A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients With Type 2 Diabetes Mellitus
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Clinical Study Protocol Addendum Version (1) I8F-JE-GPGO 
 
A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients with Type 
2 Diabetes Mellitus (SURPASS J-mono) 
NCT03861052 
Approval Date: 18-Dec-2018 

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1. Protocol Addendum I8F-JE-GPGO(1)
A Phase 3 Study of Tirzepatide Monotherapy Compared to 
Dulaglutide 0.75 mg in Patients with Type 2 Diabetes
Mellitus (SURPASS J-mono)
Confidential Information
The information contained in this protocol addendum 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 tirzepatide (LY3298176), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  This document and 
its associated attachments are subject to United States Freedom of Information Act (FOIA) 
Exemption 4. 
Tirzepatide (LY3298176)
This addendum is to be performed in addition to all procedures required by protocol 
I8F-JE-GPGO or any subsequent amendments to that protocol.
Eli Lilly Japan K.K
Kobe, Hyogo, Japan
Protocol Addendum (1) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 18-Dec-2018 GMT

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2. Table of Contents
Section
Page
1.
Protocol Addendum I8F-JE-GPGO(1) A Phase 3 Study of 
Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in 
Patients with Type 2 Diabetes Mellitus (SURPASS J-mono)...............................................1
2.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................5
4.
Protocol Additions ..............................................................................................................6
4.1.
Schedule of Activities ....................................................................................................6
4.2.
Objectives and Endpoints ...............................................................................................8
4.3.
Study Design..................................................................................................................8
Overall Design.......................................................................................................8
4.3.1.
Number of Participants...........................................................................................9
4.3.2.
Scientific Rationale for Study Design.....................................................................9
4.3.3.
Lifestyle and/or Dietary Requirements .................................................................10
4.3.4.
4.3.4.1.
Meals and Dietary Restrictions .......................................................................10
4.4.
Study Assessments and Procedures ..............................................................................10
Pharmacokinetics .................................................................................................10
4.4.1.
Meal Tolerance Test.............................................................................................11
4.4.2.
4.4.2.1.
Pharmacodynamics.........................................................................................11
4.4.2.2.
Satiety after Standardized Test Meal...............................................................11
Continuous Glucose Monitoring...........................................................................11
4.4.3.
Body Composition ...............................................................................................12
4.4.4.
4.5.
Statistical Considerations and Data Analysis ................................................................12
Sample Size Determination ..................................................................................12
4.5.1.
Statistical Analyses ..............................................................................................12
4.5.2.
4.5.2.1.
Pharmacokinetic Analyses..............................................................................12
4.5.2.2.
Pharmacodynamic Analyses ...........................................................................12
4.5.2.2.1.
Pharmacodynamic Parameter Estimation ..................................................12
4.5.2.2.2.
Pharmacodynamic Statistical Inference.....................................................13
4.5.2.3.
Continuous Glucose Monitoring Analyses ......................................................13
4.5.2.4.
Body Composition Analyses...........................................................................13
4.5.2.5.
Analyses for Satiety Evaluation ......................................................................13
5.
References ........................................................................................................................14

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List of Tables
Table
Page
Table GPGO.1.
Schedule of Activities, I8F-JE-GPGO..............................................................7
Table GPGO.2.
Objectives and Endpoints.................................................................................8

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List of Attachments
Attachment
Page
Attachment 1.
Protocol Addendum GPGO(1) Clinical Laboratory Tests...............................15
Attachment 2.
Protocol Addendum GPGO(1) Blood Sampling Summary.............................16
Attachment 3.
Protocol Addendum GPGO(1) Meal Tolerance Test ......................................17

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3. Rationale for Addendum
The Japan guidance for Clinical Pharmacokinetic Studies of Pharmaceutics (IYAKUSHIN
HATSU No.796. 2001) states that pharmacokinetic (PK) studies using the final formulation need 
to be conducted prior to submission of the new drug application (NDA). To meet this regulatory 
requirement in Japan, the PK of tirzepatide after single and multiple subcutaneous doses of 
tirzepatide using the commercial formulation will be evaluated in Japanese patients with type 2 
diabetes mellitus (T2DM).
The concentration-time profile and conventional PK parameters of tirzepatide have been
characterized in a Phase 1 study in Japanese patients with T2DM (I8F-JE-GPGC) using an early 
phase lyophilized formulation. Currently, no PK data have been generated in Japanese patients 
using the commercial solution formulation supplied in a single use pen, which is the formulation 
to be evaluated in Phase 3 in Japanese patients with T2DM.
In the Phase 1 study of tirzepatide in Japanese patients with T2DM, a meal tolerance test (MTT)
was not performed and postprandial glucose metabolic hormones were not assessed.  These data 
are frequently requested by healthcare providers. In addition, continuous glucose monitoring
(CGM) will be performed in order to show reducing daily variability of blood glucose level.
Body composition will be measured in order to confirm that majority of weight loss is due to fat 
mass reduction.
This addendum is to be performed in patients at certain participating sites for PK, glucodynamic, 
and pharmacodynamics (PD) evaluation in Protocol I8F-JE-GPGO (GPGO), which is a Phase 3 
study in Japan. The objectives of this addendum are to evaluate:
1)
the PK profile of tirzepatide in Japanese patients with T2DM at the dose level of 
5 mg, 10 mg, and 15 mg of tirzepatide at the first dose (Week 0) and steady state 
(Week 32) using the commercial formulation 
2)
detailed 6-hour postprandial data, including serum glucose profiles, insulin, 
C-peptide, glucagon, triglycerides, and satiety at Week 32
3)
continuous glycemic parameters immediately after the start of administration and at 
Week 32
4)
body composition, including total body water, protein, minerals, body fat mass, and 
lean body mass at Weeks 12, 32, and 52
These outcomes will provide supportive data to understand the mechanism of action of 
tirzepatide, and to answer the frequently asked questions by healthcare providers.

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4. Protocol Additions
4.1.
Schedule of Activities

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Table GPGO.1.
Schedule of Activities, I8F-JE-GPGO
Screen-
ing
Lead-in
Treatment
Follow-
up
Study Visit
1
2
3
4 - 5
6
7-9
10
11-12
13
ET
801
Week of Treatment
―
―
-1
0
―
―
―
1
―
12
―
31
32
―
―
―
33
―
52
―
―
Hour of Treatment
―
0
8
24
48
72
168  
―
―
0
8
24
48
72
168
―
Visit Window for PK 
(hour)
―
―
±1
±2
±4
±7
±16
-
―
―
―
±1
±2
±4
±7
±16
―
Laboratory Tests
Tirzepatide PK 
sample for 
commercial 
formulation PK
X
X
X
X
X
X
X
X
X
X
X
X
Screen-
ing
Lead-in
Treatment
Follow-
up
Study Visit
1
2
3
4 - 5
6
7-9
10
11-12 13
ET
801
Week of Treatment
―
―
-1
0
―
―
―
1
―
12
―
31
32
―
―
―
33
―
52
―
―
Day of Treatment
-7c
0
―
―
―
7c
―
-7d
0
―
―
―
7d
―
Visit Window for 
CGM and MTT (day)
―
―
―
―
―
0 to 
+1
-
―
0 to 
+3
―
―
―
―
0 to 
+1
―
Clinical Assessments
Body Composition
Xe
X
X
X
Laboratory Tests
CGM insertiona
X
X
CGM removala
X
X
Meal tolerance testb
X
X
Abbreviations: CGM = continuous glucose monitoring; ET = early termination; MTT = meal tolerance test; PK = pharmacokinetics.
a
CGM device to be applied on Day -7, and device removed on Day 7 at Week 0 and Week 32.  Although the CGM device will be applied from Day -7 through 
Day 7 at Week 0 and Week 32, the data required to be analyzed is from Day -6 through Day 6.
b
MTT samples to be collected at 0 (pre-meal), 30, 60, 90, 120, 180, 240, 300, and 360 minutes after the start of standardized test meal at Week -1 (Day-7 of 
Week 0) and Week 32.  The laboratory tests for MTT include serum glucose, insulin, c-peptide, glucagon, and triglyceride.  A perception of satiety (full and 
hungry) visual analog scale (VAS) should be completed by patients at 0 (pre-meal), 60, 120, 180, 240, 300, and 360 minutes following the standardized test 
meal on each MTT day.
c
Relative to Week 0.
d
Relative to Week 32.
e
The body composition should be measured prior to administration of investigational product.

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4.2.
Objectives and Endpoints
Table GPGO.2 shows the objectives and endpoints of this addendum, which are in addition to 
the Study GPGO protocol body.
Table GPGO.2.
Objectives and Endpoints
Objectives
Endpoints
Pharmacokinetics

To evaluate the pharmacokinetic 
profile of once-weekly tirzepatide in 
Japanese patients with T2DM using 
the commercial formulation

AUC and Cmax of tirzepatide
Exploratory

To compare the effect of once-
weekly tirzepatide versus dulaglutide 
0.75 mg on the pharmacodynamic 
profile and satiety after a 
standardized test meal at Week 32

The change from baseline in serum glucose AUC(0-6h)

The change from baseline in insulin AUC(0-6h)

The change from baseline in C-peptide AUC(0-6h)

The change from baseline in glucagon AUC(0-6h)

The change from baseline in triglyceride AUC(0-6h)

The change from baseline in satiety (full and hungry) 
in VAS

To compare the effect of once-
weekly tirzepatide versus dulaglutide 
0.75 mg on daily glucose variability
measured by CGM at Week 32

Daily average glucose (mg/dL)

Time in range ≤70 mg/dL (minutes)

Time in range >180 mg/dL (minutes)

Daily within-day SD (mg/dL)

Daily MAGE (mg/dL)

To compare the effect of once-
weekly tirzepatide versus dulaglutide 
0.75 mg on body composition at 
Week 12, 32, and 52

The change from baseline in total body water (L)

The change from baseline in protein (kg)

The change from baseline in minerals (kg)

The change from baseline in body fat mass (kg)

The change from baseline in lean body mass (kg)
Abbreviations:  AUC = area under the concentration versus time curve; AUC(0-6h) = area under the concentration 
versus time curve from time zero to 6 hours after dose; Cmax = maximum concentration; CGM = continuous 
glucose monitoring; MAGE = mean amplitude of glycemic excursion; T2DM = type 2 diabetes mellitus; 
VAS = visual analog scale. 
4.3.
Study Design
Overall Design
4.3.1.
Study GPGO is a multicenter, randomized, double-blind, parallel, active-controlled, 52-week
Phase 3 study which will assess the safety and efficacy of tirzepatide (5, 10, and 15 mg),
compared to dulaglutide 0.75 mg in approximately 636 randomized patients with T2DM who
have discontinued oral antihyperglycemic medication (OAM) monotherapy or are OAM-naïve.

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Study GPGO will consist of 3 periods:  a 4-week (OAM-naïve) or 10-week (at least 8-week 
OAM washout) screening/lead-in period, followed by a 52-week treatment period, and a 4-week 
safety follow-up period.  Patients will be randomized in a 1:1:1:1 ratio (tirzepatide 5 mg, 10 mg, 
15 mg, and dulaglutide 0.75 mg). 
Patients will be stratified based on baseline glycated hemoglobin (HbA1c) (≤8.5% and >8.5%), 
baseline body mass index (BMI) (<25 or ≥25 kg/m2), and washout of antidiabetic medication 
(yes or no).
For the PK profile, PK samples will be collected at pre-dose, 8, 24, 48, 72, and 168 hours at
Week 0 and Week 32.
For the glucodynamic and PD evaluation, MTT will be performed at Week -1 (Day-7 of Week 0)
and Week 32. Time points for blood sampling will be 0 (pre-meal), 30, 60, 90, 120, 180, 240, 
300, and 360 minutes after the start of standardized test meal.  Satiety will be also assessed at 
0 (pre-meal), 60, 120, 180, 240, 300, and 360 minutes after the start of standardized test meal. 
Investigational product material will be administered before starting standardized test meal at 
Week 32. Continuous glucose monitoring will be initiated on Day -7, and will end on Day 7 at 
Week 0 and Week 32.  
Body composition will be assessed at Weeks 0, 12, 32, and 52.  Every effort should be made to 
measure body composition in the same condition at each time point to minimize intra-individual 
variability.  
Number of Participants
4.3.2.
The total number of participants for this addendum is approximately 48 patients, which is based 
on the objectives of PK and glucodynamic effect.
To evaluate the glucodynamic effect, a total of 48 participants (12 participants per treatment) 
will be needed.  The assumptions for this sample size are described in Section 4.5.1.  To provide 
the PK and pharmacodynamic (PD) evaluation similar to the historical conventional Phase 1 
studies, samples from approximately 10 patients in the treatment arms of tirzepatide 5 mg, 
10 mg, 15 mg, and/or dulaglutide 0.75 mg will be needed.
Scientific Rationale for Study Design
4.3.3.
This addendum is designed to evaluate PK, glucodynamic, and PD effects after a standardized 
test meal.  Patients with T2DM who have diet and exercise therapy only will be enrolled to 
exclude the background effect of other antidiabetic agents.  A Japanese standardized test meal
(480 kcal, carbohydrate: protein: fat = 2.8:1:1) was selected because it was used in the previous 
MTTs conducted in Japan (Lee et al. 2010; Yabe et al. 2010; Yabe et al. 2015).
Pharmacokinetic samples will be collected at Week 0 and Week 32 to enable the evaluation of 
the PK of tirzepatide after a single dose and at steady state for all treatment arms. 

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Continuous glucose monitoring will be performed on Day -7 through Day 7 at Week 0 and 
Week 32, and MTT will be performed at Week -1 (Day-7 of Week 0) and Week 32, which are to 
enable the evaluation of tirzepatide at steady state for all treatment arms.
Body composition will be measured at Weeks 0, 12, 32, and 52 to enable evaluating time course 
of change of body composition during the study period. The time point was determined based on 
the reference data in combination of luseogliflozin and liraglutide (Seino et al. 2018).  In the
study described in the reference, time points were 0, 4, 12, 24, and 52 weeks.
Lifestyle and/or Dietary Requirements
4.3.4.
4.3.4.1.
Meals and Dietary Restrictions
Study participants should be instructed to continue diet therapy during the study period.  Study 
participants must be fasting at least 10 hours before intake of a test meal for the MTT. 
4.4.
Study Assessments and Procedures
Section 4.1 lists the Schedule of Activities, detailing the study procedures and their timing.
Attachment 1 lists the laboratory tests that will be performed for the MTT.
Attachment 2 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Attachment 3 provides a summary of MTT procedures.
Pharmacokinetics
4.4.1.
In the historical conventional Phase 1 study, the PK of tirzepatide was evaluated in 
approximately 12 Japanese subjects per treatment arm with a different titration regimen from 
Phase 3 studies. This study intends to obtain PK data from approximately 10 patients per 
treatment arm; PK samples will be collected from 12 patients in each of the treatment arms of 
tirzepatide (5-mg, 10-mg, and 15-mg arms) and the dulaglutide 0.75-mg arm.
The samples for drug concentration measurements will be handled in accordance with the 
sponsor-specified procedures.
Blood samples for PK evaluation will be collected from certain patients at participating site(s) 
during the study at Week 0 and Week 32. Blood sampling will be performed at the times 
specified in the Study Schedule of Activities (Section 4.1).
Plasma samples for drug concentration measurements will be analyzed at a laboratory approved 
by the Sponsor. Pharmacokinetic samples will be collected from patients allocated to the 
dulaglutide arm but the samples will not be assayed for dulaglutide concentration. 
Drug concentration information will not be reported to investigative sites or to other blinded 
personnel until study completion. To preserve the blinding of the study, a minimum number of 
Lilly personnel will see these results before study completion.

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Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following the last patient visit for the study, because re-assay may be 
required, based on the results of the PK analysis.
Meal Tolerance Test
4.4.2.
4.4.2.1.
Pharmacodynamics
At times specified in the Schedule of Activities (Section 4.1) and Attachment 3, venous blood 
samples will be collected and used to determine the PD effects of tirzepatide.  Blood will be 
collected by venipuncture in order to evaluate fasting serum glucose, postprandial serum glucose, 
insulin, C-peptide, glucagon, and triglyceride and will be analyzed in the central laboratory.
The following measures of PD will be evaluated:

The change from baseline in serum glucose area under the concentration versus time 
curve from time zero to 6 hours (AUC[0-6h]) at Week 32

The change from baseline in insulin (30, 60, 90, 120, 180, 240, 300, and 360 minutes) at 
Week 32

The change from baseline in insulin AUC(0-6h) at Week 32

The change from baseline in C-peptide (30, 60, 90, 120, 180, 240, 300, and 
360 minutes) at Week 32

The change from baseline in C-peptide AUC(0-6h) at Week 32

The change from baseline in glucagon (30, 60, 90, 120, 180, 240, 300, and 360 minutes) 
at Week 32

The change from baseline in glucagon AUC(0-6h) at Week 32

The change from baseline in triglyceride (30, 60, 90, 120, 180, 240, 300, and 
360 minutes) at Week 32

The change from baseline in triglyceride AUC(0-6h) at Week 32
4.4.2.2.
Satiety after Standardized Test Meal
A perception of satiety (full and hungry) visual analog scale (VAS) should be completed by 
patients at 0 (pre-meal), 60, 120, 180, 240, 300, and 360 minutes following the standardized test 
meal on each MTT day.  
Continuous Glucose Monitoring
4.4.3.
The CGM data will complement the evaluation of the glucodynamic effects of tirzepatide (5 mg, 
10 mg, and 15 mg) at Week 0 and Week 32.  
The FreeStyle Libre Pro system (Abbott) will be used for CGM in this study. The CGM sensor 
will be applied to the patients at the clinic on Day -7, and will be removed on Day 7 at Week 0
and Week 32. 
The CGM sensors will be scanned during clinic visits, and data from the CGM device will be 
uploaded to a central vendor’s secure location. Mechanisms to blind the CGM data during the 
sensor scanning and data upload process are not deemed to be necessary, because this study 

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compares the study drug to an active comparator (dulaglutide). Data will be transmitted from the 
central vendor to Lilly at determined intervals.
Body Composition
4.4.4.
Total body water (L), protein (kg), minerals (kg), and body fat mass (kg) will be measured by 
InBody 770 (Inbody Japan) at Weeks 0, 12, 32, and 52.  The lean body mass (kg) will be 
calculated based on total body water, protein, and minerals (Section 4.5.2.4).  
4.5.
Statistical Considerations and Data Analysis
Sample Size Determination
4.5.1.
A total of 48 patients will be randomized in a 1:1:1:1 ratio to 1 of 4 treatments.  Assuming 
1 dropout, the sample size of 11 patients for each treatment group would provide 79% power to 
demonstrate a statistically significant difference between the tirzepatide dose levels and
dulaglutide 0.75 mg.  This computation assumes the true treatment difference in glucose 
AUC(0-6h) is 330 mg*hr/dL, a common standard deviation of 250 mg*hr/dL.
Statistical Analyses
4.5.2.
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.  Any change to the data analysis methods described in the protocol will require an 
amendment ONLY if it changes a principal feature of the protocol. Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in the statistical analysis plan (SAP) or the clinical study report (CSR). Additional 
exploratory data analyses may be conducted, as deemed appropriate.
4.5.2.1.
Pharmacokinetic Analyses
All tirzepatide concentration data will be analyzed using noncompartmental methods 
implemented with the program WinNonlin on a computer that meets or exceeds the minimum 
system requirements. The version of any software used for the analysis will be documented and 
the program will meet the Lilly requirements of software validation.  It is possible that other
validated software programs may be utilized, if appropriate, warranted, and approved by Global 
PK/PD/TS management.
The primary parameters to be estimated will be maximum concentration (Cmax), time of maximum
observed concentration (tmax) and area under the concentration-time curve (AUC) of tirzepatide
at Week 0 and Week 32. Other noncompartmental PK parameters, such as half-life (t1/2) 
apparent clearance (CL/F) and apparent volume of distribution (V/F) may be estimated, if 
deemed appropriate.
4.5.2.2.
Pharmacodynamic Analyses
4.5.2.2.1. Pharmacodynamic Parameter Estimation
Pharmacodynamic parameters will be calculated for glucose, insulin, glucagon, C-peptide, and 
triglyceride data following the standardized test meal at Week -1 (Day-7 of Week 0) and 
Week 32.  The AUC(0-6h) will be calculated using the linear-trapezoidal method.  The 

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parameters area under the concentration versus time curve from time zero to 1 hour (AUC[0-1h]),
area under the concentration versus time curve from time zero to 2 hours (AUC[0-2h]), area under 
the concentration versus time curve from time zero to 3 hours (AUC[0-3h]), area under the 
concentration versus time curve from time zero to 4 hours (AUC[0-4h]), and area under the  
concentration versus time curve from time zero to 5 hours (AUC[0-5h]) may also be calculated.
All PD parameters will be summarized by treatment group and listed.
4.5.2.2.2. Pharmacodynamic Statistical Inference
Pharmacodynamic analyses will be conducted using data from all patients who receive at least 
1 dose of the investigational product and have evaluable PD.  
The change in PD parameters from baseline to Week 32 will be analyzed by an analysis of 
covariance (ANCOVA) model with treatment, baseline BMI group (<25 or 25 kg/m2) and 
washout of antidiabetic medication (yes or no) and baseline value (Week -1 [Day-7 of Week 0]) 
of the dependent variable as a covariate. The least-squares mean (LS Mean), standard error (SE)
and the 95% confidence interval (CI) derived from the model will be displayed for change from 
baseline by treatment group.  Treatment comparisons will be displayed showing the treatment 
difference LS Mean and the 95% CI of treatment differences along with the p-values for the 
treatment comparison.  Statistical tests will be conducted using 2-sided tests and a significance 
level of 0.05. No multiplicity adjustment will be applied.
4.5.2.3.
Continuous Glucose Monitoring Analyses
The CGM data from Day -6 to Day 6 at 2 occasions (Week 0 and Week 32) will be summarized 
and analyzed.  The CGM parameters (daily average, daily standard deviation, daily mean 
amplitude of glycemic excursion [MAGE], daily time in range [≤70 mg/dL or ≥180 mg/dL]) will 
be derived from glucose data collected by a CGM device and will be summarized by treatment 
and day for each occasion.  The baseline CGM parameters will be derived from the data 
measured prior to administration of investigational product. A comparison between tirzepatide
doses and dulaglutide 0.75 mg will be conducted. Individual (by patient) or mean by treatment,
glucose data will be plotted, if deemed appropriate.
4.5.2.4.
Body Composition Analyses
The data of total body water, protein, minerals, and body fat mass will be collected.  Lean body 
mass will be derived as the sum of 3 components (total body water, protein, and minerals).
Change in body composition parameters (body weight, total body water, protein, minerals, body 
fat mass, and lean body mass) from baseline will be summarized. A comparison between 
tirzepatide doses and dulaglutide 0.75 mg will be conducted.
4.5.2.5.
Analyses for Satiety Evaluation
Satiety after a standardized test meal (Satiety, Hunger and Satiety/Hunger) in the VAS will be 
summarized by treatment and time after a standardized test meal (0 [pre-meal], 60, 120, 180, 240, 
300, and 360 minutes).  A comparison of tirzepatide doses and dulaglutide 0.75 mg will be 
conducted.

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5. References
IYAKUSHIN HATSU No.796. Clinical Pharmacokinetic Studies of Pharmaceuticals. June 1,
2001
Lee S, Yabe D, Nohtomi K, Takada M, Morita R, Seino Y, Hirano T. Intact glucagon-like
peptide-1 levels are not decreased in Japanese patients with type 2 diabetes. Endocr J.
2010;57(2):119-126.
Seino Y, Yabe D, Sasaki T, Fukatsu A, Imazeki H, Ochiai H, Sakai S. Sodium-glucose 
cotransporter-2 inhibitor luseogliflozin added to glucagon-like peptide 1 receptor agonist 
liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese 
patients with type 2 diabetes: a 52-week, open-label, single-arm study. J Diabetes Investig. 
2018;9(2):332-340.
Yabe D, Kuroe A, Watanabe K, Iwasaki M, Hamasaki A, Hamamoto Y, Harada N, Yamane S, 
Lee S, Murotani K, Deacon CF, Holst JJ, Hirano T, Inagaki N, Kurose T, Seino Y. Early phase 
glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly 
responsible for hyperglycemia after ingestion of nutrients. J Diabetes Complications. 
2015;29(3):413-421.

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Attachment 1.Protocol Addendum GPGO(1) Clinical 
Laboratory Tests
Safety Laboratory Tests, Protocol Addendum I8F-JE-GPGO(1)
Meal tolerance test (0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes)
Serum Glucose
Insulin
C-peptide
Glucagon
Triglycerides
Note: The meal tolerance test includes the following tests:  serum glucose, insulin, C-peptide, glucagon, and 
triglycerides.

I8F-JE-GPGO (1) Clinical Protocol Addendum
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LY3298176
Attachment 2.Protocol Addendum GPGO(1) Blood Sampling 
Summary
This table summarizes the approximate blood volumes for all blood sampling during the study.  
Sampling Summary, Protocol Addendum I8F-JE-GPGO(1)
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume (mL)
Tirzepatide PK sample for commercial 
formulation PK
3
12
36
MTT (serum glucose, insulin, C-peptide, 
glucagon, and triglyceride)
8
18
144
Total
-
-
180
Abbreviations:  MTT = meal tolerance test; PK = pharmacokinetics.

I8F-JE-GPGO (1) Clinical Protocol Addendum
Page 17
LY3298176
Attachment 3.Protocol Addendum GPGO(1) Meal Tolerance 
Test
Meal Tolerance Test, Protocol Addendum I8F-JE-GPGO(1)
Time
Procedure
Before MTT
All evaluations for a regular visit
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride (for 0 min) 
Satiety evaluation (VAS) (for 0 min)
Dose of investigational product at Week 32
0 min
Start standardized test mealc
30 mina
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
60 mina
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
90 mina
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
120 mina
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
180 minb
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
240 minb
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
300 minb
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
360 minb
Blood sampling for serum glucose, insulin, C-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
Abbreviations:  min = minutes; MTT = meal tolerance test; VAS = visual analog scale.
a
For each time point, ±5 minutes for sampling window is allowed.
b
For each time point, ±10 minutes for sampling window is allowed.
c
A Japanese standard test meal (480 kcal, carbohydrate: protein: fat = 2.8:1:1) should be ingested within 
15 minutes.

Leo Document ID = 8d79f639-cfb0-47dc-ba71-d5571a192143
Approver: 
Approval Date & Time: 18-Dec-2018 02:45:37 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Dec-2018 09:18:48 GMT
Signature meaning: Approved
PPD
PPD