35
9.4.
Safety...........................................................................................................................35
9.4.1.
Clinical Laboratory Tests .....................................................................................35
9.4.2.
Amylase and Lipase Measurements......................................................................35
9.4.3.
Glucose Monitoring .............................................................................................35
9.4.3.1.
Hyperglycemia and Hypoglycemia Reporting.................................................35
9.4.3.2.
Severe Hypoglycemia.....................................................................................37
9.4.4.
Vital Signs ...........................................................................................................37
9.4.5.
Electrocardiograms ..............................................................................................37
9.4.6.
Injection-site Reactions ........................................................................................38
9.4.7.
Safety Monitoring ................................................................................................38
9.4.7.1.
Hepatic Safety................................................................................................38
9.5.
Pharmacokinetics .........................................................................................................39


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9.5.1.
Bioanalysis...........................................................................................................39
9.6.
Pharmacodynamics ......................................................................................................39
9.6.1.
Immunogenicity Assessments ..............................................................................39
9.7.
Genetics .......................................................................................................................40
9.8.
Biomarkers...................................................................................................................41
9.9.
Health Economics ........................................................................................................41
10.
Statistical Considerations and Data Analysis.....................................................................42
10.1. Sample Size Determination ..........................................................................................42
10.2. Populations for Analyses..............................................................................................42
10.2.1.
Study Participant Disposition ...............................................................................42
10.2.2.
Study Participant Characteristics ..........................................................................42
10.3. Statistical Analyses ......................................................................................................42
10.3.1.
Safety Analyses....................................................................................................43
10.3.1.1.
Clinical Evaluation of Safety..........................................................................43
10.3.1.2.
Statistical Evaluation of Safety.......................................................................43
10.3.1.3.
Injection-site Reactions...................................................................................43
10.3.2.
Pharmacokinetic Analyses....................................................................................43
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................43
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................43
10.3.3.
Pharmacodynamic Analyses.................................................................................44
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................44
10.3.5.
Evaluation of Immunogenicity .............................................................................44
10.3.6.
Data Review During the Study.............................................................................45
10.3.7.
Interim Analyses..................................................................................................45
11.
References ........................................................................................................................47


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List of Tables
Table
Page
Table GPGG.1.
Objectives and Endpoints .......................................................................16
Table GPGG.2.
Subject Groups based on Renal Impairment Status .................................17
Table GPGG.3.
Renal Function Classification for Primary Analyses ...............................44


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List of Figures
Figure
Page
Figure GPGG.1.
Illustration of study design for Groups 1 to 4..........................................18
Figure GPGG.2.
Illustration of study design for Group 5. .................................................19
Figure GPGG.3.
Interim data review decision tree. ...........................................................46


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................49
Appendix 2.
Clinical Laboratory Tests........................................................................52
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................53
Appendix 4.
Hepatic Monitoring Tests for Treatment-emergent Abnormality.............56
Appendix 5.
Blood Sampling Summary......................................................................57
Appendix 6.
Pancreatic Monitoring ............................................................................58
Appendix 7.
Permitted Concomitant Medication.........................................................60
Appendix 8.
Calculation of Estimated Glomerular Filtration Rate...............................61
Appendix 9.
Protocol Amendment I8F-MC-GPGG(b) Summary 
Pharmacokinetics of LY3298176 Following Administration to 
Subjects with Impaired Renal Function...................................................62


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1. Protocol Synopsis
Title of Study:
Pharmacokinetics of LY3298176 Following Administration to Subjects with Impaired Renal Function
Rationale:
LY3298176 is a balanced glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor 
co-agonist being developed as a weekly treatment of hyperglycemia in patients with type 2 diabetes mellitus 
(T2DM).  Renal failure is a common sequelae of diabetes; it is therefore important to understand the influence of 
differing degrees of renal impairment on the pharmacokinetics (PK) of LY3298176.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To estimate the PK parameters of LY3298176 in 
subjects with mild, moderate, or severe renal 
impairment, and in subjects with ESRD after a single 
5-mg SC dose of LY3298176 compared to control 
subjects with normal renal function.

LY3298176 PK parameters, including
AUC0-∞, AUC0-tlast, and Cmax
Secondary
To assess the tolerability of LY3298176 in subjects 
with mild, moderate, or severe renal impairment, and 
in subjects with ESRD after a single 5-mg SC dose of 
LY3298176 compared to control subjects with normal 
renal function.

Adverse events
Abbreviations: AUC0-∞= area under the concentration versus time curve from time zero to infinity; 
AUC0-tlast = area under the concentration versus time curve from time zero to the time of last measured 
concentration; Cmax = maximum drug concentration; ESRD = end-stage renal disease; PK = pharmacokinetic; 
SC = subcutaneous.
Summary of Study Design:
Study I8F-MC-GPGG is a Phase 1, multicenter, nonrandomized, open-label, parallel-design study in subjects with 
mild, moderate, or severe renal impairment, or end-stage renal disease (ESRD), and control subjects with normal 
renal function. Renal function will provide the basis for assignment to treatment group.

Group 1: control subjects with normal renal function (estimated glomerular filtration rate [eGFR]
≥90 mL/min/1.73m2)

Group 2: subjects with mild renal impairment (eGFR between 60 and 89 mL/min/1.73m2)

Group 3:  subjects with moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m2)

Group 4:  subjects with severe renal impairment (eGFR <30 mL/min/1.73m2 and not requiring dialysis)

Group 5:  subjects with ESRD (have received dialysis for at least 3 months).


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Subjects with T2DM and renal impairment will be permitted to enroll in the study.  Subjects with T2DM will not be 
included in Group 1.
Treatment Arms and Planned Duration for an Individual Subject:  
Subjects will be screened over a 28-day period prior to dosing.  Subjects will be admitted to the clinical research unit 
(CRU) on Day -1, receive a single subcutaneous injection of LY3298176 on Day 1, remain at the CRU until 
discharge on Day 5, and return to the CRU on Days 8 and 15 for PK blood sampling and other study procedures.  
Subjects will also return to the CRU for a follow-up visit at least 28 days postdose for final PK and study 
assessments.
Subjects will receive either 5 mg LY3298176 or, depending on interim analysis results, a dose of LY3298176 
reduced by approximately 50%.
Number of Subjects:
Approximately 58 subjects will be enrolled so that approximately 48 subjects complete the study, such that
approximately 8 subjects per group complete Groups 2 through 5.  Approximately 16 completers are needed from
Group 1 in order to facilitate demographic matching with the subjects in other groups.
Statistical Analysis:
Pharmacokinetics:  The primary parameters for analysis are area under the concentration versus time curve (AUC) 
from time zero to infinity (AUC0-∞), AUC from time zero to the time of last measured concentration (AUC0-tlast), 
and maximum drug concentration (Cmax); log transformation will be applied. An analysis of variance model with 
subject group as fixed factor will be used in the main analyses.  The 90% confidence interval of the ratio between 
each impaired renal function group versus the control group will be estimated. Additional supportive analysis is the 
evaluation of the relationship between the PK of LY3298176 and mean eGFR, as determined by the Modification of 
Diet in Renal Disease abbreviated equation.  Scatter plots of PK parameter versus eGFR will be produced and 
analyzed using either a mixed-effects linear or a nonlinear regression approach with eGFR as a continuous covariate 
on PK parameters.  
Safety:  Descriptive statistics will be used to summarize safety parameters.


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2. Schedule of Activities


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Study Schedule Protocol I8F-MC-GPGG
Screening
Study Days
Follow-up 
or ED
Comments
Procedure
Days -28
to -1
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8
Day 
15
Day ≥28
Informed Consent
X
Subject Admission to 
CRU
X
LY3298176 
Administration
X
Study drug will be administered after an overnight fast 
of at least 8 hours.
Subject Discharge 
from CRU
X
Subjects may stay longer at the investigator’s
discretion.
Outpatient Visit
X
X
X
Medical History
X
Physical Examination
X
X
X
X
X
After screening, medical assessment only performed to 
include medical review and targeted examination, as 
appropriate.
Weight
X
X
X
Height
X
Temperature
X
X
Urine Drug Screen
X
X
X
X
Ethanol Testing
X
X
X
Safety 12-lead ECG
(hours)
X
Predose
48
X
X
Single ECG will be collected.  ECGs must be recorded 
before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG 
collection, and remain supine but awake during ECG 
collection.
Supine Vital Signs
(hours)
X
X
Predose, 
12
24
48
72
96
168
336
X
Time points may be added, if warranted and agreed 
upon between Lilly and the investigator.
Clinical Laboratory 
Tests
X
X
X
X
X
X
X
See Appendix 2 for details.
Estimated Glomerular 
Filtration Rate
X
X
Pregnancy Test
X
X
X
X
Female subjects only.  See Appendix 2 for details.
AEs/Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Pharmacogenomic 
Sample
Predose
Single sample for pharmacogenetic analysis.


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Screening
Study Days
Follow-up 
or ED
Comments
Procedure
Days -28
to -1
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
8
Day 
15
Day ≥28
Anti-LY3298176 
Antibodies (hours)
Predose
336
X
Time-matched PK sample should be collected at each 
time point.  
In the event of drug hypersensitivity reactions 
(immediate or non-immediate), samples will be 
collected as close to event onset as possible, at event 
resolution, and 30 days following the event.  Subjects
with TE ADA at follow-up/ED will undergo additional 
follow-up.  See Section 9.6.1 for details.
Glucose Monitoring
(hours)
Predose, 
12 
24
48
72
96
168
336
X
Performed using a bedside glucose monitor.  
Additional measurements may be taken at the 
discretion of the investigator as clinically indicated.
PK Sampling (hours)
Predose, 
8, 12 
24
48
72
96
168
336
X
Up to a 10% deviation from the nominal collection 
time is permissible.
Assessment of 
Injection-site 
Reactions (hours)
Predose, 
0, 6, 12
24
48
0-hour assessment should be performed within 
approximately 5 minutes after subcutaneous injection.  
Additional assessments may be performed if deemed 
necessary by the investigator.
Abbreviations:  AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; PK = pharmacokinetic(s); 
T2DM = type 2 diabetes mellitus; TE ADA = treatment-emergent antidrug antibodies.  
Note:  All sampling times are given relative to dosing with LY3298176 (predose or hours postdose).
Note:  If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECGs, vital signs, clinical laboratory 
sample, and PK sample, with PK sampling time the priority.


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3. Introduction
3.1.
Study Rationale
Study I8F-MC-GPGG is a Phase 1, multicenter, nonrandomized, open-label, parallel-design 
study in subjects with mild, moderate, or severe renal impairment, or end-stage renal disease 
(ESRD), and control subjects with normal renal function.  
LY3298176 is currently being investigated for its use in the treatment of hyperglycemia in 
patients with type 2 diabetes mellitus (T2DM). Renal failure is a common sequelae of diabetes; 
it is therefore important to understand the influence of differing degrees of renal impairment on 
the pharmacokinetics (PK) of LY3298176.  The primary purpose of this study is to determine the 
PK of a single subcutaneous (SC) dose of LY3298176 in subjects with renal impairment 
compared to subjects with normal renal function.  The results of this study will be used to 
support appropriate dose recommendations in patients with T2DM with varying degrees of renal 
impairment.
3.2.
Background
In normal physiology following a meal, the incretins glucagon-like peptide-1 (GLP-1) and 
glucose-dependent insulinotropic polypeptide (GIP) are secreted from enteroendocrine cells in 
the gut to enhance the physiological responses to food intake, including insulin secretion, 
nutrient disposal, and the sensation of satiety.  It is now well established that T2DM patients 
have impaired incretin responses (Nauck et al. 2004), and pharmacologic interventions providing 
either GLP-1 receptor agonistic peptides or dipeptidyl peptidase (DPP)-IV inhibitors (which 
delay degradation of endogenous GIP and GLP-1) are successfully used in the treatment of 
T2DM (Drucker and Nauck 2006; Amori et al. 2007; Baynes 2010).  Although GLP-1 is 
regarded as the incretin of therapeutic utility in T2DM patients, published data demonstrates that 
overexpression of GIP may lead to improved body weight and glycemic control, and the 
combination of GLP-1 and GIP may result in improved glycemic efficacy and weight 
management compared with GLP-1 agonists alone (Kim et al. 2012; Finan et al. 2013).
LY3298176 is a long-acting, dual incretin receptor co-agonist that binds to both the GIP receptor 
and the GLP-1 receptor.  LY3298176 consists of a peptide component based on the GIP 
sequence.  
 
 
 The 
unique co-agonist properties of LY3298176 allow for pharmacological effects to be realized at 
metabolically active tissues (such as pancreatic -cells and adipose tissue) that express both GIP 
and GLP-1 receptors.  This could maximize the intended therapeutic benefit of increased energy 
utilization and greater weight loss while also improving glycemic control in patients with T2DM
(Baggio and Drucker 2007).
CCI


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The safety, tolerability, and PK/pharmacodynamics of LY3298176 were evaluated in a 3-part,
Phase 1 clinical pharmacology trial, I8F-MC-GPGA (GPGA) in healthy subjects and patients 
with T2DM.  In Study GPGA, LY3298176 was administered by SC injection as a single dose of
0.25 to 8 mg to healthy subjects (Part A); as multiple doses of 0.5 to 10 mg to healthy subjects
(Part B); and as multiple doses of 0.5 to 15 mg administered to patients with T2DM (Part C).  
Following administration of a single dose of LY3298176, the maximum drug concentration 
(Cmax) was observed to occur between 8 and 96 hours. The mean terminal half-life was 
approximately 5 days, thus supporting a QW dosing regimen. Pharmacokinetic data from the 
Phase 1 study supports apparent dose-proportionality of LY3298176.
Based on preliminary data, 52 subjects (out of 142 subjects dosed in this study) received 4.5 mg 
(6 healthy subjects) to 5 mg as a single dose or as the first dose (32 T2DM out of 47 subjects).  
There were no reported LY3298176-related SAEs.
Overall, gastrointestinal events (eg, vomiting, abdominal distension, nausea, diarrhea) were the 
most frequently reported adverse events (AEs).  These AEs increased in number and severity 
with increasing doses, and higher doses appeared to be better tolerated when LY3298176 was 
administered via dose titration. The reported gastrointestinal- (GI-) related AEs are consistent 
with GLP-1 pharmacology and those observed previously following administration of GLP-1 
receptor agonists (RAs) (Nauck et al. 2009; Dungan et al. 2014; Giorgino et al. 2015; Jendle et 
al. 2016; Nauck et al. 2016).
In Part A (SAD) of Study GPGA, with increasing doses there was an increase in the number and 
severity of AEs related to LY3298176.  At the 5-mg dose, 6 subjects reported a total of 23 AEs
that were all mild in severity.  At the 8-mg dose, 7 subjects reported a total of 31 AEs, 21 of 
which were mild and 10 moderate in severity. Two of 6 subjects who received the 5-mg dose 
reported 5 mild AEs of vomiting and 1 subject reported a mild AE of nausea, whereas at the 
8-mg dose, 3 of 7 subjects reported 12 episodes of vomiting, and 4 of 7 subjects reported 4 AEs 
of nausea. Two subjects who received 8 mg as a single dose and reported AEs of vomiting and 
nausea required treatment with antiemetics and IV fluids. Further dose escalation was stopped 
and the 5-mg dose was considered the maximum tolerated dose.
Based on preliminary data from Study GPGA, the most commonly observed cardiovascular 
changes included increased heart rate.  Consistent with other GLP-1 RAs, dose-dependent 
increases in pulse rate were observed with administration of LY3298176 in healthy subjects and 
patients with T2DM.  In Part A, the largest least squares (LS) mean time-averaged pulse rate 
change from baseline to 168 hours compared to placebo was an increase of 8.42 bpm for the 
single 8-mg dose group. For the multiple dose groups, the largest LS mean increases in pulse 
rate compare to placebo for the time-averaged change from baseline to 72 hours were 5.24 bmp 
in the 10-mg titration dose group in Part B, and 10.28 bmp in the 15-mg titration dose group in 
Part C.  However, the increases did not result in any subject discontinuations.  There were no 
clinically significant changes in systolic or diastolic blood pressure (BP) or QT/corrected QT 
(QTc) interval prolongation observed in either healthy subjects or patients with T2DM.


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3.3.
Benefit/Risk Assessment
Preclinical data and the preliminary clinical data (see Section 3.2) from Study GPGA support 
further clinical development for LY3298176.
No clinically significant safety or tolerability concerns were identified up to the highest 
single-dose level of 8 mg or following 4 QW doses titrated up to 15 mg in Study GPGA.  Based 
on this information, 5 mg doses to be administered in Study GPGG are reasonably anticipated to
be tolerable in subjects with renal impairment and in control healthy subjects.  Subjects will 
reside in the clinical research unit (CRU) under close monitoring for at least 5 days, with the 
option of being kept for longer; discharge from the CRU will be per investigator discretion.  An 
interim analysis safety, tolerability, and PK data is planned to determine whether dose 
adjustments are needed (see Section 10.3.7).
For safety purposes, blood glucose levels will be monitored for all subjects.  Section 9.4.3.1
describes glucose monitoring procedures and how episodes of hypoglycemia or hyperglycemia 
will be treated, if necessary.
Any identified potential risks are similar with the risks associated with currently available 
long-acting GLP-1 RAs (see Section 3.2), are considered to be manageable, and are able to be 
monitored.
There is no anticipated therapeutic benefit for the subjects in this study.
More information about the known and expected benefits, risks, serious AEs (SAEs), and 
reasonably anticipated AEs of LY3298176 are to be found in the Investigator’s Brochure (IB).


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LY3298176
4. Objectives and Endpoints
Table GPGG.1 shows the objectives and endpoints of the study.
Table GPGG.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To estimate the PK parameters of LY3298176 in 
subjects with mild, moderate, or severe renal 
impairment, and in subjects with ESRD after a single 
5-mg SC dose of LY3298176 compared to control 
subjects with normal renal function.

LY3298176 PK parameters, including AUC0-∞, 
AUC0-tlast, and Cmax
Secondary
To assess the tolerability of LY3298176 in subjects with 
mild, moderate, or severe renal impairment, and in 
subjects with ESRD after a single 5-mg SC dose of 
LY3298176 compared to control subjects with normal 
renal function.

Adverse events
Exploratory
To evaluate the formation of ADA to LY3298176 after a 
single 5-mg SC dose administered to subjects with mild, 
moderate, or severe renal impairment, and in subjects 
with ESRD.

Presence of ADA to LY3298176
Abbreviations:  ADA = antidrug antibodies; AUC0-∞= area under the concentration versus time curve from time 
zero to infinity; AUC0-tlast = area under the concentration versus time curve from time zero to the time of last 
measured concentration; Cmax = maximum drug concentration; ESRD = end-stage renal disease; 
PK = pharmacokinetic; SC = subcutaneous.


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LY3298176
5. Study Design
5.1.
Overall Design
This is a Phase 1, parallel-design, open-label, multicenter, single-dose study to assess PK and
tolerability of a single dose of LY3298176 in subjects with mild, moderate, or severe renal 
impairment, or ESRD, and control subjects with normal renal function.  Control Group 1 will be 
healthy subjects with normal renal function.  Subjects with T2DM will not be included in 
Group 1.  Subjects with T2DM and renal impairment will be permitted to enroll in Groups 2 to 5,
whereas subjects with T2DM and normal renal function will not be permitted.  Subjects will be 
assigned to 1 of 5 groups (Groups 1 to 5) based on criteria outlined in Table GPGG.2.  For 
description of enrollment order and interim analysis, see Section 10.3.7. Estimated glomerular 
filtration rate (eGFR) will be determined by the Modification of Diet in Renal Disease (MDRD) 
abbreviated equation (Appendix 8) using serum creatinine levels obtained at Screening and on 
Day -1; subjects will be assigned to groups based on values from Day -1. See Sections 5.2 and 
10.1 for sample size information.
The control subjects (Group 1) will be selected in order that the mean and distribution of 
Group 1 are comparable to the mean and distribution for each group with renal impairment 
(Groups 2 through 5) for age (±10 years), sex, race, weight (± 10 kg), and body mass index 
(BMI) (±20%), as far as is practically possible (additional information will be provided to the
investigators in a separate document) (FDA 2010).  An effort will be made to enroll control 
subjects that are representative of the races of the impaired subjects. One-to-one matching of 
subjects (1 impaired subject matched to 1 healthy subject in 1 or more impairment groups using 
the same criteria previously described) may be used to facilitate interim analysis.
Table GPGG.2.
Subject Groups based on Renal Impairment Status
Classification
eGFR (mL/min/1.73m2)
Group 1
Control (normal renal function)
≥90
Group 2
Mild renal impairment
60-89
Group 3
Moderate renal impairment
30-59
Group 4
Severe renal impairment
<30 and not requiring dialysis
Group 5
End-stage renal disease
Requiring dialysis
Abbreviations:  eGFR = estimated glomerular filtration rate (as determined by the Modification of Diet in Renal 
Disease abbreviated equation).
Figure GPGG.1 and Figure GPGG.2 illustrate the study design.
Subjects will visit the CRU to sign the informed consent document and undergo screening 
procedures up to 28 days prior to dosing.


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Subjects will be admitted to the CRU on Day -1. Subjects will be administered a single dose of 
LY3298176 on Day 1 and will remain in the CRU until after assessments are completed on 
Day 5.  Subjects will return for study visits on Days 8 and 15 and for a final follow-up visit at 
least 28 days postdose.  Clinical laboratory tests, physical examination, vital signs, 12-lead 
electrocardiograms (ECGs), injection-site reactions, glucose monitoring, AEs, and antidrug 
antibodies (ADA) will be monitored to assess safety and tolerability.  Blood samples for PK and 
immunogenicity analysis will be collected predose through the final follow-up visit.
For subjects with ESRD, administration of LY3298176 should occur at least 24 hours prior to the 
next planned dialysis session.  The time and dates of dialysis sessions from the session 
immediately prior to dose through Day 8 will be recorded in the case report form (CRF). To 
eliminate potential variation between different types of dialysis membrane, only high-flux 
polysulfone membranes will be used.
Study governance considerations are described in detail in Appendix 3.
Abbreviations:  ADA = antidrug antibodies; D = Day; PK = pharmacokinetic.
Figure GPGG.1.
Illustration of study design for Groups 1 to 4.


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Abbreviations:  ADA = antidrug antibody; D = Day; PK = pharmacokinetic.
Figure GPGG.2.
Illustration of study design for Group 5.
5.2.
Number of Participants
Approximately 58 subjects will be enrolled so that approximately 48 subjects complete the study, 
such that approximately 8 subjects per group complete Groups 2 through 5 (EMEA CHMP 
2016).  Approximately 16 completers are needed from Group 1 in order to facilitate demographic 
matching with the subjects in other groups.  
For purposes of this study, a subject is considered to have completed the study when all 
scheduled procedures shown in the Schedule of Activities (Section 2) have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
A comprehensive range of renal impairment is necessary to fully characterize the impact of renal 
impairment on the PK of LY3298176. Subjects undergoing dialysis (Group 5) will be included 
to determine the effect of dialysis on drug removal.
This study has been designed in accordance with the current regulatory guidances (EMEA 
CHMP 2016; FDA 2010) for the study of PK in subjects with impaired renal function.  
LY3298176 has shown linear and dose-proportional PK, based on preliminary SAD and MAD 
data in the Phase 1 Study GPGA.  Per FDA guidance “a single-dose study is satisfactory for 
cases where there is clear prior evidence that single-dose studies accurately describe the PK for 
the drug and potentially active metabolites” (FDA 2010). This renal impairment study will be 
conducted as a single-dose study.
Admission
Dose
Discharge
Follow up
Screening
Days -28 to -1
D-1   D1  D1 D1
D2     D3       D4        D5           D8           D15           D≥28
0      8      12        24        48            72            96                168              336                 ≥ 648 
0
336                 ≥ 648 
(predose)
PK and ADA Sampling
PK sampling (hours postdose) 
ADA sampling (hours postdose) 
Hemodialysis†
† The first postdose dialysis session should be scheduled to start at least 24 hours after administration of LY3298176. 
Subsequent dialysis sessions should be scheduled as clinically appropriate.


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This study will be open-label.  As the primary endpoints are objective rather than subjective, 
investigators and subjects do not need to be blinded.
Based on the molecular weight of LY3298176, its PK may be impacted by renal impairment.  
However, LY3298176 is expected to bind to albumin (because of the C20 fatty acid conjugation 
structure), thus systemically resulting in a larger molecular size and decreasing the likelihood 
that PK will be meaningfully impacted by renal impairment.  Thus the same dose of LY3298176
is planned to be administered to subjects in all groups.
An interim analysis each are planned following dosing of at least 2 subjects in Groups 2 and 3 
and appropriate matched-control subjects in Group 1, and following dosing of at least 2 subjects 
in Groups 4 and 5 and appropriate matched-control subjects in Group 1. An additional 
interim analysis will be done after completion of the Group 3 (see Section 10.3.7).  The purpose 
of the interim review(s) is to determine the dose level(s) for subsequent subjects, based on safety, 
tolerability, and PK data.  The dose of LY3298176 for subsequent subjects (any or all groups) 
may be adjusted accordingly after each interim. Data from the additional interim (completion of 
Group 3) will support Phase 3 enrollment.
5.5.
Justification for Dose
A 5-mg dose was selected based on preclinical pharmacology and toxicology data.  In addition, 
preliminary results from Study GPGA indicate the 5-mg dose was relatively well tolerated by 
healthy subjects and patients with T2DM, and is expected to be a clinically meaningful dose.  In 
Study GPGA Part A (SAD), 5 mg was considered the maximum tolerated dose.
An interim review of data from at least 2 subjects in each of the mild and moderate renal 
impairment groups and appropriate matched-control subjects will be used to determine whether 
to continue administering the 5-mg dose to the remaining subjects (see Section 10.3.7).  Another
review will be performed following dosing of 2 subjects in the severe renal impairment and 
ESRD groups and appropriate matched-control subjects.  Both reviews will assess safety and 
tolerability data.  The PK data will also be analyzed during these reviews.  If it appears that the 
PK are influenced by renal impairment and the exposure in subjects with impairment is higher 
than expected or if there are safety/tolerability events that manifest at a higher than expected rate 
in these subjects, then the dose would be reduced by approximately 50%.


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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of a screening medical 
history, physical examination, clinical laboratory tests, and ECG.  The nature of any conditions 
present at the time of the physical examination and any preexisting conditions will be 
documented.
Screening may occur up to 28 days prior to dosing.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
All subjects must meet the following criteria for enrollment (Inclusion Criteria [1] through [6]). 
Additional subgroupings of inclusion criteria below are specific to the subjects’ renal function
(Inclusion Criteria [7] through [12]) and diabetic status (Inclusion Criteria [13] through [16]).
6.1.1. Inclusion Criteria for All Subjects
[1a] Male subjects:
Men, regardless of their fertility status, with non-pregnant women of childbearing 
potential partners must agree to either remain abstinent (if this is their preferred 
and usual lifestyle) or use condoms plus one additional highly effective (less than 
1% failure rate) method of contraception (such as combination oral 
contraceptives, implanted contraceptives, or intrauterine device) or effective 
method of contraception (such as diaphragms with spermicide or cervical sponge) 
for the duration of the study and until their plasma concentrations are below the 
level that could result in a relevant potential exposure to a possible fetus, 
predicted to be approximately 30 days following dose of study drug (below the 
no-observed-adverse-effect level [NOAEL]/10).
o
Men and their partners may choose to use a double-barrier method of 
contraception.  Barrier protection methods without concomitant use of a 
spermicide are not an effective or acceptable method of contraception.  Thus, 
each barrier method must include use of a spermicide.  It should be noted,
however, that the use of male and female condoms as a double-barrier method 
is not considered acceptable due to the high failure rate when these barrier 
methods are combined.
o
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception.
Men with pregnant partners should use condoms during intercourse for the 
duration of the study and until the end of estimated relevant potential exposure in 
women of childbearing potential (below the NOAEL/10).


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Men who are in exclusively same sex relationships (as their preferred and usual 
lifestyle) are not required to use contraception.
Men should refrain from sperm donation for the duration of the study and until 
their plasma concentrations are below the level that could result in a relevant 
potential exposure to a possible fetus, predicted to be approximately 30 days 
following dose of study drug (below the NOAEL/10).
[1b] Female subjects:
Women of childbearing potential are excluded from the study.
Women not of childbearing potential may participate and include those who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as mullerian agenesis; or
B. postmenopausal – defined as either:
i.
A woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either:
a) cessation of menses for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 IU/mL; or
ii.
A woman 55 or older not on hormone therapy, who has had at least 
6 months of spontaneous amenorrhea; or
iii.
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
[2]
Are between the ages of 18 and 85 years, inclusive.
[3]
Are between the BMI of 19.0 and 40.0 kg/m2, inclusive, at screening.
[4]
Have venous access sufficient to allow blood sampling as per the protocol.
[5]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[6]
Have given written informed consent approved by Lilly and the ethical 
review board (ERB) governing the site.
6.1.2. Additional Inclusion Criteria for Control Subjects
[7]
Healthy males or females as determined by medical history, physical 
examination, and other screening procedures, with normal renal function, 
assessed by eGFR ≥90 mL/min at screening.
[8]
Have clinical laboratory test results within normal reference range for the 
population or investigator site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.


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[9]
Have normal BP and pulse rate, as determined by the investigator.
6.1.3. Additional Inclusion Criteria for Subjects with Mild to Severe 
Renal Impairment or ESRD
[10] Males or females with stable mild to severe renal impairment, assessed by 
eGFR or with ESRD (having received dialysis for at least 3 months).
[11] Clinical laboratory test results with deviations that are judged by the 
investigator to be compatible with the renal condition of the subject or of no 
additional clinical significance for this study.
[12] Have acceptable BP and pulse rate, as determined by the investigator.
6.1.4. Additional Inclusion Criteria for Subjects with T2DM and Renal 
Impairment or ESRD
[13] Have T2DM treated with diet or exercise alone or with stable doses of
metformin and/or insulins for at least 8 weeks.
[14] Subjects taking stable doses of over-the-counter or prescription medications 
(eg, antihypertensive agents, aspirin, lipid-lowering agents) for treatment of 
concurrent medical conditions are permitted to participate providing they 
have been stable on their treatment regimen for at least 4 weeks.
[15] Have a hemoglobin A1c (HbA1c) ≥6.0% and ≤11.0% at the screening visit.
[16] Have clinical laboratory test results within normal range or deemed clinically 
insignificant by the investigator. Abnormalities of serum glucose, serum 
lipids, urinary glucose, and urinary protein consistent with T2DM are 
acceptable.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment.  For all subjects, Exclusion Criteria [17] through [42] apply; 
additional subgroupings of exclusion criteria below are specific to the subjects’ renal function 
(Exclusion Criteria [43] through [45]) and diabetic status (Exclusion Criteria [46] through [49]).
6.2.1. Exclusion Criteria for All Subjects
[17] Are investigator site personnel directly affiliated with this study and their 
immediate families. Immediate family is defined as a spouse, parent, child,
or sibling, whether biological or legally adopted.
[18] Are Lilly employees.
[19] Are currently enrolled in a clinical study involving an investigational product 
(IP) or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[20] Have known allergies to LY3298176 or related compounds.


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[21] Have a history of atopy or clinically significant multiple or severe drug
allergies, intolerance to topical corticosteroids, or severe posttreatment
hypersensitivity reactions (including, but not limited to, erythema multiforme
major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis).
[22] Have previously completed or withdrawn from this study or any other study 
investigating LY3298176.
[23] Persons who have a current, functioning organ transplant.  Nonfunctional 
renal allografts may be allowed.
[24] Have a personal or family history of medullary thyroid carcinoma or have
multiple endocrine neoplasia syndrome type 2.  
[25] Febrile illness within 3 days prior to screening.
[26] Have a history of second- or third-degree heart block or any abnormality in 
the 12-lead ECG at screening that, in the opinion of the investigator, 
increases the risks associated with participating in the study.
[27] Have a significant history or presence of cardiovascular (eg, myocardial 
infarction, cerebrovascular accident, etc. within the past 6 months), 
respiratory, hepatic, renal (applies to Group 1 only), GI, endocrine (except 
T2DM), hematological, or neurological disorders capable of significantly 
altering the absorption, metabolism, or elimination of drugs; of constituting a 
risk when taking the study medication; or of interfering with the 
interpretation of data.
[28] Show evidence of significant active neuropsychiatric disease.
[29] Have a history of malignancy within 5 years prior to screening.
[30] Have a history or presence of pancreatitis (history of chronic pancreatitis or
idiopathic acute pancreatitis), elevation in serum amylase or lipase or GI 
disorder (eg, relevant esophageal reflux or gall bladder disease) or any GI 
disease which impacts gastric emptying (eg, gastric bypass surgery, pyloric 
stenosis, with the exception of appendectomy) or could be aggravated by 
GLP-1 analogs or DPP-IV inhibitors. Subjects with dyslipidemia and 
subjects who had cholecystolithiasis (removal of gall stones) and/or 
cholecystectomy (removal of gall bladder) in the past, with no further 
sequelae, may be included in the study at the discretion of the investigator.
[31] Have serum aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) >2× the upper limit of normal (ULN) or total bilirubin (TBL) >1.5×
ULN.
[32] Have a serum triglyceride ≥5 mmol/L (442.5 mg/dL) at screening.
[33] Show evidence of human immunodeficiency virus (HIV) and/or positive 
HIV antibodies.


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[34] Show evidence of hepatitis C and/or positive hepatitis C antibody.
[35] Show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[36] Are women with a positive pregnancy test or women who are lactating.
[37] Regularly use known drugs of abuse and/or show positive findings on 
urinary drug screen that are not otherwise explained by permitted 
concomitant medications.
[38] Intend to use:
a.
over-the-counter medication within 7 days prior to dosing.
b. prescription medication (other than those listed in Section 7.7 and 
Appendix 7) within 14 days prior to dosing.
c.
herbal preparations within the 14 days prior to screening.
If this situation arises, an otherwise suitable subject may be included at the 
discretion of the investigator.
[39] Have donated blood of more than 450 mL within the last month.
[40] Have an average weekly alcohol intake that exceeds 21 units per week 
(males up to age 65) and 14 units per week (males over 65 and females), and 
are unwilling to stop alcohol consumption 24 hours prior to dosing until 
discharge from the study or completion of all study procedures (1 unit = 
12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of 
distilled spirits).
[41] Are unwilling to refrain from smoking on the day of LY3298176 
administration or are unable to abide by CRU restrictions.
[42] Are determined to be unsuitable by the investigator for any reason.
6.2.2. Additional Exclusion Criteria for Subjects with Mild to Severe 
Renal Impairment or ESRD
[43] Have hemoglobin <8.5 g/dL or significant active hematological disease from 
causes other than underlying renal disease.
[44] Have used any drug indicated for medical care of the subject’s renal 
impairment, which is not established in dose and administered for at least 
7 days before LY3298176 administration.
[45] Positive findings on ethanol testing and use of drugs of abuse and/or positive 
findings on urinary drug screen except those prescribed for related 
complications (ie, pain, insomnia, anxiety) of renal disease.  A serum or 
salivary drug screen may be performed on subjects who are unable to 
produce a urine sample.


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6.2.3. Additional Exclusion Criteria for Subjects with T2DM and Renal 
Impairment or ESRD
[46] Have taken any glucose-lowering medications other than metformin and/or
insulins (refer to Inclusion Criterion [13]) in the past 3 months before 
screening. In general, stable dosages of metformin and insulins will be 
continued; however, a washout period or dose modifications may be 
necessary to allow for optimal blood glucose monitoring throughout the 
dosing period at the discretion of the investigator.
[47] Have had more than 1 episode of severe hypoglycemia, as defined by the 
American Diabetes Association criteria, within 6 months before entry into 
the study or has a history of hypoglycemia unawareness or poor recognition 
of hypoglycemic symptoms.  Any subject that cannot communicate an 
understanding of hypoglycemic symptoms and the appropriate treatment of 
hypoglycemia prior to the first dose of study drug should also be excluded.
[48] Have had a blood transfusion or severe blood loss or have known 
hemoglobinopathy (alpha-thalassemia), hemolytic anemia, sickle cell 
anemia, or any other condition known to interfere with HbA1c methodology.
[49] Have received chronic (lasting >14 consecutive days) systemic 
glucocorticoid therapy (excluding topical, intra-articular, and inhaled 
preparations) in the past year or have received any glucocorticoid therapy 
within 30 days before screening.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
Subjects will be required to fast overnight for at least 8 hours before being given an SC dose of 
LY3298176, and when clinical laboratory test samples are taken (see Schedule of Activities 
[Section 2]). Water may be consumed freely. Standard meals will be administered while 
subjects are resident at the CRU.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed from 24 hours prior to dosing until discharge from the study or 
completion of all study procedures. No nicotine use will be permitted while in the CRU. While 
not resident in the CRU, subjects must consume no more than 10 cigarettes or the equivalent per 
day.
Subjects will be allowed to maintain their regular caffeine consumption throughout the study 
period.


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6.3.3. Activity
Subjects should not engage in strenuous physical exercise or activities from 48 hours prior to 
dosing until discharge from the study or completion of all study procedures.  When certain study 
procedures are in progress at the site, subjects may be required to remain supine or sitting.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  


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7. Treatment
7.1.
Treatment Administered
LY3298176 will be administered at the CRU as a single SC injection of either 5 mg or, 
depending on the results of interim analysis, a dose reduced by approximately 50%.  Instructions 
for preparation and handling are summarized in Section 7.5.
Whenever possible, study drug administration should be carried out by the same personnel.  
Dosing will commence at approximately the same time of day in all dose groups.  The actual 
time of dosing will be recorded in the subject’s CRF.
The investigator or designee is responsible for:

explaining the correct use of the IP to the site personnel

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
LY3298176 will be supplied by Lilly or its representative in accordance with current good 
manufacturing practices and will be supplied with lot numbers.
LY3298176 is supplied as 5-mg lyophilized powder in a glass vial intended for single-dose
administration.  When reconstituted according to instructions, the LY3298176 solution should be 
clear, colorless, and free of any visible particulate matter.
A pharmacist at the site or other site personnel will use the vials provided to prepare the syringes.
7.2.
Method of Treatment Assignment
Subjects will be assigned to groups based on mean eGFR as determined by the MDRD 
abbreviated equation using serum creatinine levels obtained on Day -1 (see Table GPGG.2). The 
allocation and dispensing of the IP will be fully documented and verified by a second person.  
Detailed records of the amounts of the IP received, dispensed, and remaining at the end of the 
study will be maintained by the site pharmacist.
7.2.1. Selection and Timing of Doses
A single dose will be administered by site personnel to each subject in the morning of Day 1.  
The site of injection administration will be recorded.  


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7.3.
Blinding
Not applicable.  This will be an open-label study.
7.4.
Dose Modification
The planned dose for subjects in this study is 5 mg.  Following dosing of at least 2 subjects each 
with mild and moderate renal impairment (Group 2 and Group 3, respectively) and appropriate 
matched-control subjects (Group 1),  an interim analysis, to include safety, tolerability, and PK 
data, is planned (Section 10.3.7 and Figure GPGG.3).  Safety data will be reviewed by the Lilly 
study team on a regular basis while subjects are enrolled in the study.  After dosing of the first 
2 subjects with severe renal impairment and ESRD (Groups 4 and 5) and appropriate 
matched-control subjects (Group 1), another interim analysis will be performed.  The purpose of 
the interim review(s) is to determine the dose level(s) for subsequent subjects.  The dose of 
LY3298176 for subsequent subjects (any or all groups) may be adjusted accordingly after each 
interim review.  The final dose determinations will be made by the investigator and the Lilly 
study team.
7.5.
Preparation/Handling/Storage/Accountability
LY3298176 lyophilized powder is to be reconstituted with Sterile Water for Injection (United 
States Pharmacopoeia).  The reconstituted product solution in the vial(s) may be held at room 
temperature and/or refrigerated (2°C to 8°C), and should be administered within 4 hours from the 
time of reconstitution.  Detailed instructions for the preparation and handling of LY3298176 will 
be provided by the sponsor.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all IP received and any discrepancies 
are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply or administer IP. All IP should be stored in an environmentally controlled 
and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Stable doses of over-the-counter or prescription medications (eg, antihypertensive agents, 
aspirin, lipid-lowering agents) for treatment of concurrent medical conditions are allowed for 
subjects with renal impairment.  Refer to Appendix 7 for common medications prescribed to 


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patients with renal impairment.  Subjects on stable concomitant medication(s) at the time of 
study entry should continue their regular, unchanged dose throughout the study.  
Stable single oral doses of metformin and/or stable doses of insulins (for at least 8 weeks) are 
allowed for subjects with T2DM.  Refer to Exclusion Criterion [46] in Section 6.2.3.
In the case of mild intercurrent illness during the study, concomitant treatment with 
paracetamol/acetaminophen may be allowed at the discretion of the investigator and is to be
recorded in the CRF.
No start of new concomitant therapy, apart from occasional intake of vitamin/mineral 
supplements, allowable antiemetics, and acetaminophen, will be permitted for 14 days before the 
first dose of LY3298176 through the final poststudy follow-up visit.  If the need for new or 
changes to concomitant medication arises, inclusion or continuation of the subject may be at the 
discretion of the investigator, preferably after consultation with a Lilly clinical pharmacologist 
(CP) or clinical research physician (CRP).
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.  Any drug given for the treatment of an AE should be 
documented as such.
7.8.
Treatment after the End of the Study
Not applicable.  LY3298176 will not be made available to subjects after conclusion of the study.


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8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
IP.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of T2DM, discontinuation 
from the study should occur prior to introduction of the new agent

Subject Decision
o
the subject requests to be withdrawn from the study

Adverse event
o
if a clinically significant event (CSE) occurs, the subject is to be discontinued and 
appropriate measures taken.  Lilly or its designee should be alerted immediately.  
A CSE will be defined as a moderate-to-severe AE, abnormal clinical sign, or 
clinical laboratory finding that may pose a risk to the well-being of the subject
o
a clinically significant systemic hypersensitivity reaction occurs following 
administration of the IP (eg, drug-related symptomatic bronchospasm, allergy-
related edema/angioedema, or hypotension) that requires parenteral medication, 
does not respond to symptomatic medication, or results in clinical sequelae or an 
anaphylactic reaction


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
At the discretion of the investigator, if the participant has 2 or more symptomatic 
hypoglycemic episodes (defined as an event with typical hypoglycemic symptoms 
and a measured blood glucose ≤63 mg/dL [3.5 mmol/L], equivalent to plasma/serum
glucose ≤70 mg/dL [3.9 mmol/L]; refer to Section 9.4.3)

Fasting plasma/serum glucose values are >270 mg/dL (approximately 15 mmol/L, 
equivalent to a fasting blood glucose >241 mg/dL [13.4 mmol/L]) on 3 or more 
separate days over any 2-week period between screening and the end of the dosing 
period

Discontinuation for abnormal pancreatic tests should be considered by the investigator if
a subject’s lipase and/or amylase are confirmed to be ≥3× ULN. Please refer to the
algorithm for the monitoring of pancreatic events in Appendix 6.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the informed consent form is signed, study site personnel will record, via CRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, study device, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/CP, or designee, of any SAE as soon as practically 
possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received IP.  However, if 
an SAE occurs after signing informed consent, but prior to receiving IP, AND is considered 
Reasonably Possibly Related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event Reasonably Possibly Related to 
the study treatment or study participation, the investigator must promptly notify Lilly.  
Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.


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9.2.2. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3298176 is considered any dose higher than the 
assigned dose.  Treatment for overdose is supportive care (refer to IB for LY3298176).
9.4.
Safety
9.4.1. Clinical Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
Additional blood draws may be drawn for safety purposes at the investigator’s discretion.  
9.4.2. Amylase and Lipase Measurements
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing and as specified in the Schedule of Activities (Section 2).  Additional measurements may 
be performed at the investigator’s discretion. Further diagnostic assessments will be 
recommended as per the algorithm (refer to Appendix 6) for the monitoring of pancreatic events 
whenever lipase and/or amylase is confirmed to be ≥3× ULN at any visit postdose, even if the 
subject is asymptomatic.
9.4.3. Glucose Monitoring
For safety purposes, blood glucose measurements will be performed using a bedside glucose 
monitor as specified in the Schedule of Activities (Section 2).  Additional safety blood glucose 
measurements may also be taken during the study as deemed necessary by the investigator. 
9.4.3.1.
Hyperglycemia and Hypoglycemia Reporting
Episodes of hyperglycemia (fasting plasma/serum glucose >270 mg/dL [15 mmol/L]) or 
hypoglycemia (plasma/serum glucose ≤70 mg/dL [3.9 mmol/L]) will be reported by the 
investigator or designated physician who will be responsible for advising the subject on what 
further actions to take. Additional monitoring may be requested at the investigator’s discretion.
If the fasting plasma/serum glucose during the dosing period exceeds the acceptable level 
defined as hyperglycemia on 3 or more separate days over any 2-week period between screening 
and the end of the dosing period, the subject will be evaluated further at the study site. If fasting 
plasma/serum glucose continues to exceed the acceptable level, the IP will be discontinued, and 
treatment with an appropriate antidiabetic agent may be initiated by the investigator. If 


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hyperglycemia occurs during the follow-up period, the subject will remain in the study until 
completion of the planned follow-up.
Hypoglycemia episodes will be recorded on specific CRF pages. Hypoglycemia will be treated 
appropriately by the investigator and additional monitoring of plasma/serum glucose levels may 
be performed. The following categories of the 2017 American Diabetes Association position 
statement on glycemic targets (ADA 2017) based on recommendations of the International 
Hypoglycaemia Study Group (IHSG 2017) should be applied for reporting in the CRF and 
evaluating hypoglycemic events.
Hypoglycemia will be described using the following definitions:  

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70mg/dL 
(3.9 mmol/L):  
o
Symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms 
of hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
o
Unspecified hypoglycemia: an event during which PG ≤70 mg/dL (3.9 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded

Documented Clinically Significant Hypoglycemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG <54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms 
of hypoglycemia but with PG <54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia: an event during which PG <54 mg/dL (3.0 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded

Severe hypoglycemia (Level 3): an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  During these 
episodes, the subject has an altered mental status and cannot assist in their care, is 
semiconscious or unconscious, or experienced coma with or without seizures and may 
require parenteral therapy. PG measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of blood glucose concentration to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration (PG ≤70 mg/dL [3.9 mmol/L])
o
Severe hypoglycemia requiring medical attention: a severe hypoglycemic 
event when subjects require therapy by healthcare professionals (eg, emergency 
medical technicians, emergency room personnel, etc.)
Other Hypoglycemia:

Nocturnal hypoglycemia: any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycemia) that occurs between 
bedtime and waking


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
Relative hypoglycemia: an event during which typical symptoms of hypoglycemia, that 
do not require the assistance of another person, are accompanied by PG >70 mg/dL 
(3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL (3.9 mmol/L) 
threshold

Overall (or total) hypoglycemia: This optional category combines all cases of 
hypoglycemia. If an event of hypoglycemia falls into multiple subcategories, the event is 
only counted once in this category

Probable symptomatic hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a PG measurement but that was presumably 
caused by a blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
9.4.3.2.
Severe Hypoglycemia
The determination of a hypoglycemic event as an episode of severe hypoglycemia as defined 
above will be made by the investigator based on the medical need of the subject to have required 
assistance and is not predicated on the report of a subject simply having received assistance.
All hypoglycemic events are AEs of special interest and will be recorded in the hypoglycemia 
module of the CRF (see Section 9.2 for details). All episodes of severe hypoglycemia must be 
reported as SAEs.  
9.4.4. Vital Signs
For each subject, vital signs (BP, pulse rate, and body temperature) measurements should be 
conducted according to the Schedule of Activities (Section 2).
Blood pressure and pulse rate should be measured after the subject has been supine for 
approximately 5 to 10 minutes.
During any AE of dizziness or posture-induced symptoms, unscheduled orthostatic vital signs 
should be assessed if possible.  If the subject feels unable to stand, supine vital signs only will be 
recorded.  Additional vital signs may be measured during the study if warranted.
9.4.5. Electrocardiograms
For each subject, single 12-lead digital ECGs should be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.
Subjects must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  Electrocardiograms may be obtained at additional 
times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant visit 
and for immediate subject management, should any clinically relevant findings be identified.  


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If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE to Lilly or its designee via CRF.
9.4.6. Injection-site Reactions
For each subject, injection-site reactions should be assessed according to the Schedule of 
Activities (Section 2).  Additional assessments may be performed if deemed necessary by the 
investigator.
If an injection-site reaction is present, it will be fully characterized (including erythema, 
induration, pain, itching, and swelling) and will be closely monitored until resolution.
Investigational site staff will be provided with separate instructions/training on how to
consistently evaluate injection-site reactions and their severity. Photographs of injection-site 
reactions may be taken in a standardized fashion for record-keeping purposes; however, the 
photographs will not be used to evaluate injection-site reaction severity.
9.4.7. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes including glucose, amylase, and lipase

serious and nonserious AEs, including AEs of interest (GI events, hypoglycemia,
injection-site reactions, hypersensitivity reactions) and reported and adjudicated 
pancreatitis
Further diagnostic assessments will be recommended whenever lipase and/or amylase are 
confirmed to be ≥3× ULN at any visit postdose even if the subject is asymptomatic (as per the 
algorithm for the monitoring of pancreatic events in Appendix 6) and, if pancreatitis is suspected, 
the case will be further defined during an adjudication process.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.7.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3× ULN, alkaline phosphatase (ALP) ≥2× ULN, or 
elevated TBL ≥2× ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to 


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confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator 
based on consultation with the Lilly CP or CRP.  Monitoring should continue until levels 
normalize and/or are returning to approximate baseline levels.  
Additional safety data should be collected if 1 or more of the following conditions occur:  

elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests

subject discontinued from treatment due to a hepatic event or abnormality of liver
tests

hepatic event considered to be an SAE.
9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
LY3298176.  A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and 24-hour clock time of each sampling will be recorded.
9.5.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3298176 will be assayed using a validated liquid chromatography mass 
spectrometry method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.  
9.6.
Pharmacodynamics
Not applicable.  
9.6.1. Immunogenicity Assessments
For immunogenicity testing, venous blood samples of approximately 10 mL will be collected 
from each subject according to the Schedule of Activities (Section 2) to determine antibody 
production against LY3298176.  Additional samples may be collected if there is a possibility that 
an AE is immunologically mediated. All samples for immunogenicity testing should have a 
time-matched sample for PK analysis. In the event of drug hypersensitivity reactions (immediate 
or nonimmediate), additional samples will be collected as close to the onset of the event as 
possible, at the resolution of the event, and 30 days following the event.  Instructions for the 


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collection and handling of blood samples will be provided by the sponsor.  The actual date and 
24-hour clock time of each sampling will be recorded.
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of 
LY3298176.  Antibodies may be further evaluated for their ability to neutralize the activity of 
LY3298176.  Positive LY3298176 ADA samples may also be tested for cross-reactivity with 
native GLP-1 and GIP, and, if positive, may then be tested for neutralizing antibodies against 
native GLP-1 and GIP.
All subjects will have an ADA sample measured at early discontinuation or at the follow-up 
visit.  A risk-based approach will be used to monitor subjects who develop treatment-emergent 
ADA (TE ADA), defined as a titer 2-fold (1 dilution) greater than the minimum required dilution 
of the assay if no ADA were detected at baseline, or a 4-fold (2 dilutions) increase in titer, 
compared to baseline, if ADA were detected at baseline.  
Clinically significant TE ADA will be defined as any TE ADA at the last visit with:

a high titer (1280) or an increasing titer from last measured value

an association with a moderate-to-severe injection-site reaction or infusion-related 
reaction

cross-reactive and/or neutralizing binding of an ADA with endogenous GLP-1 or GIP.
Subjects who have clinically significant TE ADA at early discontinuation or at the follow-up 
visit should be followed with ADA testing every 3 months for approximately 1 year or until the 
ADA titers have returned to the baseline ADA titer (defined as ADA titer within 2-fold of 
baseline). A PK sample may be collected at the follow-up immunogenicity assessment(s), if 
warranted and agreed upon by the investigator and sponsor.
Every attempt should be made to contact subjects for the follow-up immunogenicity assessment; 
however, if subjects are unwilling or unable to return for the visit, this is not considered a 
protocol violation.
Subjects followed for at least 1 year since last dose who have not returned to baseline, as defined 
above, will be assessed for safety concerns and, if no clinical sequelae are recognized by the 
clinical team, no further follow-up will be required.  Subjects who have clinical sequelae that are 
considered potentially related to the presence of TE ADA may also be asked to return for 
additional follow-up testing.
Samples will be retained for a maximum of 15 years after the last subject visit or for a shorter 
period, if local regulations and ERBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to LY3298176.  Any samples 
remaining after 15 years will be destroyed.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  


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Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3298176 and to investigate genetic variants thought to play a role in T2DM.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of LY3298176 or after LY3298176 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
Not applicable.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 58 subjects will be enrolled so that approximately 48 subjects complete the study, 
such that approximately 8 subjects per group complete Groups 2 through 5.  Approximately
16 completers are needed from Group 1 in order to facilitate demographic matching with the 
subjects in other groups.  
The sample size is not selected to satisfy a priori statistical requirement.  However, the sample 
size (16 subjects for the control group and 8 subjects per group for the other groups) will provide 
a 90% coverage probability of the half-width of the 90% confidence interval within 0.29 on a 
log-scale for comparison of each group to the control group for AUC or Cmax. Assuming the 
variability (coefficient of variation [CV]) is 32%.  In the natural scale, assuming the ratio is r, the 
90% confidence interval for the ratio should be within (0.74r, 1.34r).
Subjects who are enrolled but not administered treatment may be replaced to ensure that a 
sufficient number of subjects complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.  All 
subjects who discontinue from the study will be identified, and the extent of their participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, height, smoking habits, or other demographic characteristics will 
be recorded and may be used in the PK and safety analyses as quantitative or classification 
variables.  Study participants’ renal status grouping will be determined using a mean of the 
eGFR estimates, determined by the MDRD abbreviated equation and based on measurements of 
serum creatinine levels obtained on Day -1.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least one 
dose of the IP and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Immunogenicity analyses will be conducted for all subjects who receive at least one dose of IP.


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Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and, if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to study entry will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety clinical laboratory parameters (including 
amylase, lipase, and blood glucose), vital signs, physical examinations, and ECG parameters.  
The parameters will be listed and summarized using standard descriptive statistics.  Physical 
examinations and ECGs will be performed for safety monitoring purposes and will not be 
presented.  If warranted, additional analysis will be performed upon review of the data.
10.3.1.3. Injection-site Reactions
Incidence of erythema, induration, pain, itching, and swelling will be listed and summarized by 
treatment.  The post-injection pain score will be summarized by treatment.  Additional analyses 
may be performed, if appropriate.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3298176 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be area under the concentration versus time curve
(AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the time of last measured 
concentration (AUC0-tlast), and maximum drug concentration (Cmax).  Other noncompartmental 
parameters, such as half-life, apparent clearance, and apparent volume of distribution, may be 
reported.
10.3.2.2. Pharmacokinetic Statistical Inference
The main analysis is the evaluation of log-transformed AUC0-∞, AUC0-tlast, and Cmax using an 
analysis of variance model with subject group as a fixed factor.  The 90% confidence interval of 
the ratio between each impaired renal function group versus the control group will be estimated.  
The above analyses will be conducted twice, using different renal function group assignments 
(eGFR or creatinine clearance [CLcr] based on Day -1 measurements) (Table GPGG.3).  The 


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analysis based on CLcr will be exploratory.  Additionally an exploratory analysis based on 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method of renal impairment 
classification (Chronic Kidney Disease Epidemiology Collaboration, 2009) may also be 
performed.
Table GPGG.3.
Renal Function Classification for Primary Analyses
Group
Classification
eGFR (mL/min/1.73 m2)a
CLcr (mL/min)b
1
Control (normal renal function)
≥90
≥90
2
Mild renal impairment
60-89
60-89
3
Moderate renal impairment
30-59
30-59
4
Severe renal impairment
<30, not requiring dialysis
<30, not requiring dialysis
5
End-stage renal disease
Requiring dialysis
Requiring dialysis
Abbreviations:  CLcr = creatinine clearance; eGFR = estimated glomerular filtration rate.
a
Per enrollment classification; eGFR will be calculated using the Modification of Diet in Renal Disease
abbreviated equation.
b
CLcr will be calculated using the Cockcroft-Gault formula (Cockcroft and Gault 1976).
The supporting additional analysis is the evaluation of the relationship between the PK of 
LY3298176 and mean eGFR, as determined by the MDRD abbreviated equation.  Scatter plots 
of PK parameter versus eGFR will be produced and analyzed using either a mixed-effects linear 
or a nonlinear regression approach with eGFR as a continuous covariate on PK parameters.  
The time to Cmax will be analyzed using a Wilcoxon rank sum test.
If a dose adjustment after interim is needed, descriptive statistics for the PK parameters will be 
summarized by dose and subject groups.  Dose normalization or other methods may be employed 
for statistical analyses. Details of methods will be described in the Statistical Analysis Plan.
10.3.3. Pharmacodynamic Analyses
Not applicable.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.5. Evaluation of Immunogenicity
Subjects will be assessed for the development of TE ADA; the distribution of maximum titers 
will be described.  If cross-reactivity with native GLP-1 and GIP or neutralizing antibodies 
against native GLP-1 and GIP assays are performed, the frequency of each will be reported.
The relationship between the presence of antibodies and the PK parameters and safety may be 
assessed.


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10.3.6. Data Review During the Study
Data may be analyzed while the trial is ongoing.  An assessment committee will not be formed.  
Safety data will be reviewed by the Lilly study team on a regular basis while subjects are 
enrolled in the study.
10.3.7. Interim Analyses
Interim analyses are planned to occur during Study GPGG. Figure GPGG.3 illustrates the 
interim data review decision tree.  
Two subjects each from Groups 2 and 3 (subjects with mild and moderate renal impairment, 
respectively) and at least 2 subjects in Group 1 (appropriate matched-control subjects with 
normal renal function) will be enrolled in parallel and dosed with 5 mg LY3298176, followed by 
an interim analysis to evaluate safety, tolerability, and PK data.  Based on this interim analysis, a 
decision will be made about whether or not a dose adjustment is needed, and the study will 
continue with dosing of the remaining subjects in 2 and 3, along with the first 2 subjects from 
Groups 4 and 5 (subjects with severe renal impairment and ESRD, respectively) and appropriate 
matched-control subjects in Group 1.  
A second interim analysis to evaluate safety, tolerability, and PK data will be performed for all 
subjects in Group 3 (moderate renal impairment) on completion of follow-up visit. Data from 
this interim will support Phase 3 enrollment.
After dosing of the first 2 subjects in each of Groups 4 and 5 and their appropriate 
matched-control subjects, a third interim analysis will be performed to evaluate safety, 
tolerability, and PK data. Based on data from the third interim review, a decision will be made 
regarding dose level.  The study will then continue with the remaining subjects with severe renal 
impairment and ESRD (Groups 4 and 5, respectively) and their applicable matched-control 
subjects (Group 1).
The purpose of the interim review(s) is to determine the dose level(s) for subsequent subjects.  
The dose of LY3298176 for subsequent subjects (any or all groups) may be adjusted accordingly 
after each interim. A reduced dose of approximately 50% is planned, if needed. The final dose 
determinations will be made by the investigator and the Lilly study team.
If an additional unplanned interim analysis is deemed necessary, the Lilly CP, CRP, investigator, 
or designee will consult with the appropriate medical director or designee to determine if it is 
necessary to amend the protocol.


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Abbreviations:  ESRD = end-stage renal disease; PK = pharmacokinetic; RI = renal impairment;
t-conference = teleconference.
*If the subjects with severe RI or ESRD are already being administered a reduced dose, it may be necessary to 
discontinue enrollment of 1 or both of these groups.
Figure GPGG.3.
Interim data review decision tree.
cv
cv
cv
cv
cv
0
cv
At least 2 subjects with mild RI, 2 subjects with 
moderate RI, and at least 2 control subjects dosed at 
5.0 mg
Safety / PK review t-conference:
Dose tolerated?
Yes
Yes
Yes
No
No
Continue to dose mild/moderate RI subjects 
and dose first 2 subjects with severe RI and 
first 2 subjects with ESRD at 5.0 mg
Dose tolerated by subjects with mild RI but 
not by subjects with moderate RI?
Safety review t-conference following dosing 
of first 2 subjects with severe RI and first            
2 subjects with ESRD: Dose tolerated?
Dose not 
tolerated by 
either group
Dose remaining 
subjects with mild 
RI with 5.0 mg              
and reduce dose by 
approximately 50% 
for remaining 
subjects with 
moderate RI
Reduce dose by 
approximately 50% 
for remaining 
subjects with mild 
or moderate RI
Dose remaining 
subjects with 
severe RI or 
ESRD at same 
dose
Perform interim 
review and adjust 
dose for remaining 
subjects with      
severe RI 
or ESRD*
Reduce dose by 
approximately 50% 
for subjects with 
severe RI or ESRD


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11.
References
[ADA] American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a
report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care.
2005;28(5):1245-1249.
[ADA] American Diabetes Association. 2017 Standards of medical care in diabetes: glycemic 
targets position statement. Diabetes Care. 2017:40(Suppl 1):S48-S56.
Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: 
systematic review and meta-analysis. JAMA. 2007;298(2):194-206.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 
2007;132(6):2131-2157.
Baynes KC. The evolving world of GLP-1 agonist therapies for type 2 diabetes. Ther Adv 
Endocrinol Metab. 2010;1(2):61-67.
Chronic Kidney Disease Epidemiology Collaboration. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009;150:604-612.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and 
dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.
Dungan KM, Povedano ST, Forst T, González JG, Atisso C, Sealls W, Fahrbach JL. 
Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 
2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 
2014;384(9951):1349-1357.
[EMEA CHMP] The European Medicines Agency Committee for Medicinal Products for 
Human Use. 2016. Guideline on the evaluation of pharmacokinetics of medicinal products in 
patients with decreased renal function.
[FDA] Food and Drug Administration. 2010. Guidance for Industry: Pharmacokinetics in 
patients with impaired renal function—study design, data analysis, and impact on dosing and 
labeling.
Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, Kirchner H, Holland J, 
Hembree J, Raver C, Lockie SH, Smiley DL, Gelfanov V, Yang B, Hofmann S, Bruemmer D, 
Drucker DJ, Pfluger PT, Perez-Tilve D, Gidda J, Vignati L, Zhang L, Hauptman JB, Lau M, 
Brecheisen M, Uhles S, Riboulet W, Hainaut E, Sebokova E, Conde-Knape K, Konkar A, 
DiMarchi RD, Tschöp MH. Unimolecular dual incretins maximize metabolic benefits in 
rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151.
Giorgino F, Benroubi M, Sun J, Zimmermann AG, Pechtner V. Efficacy and safety of once-
weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and 
glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241-2249.
Herbst R, Bolton W, Shariff A, Green JB. Cardiovascular outcome trial update in diabetes: new 
evidence, remaining questions. Curr Diab Rep. 2017;17(9):67.


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[IHSG] International Hypoglycaemia Study Group. Glucose concentrations of less than 
3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the 
American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017;40(1):155-157.
Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. Efficacy and safety of 
dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide 
clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev. 
2016;32(8):776-790.
Kim SJ, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CH. GIP-overexpressing mice 
demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. 
PLoS One 7. 2012;7(7):e40156.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F. 
Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine 
values in the modification of diet in renal disease study equation for estimating glomerular 
filtration rate. Ann Intern Med. 2006;145(4):247-54.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the 
pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, 
Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, 
glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD 
(liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84-90.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges JP, Lindegaard ML, Jensen CB, Atkin 
SL; Study 1821 investigators. A Phase 2, randomized, dose-finding study of the novel once-
weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide 
in patients with type 2 diabetes. Diabetes Care. 2016;39(2):231-241.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, 
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care. 
2013;36(5):1384-1395.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-∞
area under the concentration versus time curve from time zero to infinity
AUC0-tlast
area under the concentration versus time curve from time zero to the time of last measured 
concentration
BP
blood pressure
BMI
body mass index
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CLcr
creatinine clearance
Cmax
maximum drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist


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CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit
CSE
clinically significant event
DPP
dipeptidyl peptidase
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
ESRD
end-stage renal disease
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus 
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
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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investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IP
investigational product:  A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical study, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the authorized 
form, or marketed products used for an unauthorized indication, or marketed products used 
to gain further information about the authorized form.
LS
least squares
MDRD
Modification of Diet in Renal Disease
NOAEL
no-observed-adverse-effect level
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PG
plasma glucose
PK
pharmacokinetic(s)
QTc
corrected QT interval
QW
once weekly
RA
receptor agonist
SAE
serious adverse event
SC
subcutaneous
Scr
serum creatinine
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.  
SUSARs
suspected unexpected serious adverse reactions 
T2DM
type 2 diabetes mellitus 
TBL
total bilirubin
TE ADA
treatment-emergent antidrug antibodies
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya:
Clinical Chemistrya:
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Magnesium
Absolute counts of:
Glucose, fasting
Neutrophils
Blood urea nitrogen 
Lymphocytes
Uric acid
Monocytes
Total cholesterol
Eosinophils
Triglycerides
Basophils
Total protein
Platelets
Albumin
Cell morphologyb
Total bilirubin
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Urinalysisa:
Creatinine
Specific gravity
Gamma-glutamyl transferase 
pH
Amylase
Protein
Lipase
Glucose
Ketones
Ethanol testingd
Bilirubin
Urine drug screend
Urobilinogen
Hepatitis B surface antigenc
Blood
Hepatitis C antibodyc
Nitrite
HIVc
Microscopic examination of sedimentb
Pregnancy teste
FSHc,f
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Performed by local laboratory at screening and by central laboratory at all other time points.
b
If clinically indicated, per investigator’s discretion.  
c
Performed by local laboratory at screening only.
d
Urine drug screen performed in clinic or by local laboratory at screening and repeated prior to admission to the 
clinical research unit.  Ethanol testing will be performed at admission to the clinical research unit.  Urine drug 
screen and ethanol level will be repeated at other times indicated in the Schedule of Activities.  A serum or 
salivary drug screen may be performed on subjects who are unable to produce a urine sample.
e
Female subjects only.  Serum pregnancy test performed by local laboratory at screening; urine pregnancy test 
performed in clinic at all other times.
f
Female subjects only.  To confirm postmenopausal status as needed.


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


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled subjects will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the case report forms (CRFs), and 
study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.


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
review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPGG Sampling Summary
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume (mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12
5
60
Pharmacokineticsa
3
13
26
Immunogenicitya
10
3
30
Pharmacogenetics
10
1
10
Glucose monitoringa
0.5
9
4.5
Total
175.5
Total for clinical purposes rounded up to nearest 10 mL
180
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Pancreatic Monitoring
Glucagon-like peptide-1 (GLP-1) agonists have been associated with a possible risk of acute 
pancreatitis.  In 2006, the US prescribing information for exenatide was revised to include the 
event of pancreatitis.  In 2007, the US prescribing information for this medication was amended 
to include pancreatitis under precautions.  Epidemiologic studies have indicated that there is an 
increased incidence and prevalence of pancreatitis in persons with type 2 diabetes mellitus 
(T2DM).
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and to assess for any potential effects of LY3298176 on the exocrine pancreas, 
amylase and lipase values will be monitored in all current and future clinical trials with 
LY3298176.
Additional monitoring will be requested for amylase or lipase values ≥3× upper limit of normal 
(ULN) at any visit postdose, even in asymptomatic subjects (see figure below).  Lipase and 
amylase may also be obtained at any time during the clinical trials for any subject suspected of 
having symptoms suggestive of pancreatitis (such as severe gastrointestinal signs and/or 
symptoms), at the investigator’s discretion.
Acute pancreatitis is an adverse event defined as an acute inflammatory process of the pancreas 
that may also involve peripancreatic tissues and/or remote organ systems.  The diagnosis of acute 
pancreatitis requires 2 of the following 3 features:

abdominal pain characteristic of acute pancreatitis

serum amylase and/or lipase >3× ULN

characteristic findings of acute pancreatitis on computed tomography scan or 
magnetic resonance imaging
Most patients/subjects with acute pancreatitis experience abdominal pain that is located generally 
in the epigastrium and radiates to the back in approximately half the cases.  The pain is often 
associated with nausea and vomiting.  However, experience with GLP-1 agonists has 
demonstrated that some patients/subjects asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  For patients/subjects considered by investigators 
to be asymptomatic for pancreatitis, but whose value(s) for lipase and/or amylase are ≥3× ULN, 
an algorithm is in place to follow these patients/subjects safely and to quickly reach/or not a 
diagnosis of pancreatitis.


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Pancreatic Enzymes:  Safety Monitoring Algorithm in 
Patients without Symptoms of Pancreatitis1,2
Follow this algorithm when the value(s) for serum amylase and/or lipase are ≥3× upper limit of normal.
1.
Symptomatic – related to abdominal pain consistent 
with pancreatitis; however, in the opinion of the 
investigator, severe nausea and vomiting plus other 
symptoms consistent with pancreatitis may be 
considered symptomatic as well.
2.
If in the opinion of the investigator, the subject has 
symptoms of acute pancreatitis:
(a) Discontinue subject
(b) Consult for assessment and management
(c) Assess for causes of pancreatitis
(d) Notify Lilly
3.
A/L = amylase and/or lipase.  Either or both 
enzymes can be used to meet algorithm criteria.
4.
Abdominal imaging is most valuable when 
performed at the time of elevated enzymes.  If, in 
the opinion of the investigator, it is safe for the 
subject to receive contrast, and enhanced abdominal 
CT is preferred.  MRI is also an acceptable imaging 
modality.
5.
At a minimum, order a CBC and a pancreatic panel 
(which includes LFTs, calcium, and trigycerides).  
Record all concomitant medications
Abbreviations:  A/L = amylase and/or lipase; CBC = complete blood count; CT = computed tomography; 
LFT = liver function tests; MRI = magnetic resonance imaging; ULN = upper limit of normal.


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Appendix 7.
Permitted Concomitant Medication
Common medications prescribed to patients with renal impairment
Other drugs not listed in this table may be authorized for use during the study at the discretion of 
the investigator in consultation with the Lilly clinical pharmacologist or clinical research 
physician.
Therapeutic Category
Medication
Vitamin D compounds 
Doxercalciferol 
Anemia / iron deficiency 
Erythropoietin, intravenous or oral iron
Antihypertensives 
Beta blockers, ACE inhibitors, controlled release 
calcium channel blockers, angiotensin II receptor 
agonists 
Hypolipidemics
HMG-CoA reductase inhibitors (Atorvastatin, 
Simvastatin, Pravastatin, Fluvastatin) 
Antihyperuricemics 
Allopurinol 
Vasodilators 
Nitrates
Diuretics 
Furosemide, Hydrochlorothiazide, Spironolactone 
Phosphate binding agents
Calcium acetate, calcium carbonate, Sevelamer


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Appendix 8.
Calculation of Estimated Glomerular 
Filtration Rate
Calculation of estimated glomerular filtration rate (eGFR) from serum creatinine (Scr) assayed 
using an isotope dilution mass spectrometry method and using the Modification of Diet in Renal 
Disease abbreviated equation (Levey et al. 2006).  The equation does not require weight or 
height variables because the results are reported normalized to an accepted average adult body 
surface area of 1.73 m2.  The equation has been validated extensively in Caucasian and African 
American populations between the ages of 18 and 70 with impaired kidney function (eGFR 
<60 mL/min/1.73 m2) and has shown good performance for patients with all common causes of 
kidney disease.
eGFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)


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Appendix 9.
Protocol Amendment I8F-MC-GPGG(b) 
Summary 
Pharmacokinetics of LY3298176 Following 
Administration to Subjects with Impaired Renal Function
Overview
Protocol I8F-MC-GPGG, Pharmacokinetics of LY3298176 Following Administration to 
Subjects with Impaired Renal Function, 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 as follows:

Based on early recruiting experience with subjects with severe renal impairment, the 
protocol was amended to facilitate enrollment of subjects in Group 4.
o
Severe renal impairment classification is revised to include subjects with eGFR 
<30 mL/min/1.73m2 and not requiring dialysis, as defined in the EMEA guideline 
(EMEA CHMP 2016).
o
Subjects with T2DM are now allowed to use insulin, outside of metformin.


I8F-MC-GPGG(b) Clinical Pharmacology Protocol
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LY3298176
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1.
Protocol Synopsis
Summary of Study Design:
Study I8F-MC-GPGG is a Phase 1, multicenter, nonrandomized, open-label, parallel-design study in subjects with 
mild, moderate, or severe renal impairment, or end-stage renal disease (ESRD), and control subjects with normal 
renal function.  Renal function will provide the basis for assignment to treatment group.

Group 1: control subjects with normal renal function (estimated glomerular filtration rate [eGFR]
≥90 mL/min/1.73m2)

Group 2: subjects with mild renal impairment (eGFR between 60 and 89 mL/min/1.73m2)

Group 3:  subjects with moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m2)

Group 4:  subjects with severe renal impairment (eGFR between 15 and 29<30 mL/min/1.73m2 and not 
requiring dialysis)

Group 5:  subjects with ESRD (have received hemodialysis for at least 3 months).
5.1.
Overall Design
Table GPGG.2.
Subject Groups based on Renal Impairment Status
Classification
eGFR (mL/min/1.73m2)
Group 1
Control (normal renal function)
≥90
Group 2
Mild renal impairment
60-89
Group 3
Moderate renal impairment
30-59
Group 4
Severe renal impairment
15-29<30 and not requiring dialysis
Group 5
End-stage renal disease
Requiring dialysis
Abbreviations:  eGFR = estimated glomerular filtration rate (as determined by the Modification of Diet in Renal 
Disease abbreviated equation).
5.4.
Scientific Rationale for Study Design
A comprehensive range of renal impairment is necessary to fully characterize the impact of renal 
impairment on the PK of LY3298176.  Subjects undergoing hemodialysis (Group 5) will be 
included to determine the effect of dialysis on drug removal.


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LY3298176
6.1.3.
Additional Inclusion Criteria for Subjects with Mild to Severe Renal 
Impairment or ESRD
[10] Males or females with stable mild to severe renal impairment, assessed by eGFR or with 
ESRD (having received hemodialysis for at least 3 months).
6.1.4.
Additional Inclusion Criteria for Subjects with T2DM and Renal 
Impairment or ESRD
[13] Have T2DM controlledtreated with diet or exercise alone or with stable doses of on
metformin and/or insulins for at least 8 weeks.
[15] Have a hemoglobin A1c (HbA1c) ≥7.06.0% and ≤11.0% at the screening visit.
6.2.3.
Additional Exclusion Criteria for Subjects with T2DM and Renal 
Impairment or ESRD
[46] Have taken any glucose-lowering medications other than metformin and/or insulins (refer 
to Inclusion Criterion [13]), including insulin, in the past 3 months before screening.  In 
general, stable dosages of metformin and insulins will be continued; however, a washout 
period or dose modifications may be necessary to allow for optimal blood glucose
monitoring throughout the dosing period at the discretion of the investigator.
7.7.
Concomitant Therapy
Stable single oral doses of metformin and/or stable doses of insulins (for at least 8 weeks) are 
allowed for subjects with T2DM.  Refer to Exclusion Criterion [46] in Section 6.2.3.Additional 
concomitant medications for treatment of T2DM, other than metformin, are not permitted during 
the study.
Table GPGG.3.
Renal Function Classification for Primary Analyses
Group
Classification
eGFR (mL/min/1.73 m2)a
CLcr (mL/min)b
1
Control (normal renal function)
≥90
≥90
2
Mild renal impairment
60-89
60-89
3
Moderate renal impairment
30-59
30-59
4
Severe renal impairment
15-29<30, not requiring 
dialysis
15-29<30, not requiring 
dialysis
5
End-stage renal disease
Requiring dialysis
Requiring dialysis
Abbreviations:  CLcr = creatinine clearance; eGFR = estimated glomerular filtration rate.
a
Per enrollment classification; eGFR will be calculated using the Modification of Diet in Renal Disease 
abbreviated equation.
b
CLcr will be calculated using the Cockcroft-Gault formula (Cockcroft and Gault 1976).


Leo Document ID = a4c382cc-21ac-4798-a6a3-c1f096dfe2d1
Approver: 
Approval Date & Time: 03-May-2019 14:26:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-May-2019 15:03:22 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan 
Title: Pharmacokinetics of LY3298176 Following Administration to Subjects with Impaired Renal 
Function 
 
NCTID: NCT03482024 
 
Approval Date: 11-Apr-2018 
 


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STATISTICAL ANALYSIS PLAN
Pharmacokinetics of LY3298176 Following Administration to Subjects with Impaired 
Renal Function
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  11-April-2018
Study Drug:  LY3298176
Sponsor Reference:  I8F-MC-GPGG
Covance CRU Study: 1000071-8378513
Clinical Phase I
Approval Date: 11-Apr-2018 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8378513
Sponsor Reference I8F-MC-GPGG
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objective................................................................................................ 5
4.3
Exploratory Objective.............................................................................................. 6
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENT ............................................................................................................... 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 8
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
9.
STATISTICAL METHODOLOGY ............................................................................... 9
9.1
General.................................................................................................................... 9
9.2
Demographics and Subject Disposition.................................................................... 9
9.3
Pharmacokinetic Assessment................................................................................... 9
9.3.1
Pharmacokinetic Analysis............................................................................... 9
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 13
9.4
Safety and Tolerability Assessments...................................................................... 14
9.4.1
Adverse Events............................................................................................. 14
9.4.2
Concomitant Medication............................................................................... 15
9.4.3
Clinical Laboratory Parameters..................................................................... 15
9.4.4
Vital Signs.................................................................................................... 15
9.4.5
Electrocardiogram (ECG)............................................................................. 15
9.4.6
Injection Site Assessment ............................................................................. 15
9.4.7
Glucose Monitoring and Hyperglycemia/Hypoglycemia Reporting............... 15
9.4.8
Immunogenicity ........................................................................................... 15
9.4.9
Hepatic Monitoring ...................................................................................... 16
9.4.10
Other Assessments ....................................................................................... 16
9.4.11
Safety and Tolerability Statistical Methodology............................................ 16
10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 19
12. REFERENCES ............................................................................................................ 19
13. DATA PRESENTATION ............................................................................................ 19
13.1 Derived Parameters ............................................................................................... 19
13.2 Missing Data ......................................................................................................... 19
13.3 Insufficient Data for Presentation .......................................................................... 19


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8378513
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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
percentage of AUC(0-∞) extrapolated
AE
adverse event
ADA
antidrug antibodies
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
area under the concentration versus time curve from time zero to time 
t, where t is the last time point with a measurable concentration
BMI
body mass index
BQL
below the lower limit of quantification
CL/F
apparent total body clearance of drug calculated after extravascular
administration
Clast
last quantifiable drug concentration
CLcr
creatinine clearance
Cmax
maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
coefficient of variation
e.g.
for example (Latin: exempli gratia)
EC
Early Clinical 
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
ESRD
end-stage renal disease
ICH
International Council on Harmonisation
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MDRD
Modification of Diet in Renal Disease
PK
Pharmacokinetic(s)


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8378513
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SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation 
T2DM
Type 2 Diabetes Mellitus
TFLs
Tables, Figures, and Listings
t½
Half-life associated with the terminal rate constant (λz) in
noncompartmental analysis
tmax
time of maximum observed drug concentration
ULN
upper limit of normal
Vss/F
apparent volume of distribution at steady state after extravascular 
administration
Vz/F
apparent volume of distribution during the terminal phase after
extravascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8378513
Sponsor Reference I8F-MC-GPGG
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
15 January 2018).
This SAP describes the planned analysis of the pharmacokinetic (PK) and tolerability data from 
this study. A detailed description of the planned TFLs to be presented in the clinical study report 
(CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To estimate the PK parameters of LY3298176 in subjects with mild, moderate, or severe 
renal impairment, and in subjects with end-stage renal disease (ESRD) after a single 
5-mg subcutaneous (SC) dose of LY3298176 compared to control subjects with normal 
renal function.
4.2
Secondary Objective

To assess the tolerability of LY3298176 in subjects with mild, moderate, or severe renal 
impairment, and in subjects with ESRD after a single 5-mg SC dose of LY3298176 
compared to control subjects with normal renal function.


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4.3
Exploratory Objective

To evaluate the formation of antidrug antibodies (ADA) to LY3298176 after a single 
5-mg SC dose administered to subjects with mild, moderate, or severe renal impairment, 
and in subjects with ESRD.
5. STUDY DESIGN
This is a Phase 1, parallel-design, open-label, multicenter, single-dose study to assess PK and 
tolerability of a single dose of LY3298176 in subjects with mild, moderate, or severe renal 
impairment, or ESRD, and control subjects with normal renal function.  Control Group 1 will be 
healthy subjects with normal renal function.  Subjects with Type 2 Diabetes Mellitus (T2DM)
will not be included in Group 1.  Subjects with T2DM and renal impairment will be permitted to 
enroll in Groups 2 to 5, whereas subjects with T2DM and normal renal function will not be 
permitted.  Subjects will be assigned to 1 of 5 groups (Groups 1 to 5) based on criteria outlined 
in Table 1. Estimated glomerular filtration rate (eGFR) will be determined by the Modification 
of Diet in Renal Disease (MDRD) abbreviated equation using serum creatinine levels obtained at 
Screening and on Day -1;  subjects will be assigned to groups based on values from Day -1. 
The control subjects (Group 1) will be selected in order that the mean and distribution of 
Group 1 are comparable to the mean and distribution for each group with renal impairment 
(Groups 2 through 5) for age (± 10 years), sex, race, weight (±10 kg), and body mass index 
(BMI) (± 20%), as far as is practically possible3.
Table 1. Subject Groups based on Renal Impairment Status
Classification
eGFR (mL/min/1.73m2)
Group 1
Control (normal renal function)
≥90
Group 2
Mild renal impairment
60-89
Group 3
Moderate renal impairment
30-59
Group 4
Severe renal impairment
15-29
Group 5
End-stage renal disease
Requiring dialysis
Abbreviations: eGFR = estimated glomerular filtration rate (as determined by the Modification of Diet in Renal 
Disease abbreviated equation).
Figure 1 and Figure 2 illustrate the study design.
Subjects will visit the Clinical Research Unit (CRU) to sign the informed consent document and 
undergo screening procedures up to 28 days prior to dosing.
Subjects will be admitted to the CRU on Day -1. Subjects will be administered a single dose of 
LY3298176 on Day 1 and will remain in the CRU until after assessments are completed on 
Day 5. Subjects will return for study visits on Days 8 and 15 and for a final follow-up visit at 
least 28 days postdose.


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Covance Clinical Study No. 1000071-8378513
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For subjects with ESRD, administration of LY3298176 should occur at least 24 hours prior to the 
next planned dialysis session. The time and dates of dialysis sessions from the session 
immediately prior to dose through Day 8 will be recorded in the case report form (CRF). To 
eliminate potential variation between different types of dialysis membrane, only high-flux 
polysulfone membranes will be used.
Abbreviations: ADA = antidrug antibodies; D = Day; PK = pharmacokinetic.
Figure 1. Illustration of study design for Groups 1 to 4.
Abbreviations: ADA = antidrug antibodies; D = Day; PK = pharmacokinetic.
Figure 2. Illustration of study design for Group 5.


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Covance Clinical Study No. 1000071-8378513
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6. TREATMENT
The TFLs will include a subheader for treatment (X mg LY3298176 SC) throughout.  The 
following is a list of group abbreviations that will be used in the TFLs.
Group
Order in TFL
Control (normal renal function)
1
Mild renal impairment
2
Moderate renal impairment
3
Severe renal impairment
4
End-stage renal disease
5
7. SAMPLE SIZE JUSTIFICATION
Approximately 58 subjects will be enrolled so that approximately 48 subjects complete the study, 
such that approximately 8 subjects per group complete Groups 2 through 5.  Approximately 
16 completers are needed from Group 1 in order to facilitate demographic matching with the 
subjects in other groups.
The sample size is not selected to satisfy an a priori statistical requirement.  However, the sample 
size (16 subjects for the control group and 8 subjects per group for the other groups) will provide 
a 90% coverage probability of the half-width of the 90% confidence interval within 0.29 on a 
log-scale for comparison of each group to the control group for the area under the concentration 
versus time curve (AUC) or maximum observed drug concentration (Cmax),  assuming the 
variability (coefficient of variation [CV]) is 32%.  In the natural scale, assuming the ratio is r, the 
90% confidence interval for the ratio should be within (0.74r, 1.34r).
Subjects who are enrolled but not administered treatment may be replaced to ensure that a 
sufficient number of subjects complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.


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Covance Clinical Study No. 1000071-8378513
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9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max, and N; for log-normal data (e.g., the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subject’s change-from-baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change-from-baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, site ID,
body weight, height, BMI, and eGFR will be summarized by group and listed.  All other 
demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined using noncompartmental methods in the 
validated software program, Phoenix WinNonlin (Certara, Version 6.4 or later).
Plasma concentrations of LY3298176 will be used to determine the following PK parameters, 
when possible:  


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8378513
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Parameter
Units
Definition
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to time 
t, where t is the last time point with a measurable concentration
%AUC(tlast-)
%
percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in 
noncompartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after extravascular 
administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extravascular administration
Vss/F
L
apparent volume of distribution at steady state after extravascular 
administration
Additional PK parameters may be determined where appropriate.  The software and version used 
for the final analysis will be specified in the CSR.  Any exceptions or special handling of data will 
be clearly documented within the final study report.
PK analysis will, where possible, be carried out using actual postdose times recorded in the raw 
data. If actual times are missing, nominal times may be used with sponsor approval. 
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool:  
NONCOMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed. 
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus predose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than 1 time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax.  The 
minimum requirement for the calculation of AUC will be the inclusion of at least 3
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax.  AUC(0-) values where the 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8378513
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percentage of the total area extrapolated is more than 20% will be flagged.  Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.  If AUC(0-∞) cannot be determined for all subjects an alternative AUC 
measure, such as AUC to a fixed time point, may be used in the assessment exposure 
between dose groups.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  t½ will only be calculated when a reliable estimate for this parameter can 
be obtained comprising of at least 3 data points.  If t½ is estimated over a time window of 
less than 2 half-lives, the values will be flagged in the data listings. Any t½ value 
excluded from summary statistics will be documented in the footnote of the summary 
table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on the predicted last quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantification (BQL).  Plasma concentrations reported as BQL will be set to a value of 
zero when all of the following conditions are met:
o
The compound is nonendogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where 2 or more consecutive concentrations are BQL towards the end of a profile, 
the profile will be deemed to have terminated and, therefore, any further quantifiable 
concentrations will be set to missing for the calculation of the PK parameters unless 
considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semilogarithmic plot.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8378513
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Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The predose average concentration for single-dose data from nonendogenous compounds 
will be set to zero.  Otherwise, only quantifiable concentrations will be used to calculate 
average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate.  This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the predose sample exceeds 
all measured concentrations for that individual in the subsequent postdose samples.

For PK profiles during single dosing of nonendogenous compounds, the concentration in 
a predose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8378513
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1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log-transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ± 3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ± 3*SD, then it is not 
an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ± 3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n≥6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only 1 suspected outlier in each iteration, until all data remaining 
in the dataset fall within the range of arithmetic mean ± 3*SD of the log-transformed values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
The main analysis is the evaluation of log-transformed AUC(0-∞), AUC(0-tlast), and Cmax using 
an analysis of variance model with subject group as a fixed factor.  The 90% confidence interval 
of the ratio between each impaired renal function group versus the control group will be 
estimated.
Example SAS code:
proc mixed data=DATA;
    class group;
    model log_pk = group / ddfm=kr;
    lsmeans group / pdiff cl alpha=0.1;
    ods output lsmeans=lsmeans;
    ods output diffs=diffs;
run;


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The above analyses will be conducted twice, using different renal function group assignments 
(eGFR or creatinine clearance [CLcr] based on Day -1 measurements) (Table 2).  The analysis 
based on CLcr will be exploratory.
Table 2.  Renal Function Classification for Primary and Exploratory Analyses
Group
Classification
eGFR (mL/min/1.73m2)a
CLcr (mL/min)b
1
Control (normal renal function)
≥90
≥90
2
Mild renal impairment
60-89
60-89
3
Moderate renal impairment
30-59
30-59
4
Severe renal impairment
15-29
15-29
5
End-stage renal disease
Requiring dialysis
Requiring dialysis
Abbreviations: CLcr = creatinine clearance; eGFR = estimated glomerular filtration rate.
a Per enrollment classification; eGFR will be calculated using the Modification of Diet in Renal Disease abbreviated 
equation.
b CLcr will be calculated using the Cockcroft-Gault formula (Cockcroft and Gault 1976).
The supporting additional analysis is the evaluation of the relationship between the PK of
LY3298176 and mean eGFR, as determined by the MDRD abbreviated equation. Scatter plots
of PK parameter versus eGFR will be produced and analyzed using either a mixed-effects linear
or a nonlinear regression approach with eGFR as a continuous covariate on PK parameters.
tmax will be analyzed using a Wilcoxon rank sum test.
If a dose adjustment after interim is needed, descriptive statistics for the PK parameters will be
summarized by dose and subject groups. Dose normalization or other methods may be employed
for statistical analyses.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse Events
Where changes in severity of an AE are recorded in the CRF, each separate severity of the AE
will be reported in the listings, only the most severe will be used in the summary tables. A 
pre-existing condition is defined as an AE that starts before the subject has provided written 
informed consent and is ongoing at consent. A non-treatment-emergent AE is defined as an AE 
that starts after informed consent but prior to dosing. A treatment-emergent AE is defined as an 
AE that occurs postdose or is present prior to dosing and becomes more severe postdose.
All AEs will be listed.  Treatment-emergent AEs will be summarized by group, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects
experiencing an AE, and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by group, Medical Dictionary for Regulatory Activities (MedDRA)
version 20.1 system organ class and preferred term. The summary and frequency AE tables will 


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be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.4.2
Concomitant Medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version September 2017). Concomitant medication will be listed.
9.4.3
Clinical Laboratory Parameters
All clinical chemistry, hematology, and urinalysis data will be summarized by parameter and 
group, and listed. Additionally clinical chemistry, hematology and urinalysis data outside the 
reference ranges will be listed.
Values for any clinical chemistry, hematology, and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.4.4
Vital Signs
Vital signs data will be summarized by group together with changes from baseline, where 
baseline is defined as Day 1 predose. Figures of mean vital signs and mean 
changes-from-baseline profiles will be presented by group. 
Furthermore, values for individual subjects will be listed.
9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented.
9.4.6
Injection Site Assessment 
Injection site assessment data (erythema, induration, categorical pain, pruritus, and edema) will 
be listed and summarized by group in frequency tables.
9.4.7
Glucose Monitoring and Hyperglycemia/Hypoglycemia Reporting
Hypoglycemic events will be appropriately recorded in the CRF.  In the case of a hypoglycemic
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered.  Each category of hypoglycemic event (defined in Section 9.4.3.1 
of the Protocol) will be listed and summarized by group.
Blood glucose levels will be listed for individual patients and summarized by group.
9.4.8
Immunogenicity 
Immunogenicity data will be listed and frequency tables will be presented.  The frequency of 
treatment-emergent ADAs will also be calculated.  If cross-reactivity with native GLP-1 and GIP 
or neutralizing antibodies against native GLP-1 and GIP assays are performed, the frequency of 
each will be reported.  Treatment-emergent ADAs are those that are induced or boosted by 


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Covance Clinical Study No. 1000071-8378513
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exposure to study drug, with a 4-fold increase in titer compared to baseline if ADAs were 
detected at baseline or a titer 2-fold greater than the minimum required dilution if no ADAs were 
detected at baseline.
To show the association of treatment-emergent ADAs with AEs, the frequency of 
treatment-emergent ADAs will be presented by MedDRA preferred term.
The relationship between the presence of antibodies and the PK parameters may be assessed.
9.4.9
Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase ≥3× upper limit of normal (ULN), 
alkaline phosphatase ≥2× ULN, or elevated total bilirubin ≥2× ULN, liver tests will be 
performed to confirm the abnormality.
Each subject’s liver disease history and associated person liver disease history data will be listed. 
Any concomitant medication of acetaminophen/paracetamol will be listed.  Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography scan, and a biopsy 
assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed.  Liver-related signs and symptoms data will be 
summarized by treatment and listed.  Alcohol and recreational drug use data will also be listed. 
All hepatic chemistry, hematology, coagulation, and serology data will be listed.  Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.10
Other Assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.
9.4.11
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
An interim analysis is planned to occur during Study GPGG. Figure 3 illustrates the interim data 
review decision tree.
Two subjects each from Groups 2 and 3 (subjects with mild and moderate renal impairment,
respectively) and Group 1 (appropriate matched-control subjects with normal renal function)  
will be enrolled in parallel and dosed with 5 mg LY3298176, followed by an interim analysis to
evaluate safety, tolerability, and PK data. Based on this interim analysis, a decision will be made
about whether or not a dose adjustment is needed, and the study will continue with dosing of the
remaining subjects in Groups 2 and 3, along with the first 2 subjects from Groups 4 and 5 
(subjects with severe renal impairment and ESRD, respectively) and appropriate matched-control 
subjects in Group 1. If deemed necessary after dosing of the first 2 subjects in each of Groups 4 


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Covance Clinical Study No. 1000071-8378513
Sponsor Reference I8F-MC-GPGG
and 5 and their appropriate matched-control subjects, a second interim analysis may be 
performed. Preliminary PK review will be optional for this interim analysis of subjects in Groups 
4 and 5. Based on data from the second interim review, a decision will be made regarding dose 
level. The study will then continue with the remaining subjects with severe renal impairment 
and ESRD (Groups 4 and 5, respectively) and their applicable matched-control subjects (Group 
1).
The purpose of the interim review(s) is to determine the dose level(s) for subsequent subjects. 
The dose of LY3298176 for subsequent subjects (any or all groups) may be adjusted accordingly 
after each interim. A reduced dose of approximately 50% is planned, if needed. The final dose 
determinations will be made by the investigator and the Lilly study team.
If an additional unplanned interim analysis is deemed necessary, the Lilly clinical 
pharmacologist, clinical research physician, investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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Abbreviations: ESRD = end-stage renal disease; PK = pharmacokinetic; RI = renal 
impairment;  t-conference = teleconference. *If the subjects with severe RI or ESRD are already 
being administered a reduced dose, it may be necessary to discontinue enrollment of one or both 
of these groups.
Figure 3. Interim data review decision tree.


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Sponsor Reference I8F-MC-GPGG
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. [FDA] Food and Drug Administration. 2010. Guidance for Industry: Pharmacokinetics in 
patients with impaired renal function—study design, data analysis, and impact on dosing and 
labelling.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g., PK parameters) and appropriate summary statistics will be 
reported to 3 significant figures. Observed concentration data (e.g., Cmax) should be reported as 
received. Observed time data (e.g., tmax) should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = e5f2b0b0-9544-4bd1-bb54-2ff95d05686f
Approver:
Approval Date & Time: 11-Apr-2018 16:06:20 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Apr-2018 16:06:20 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Apr-2018 16:06:20 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Apr-2018 16:06:20 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD