Clinical trial NCT04172987
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-02-26; Completion date: 2021-02-09
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to look at how the body processes the commonly prescribed birth control pill, ethinylestradiol + norgestimate (EE/NGM), in healthy female participants and the effect of tirzepatide on how EE/NGM is processed by the body. Information about any side effects that may occur will also be collected.

Screening is required within 28 days prior to the start of the study. For each participant, the study will last about 20 weeks, including screening.

Detailed description:

Arms: arm 1: Participants received a 28-day packet of a combination oral contraceptive (OC) containing 21 days of tablets that consist of active ingredients (0.035 mg ethinyl estradiol (EE) and 0.25 mg norgestimate (NGM)) self-administered orally once-daily (QD) on Day 1 to Day 21, and 7 days of non-active tablets self-administer orally QD on Day 22 to Day 28 approximately the same time each day. arm 2: Participants received a 28-day packet of a combination OC containing 21 days of tablets that consist of active ingredients (0.035 mg EE and 0.25 mg NGM) self-administered orally QD on Day 1 to Day 21, and 7 days of non-active tablets self-administer orally QD on Day 22 to Day 28 approximately the same time each day and a single dose 5 mg tirzepatide administered subcutaneously (SC).
Interventions: intervention 1: Tirzepatide intervention 2: EE/NGM
Intervention descriptions: intervention 1: Administered SC intervention 2: Combination oral contraceptive administered orally

Protocol documents:
Prot_000.pdf: 
Protocol I8F-MC-GPGR (b) 
 
Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics in Healthy Female Subjects 
 
NCT04172987 
 
Approval Date: 14-May-2020 


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
Page 1
Tirzepatide (LY3298176)
Protocol I8F-MC-GPGR (b)
Effect of Tirzepatide on Oral Contraceptive 
Pharmacokinetics in Healthy Female Subjects
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 
tirzepatide (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 Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.
Tirzepatide (LY3298176)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on 18 Oct
2019.
Amendment (a) Electronically Signed and Approved by Lilly: 06 Dec 2019
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 14-May-2020 GMT


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
Table of Contents
Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics 
in Healthy Female Subjects
Section
Page
Protocol I8F-MC-GPGR (b) Effect of Tirzepatide on Oral Contraceptive 
Pharmacokinetics in Healthy Female Subjects.....................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.2.
Number of Participants.................................................................................................20
5.3.
End of Study Definition ...............................................................................................20
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................21
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................25
6.3.
Lifestyle and/or Dietary Requirements .........................................................................25
6.3.1.
Meals and Dietary Restrictions.............................................................................25
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................26
7.
Treatment..........................................................................................................................27
7.1.
Treatment Administered...............................................................................................27
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Selection and Timing of Doses.............................................................................29
7.3.
Blinding .......................................................................................................................29


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Tirzepatide (LY3298176)
7.4.
Dose Modification........................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................30
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..........................................35
9.2.2.
Complaint Handling.............................................................................................35
9.3.
Treatment of Overdose.................................................................................................35
9.4.
Safety...........................................................................................................................35
9.4.1.
Laboratory Tests ..................................................................................................35
9.4.1.1.
Amylase and Lipase Measurements ................................................................35
9.4.2.
Glucose Monitoring .............................................................................................35
9.4.2.1.
Hyperglycemia and Hypoglycemia Reporting.................................................36
9.4.3.
Vital Signs ...........................................................................................................37
9.4.4.
Electrocardiograms ..............................................................................................37
9.4.5.
Injection-site Reactions ........................................................................................38
9.4.6.
Hypersensitivity Reactions...................................................................................39
9.4.7.
Safety Monitoring ................................................................................................39
9.4.7.1.
Hepatic Safety................................................................................................40
9.5.
Pharmacokinetics .........................................................................................................40
9.5.1.
Bioanalysis...........................................................................................................40
9.6.
Pharmacodynamics ......................................................................................................41
9.6.1.
Immunogenicity Assessments ..............................................................................41
9.7.
Genetics .......................................................................................................................41
9.8.
Biomarkers...................................................................................................................42
9.9.
Health Economics ........................................................................................................42
10.
Statistical Considerations and Data Analysis.....................................................................43
10.1. Sample Size Determination ..........................................................................................43
10.2. Populations for Analyses..............................................................................................43


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Tirzepatide (LY3298176)
10.2.1.
Study Participant Disposition ...............................................................................43
10.2.2.
Study Participant Characteristics ..........................................................................43
10.3. Statistical Analyses ......................................................................................................43
10.3.1.
Safety Analyses....................................................................................................44
10.3.1.1.
Clinical Evaluation of Safety..........................................................................44
10.3.1.2.
Statistical Evaluation of Safety.......................................................................44
10.3.2.
Pharmacokinetic Analyses....................................................................................44
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................44
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................44
10.3.3.
Pharmacodynamic Analyses.................................................................................44
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................45
10.3.5.
Evaluation of Immunogenicity .............................................................................45
10.3.6.
Data Review During the Study.............................................................................45
10.3.7.
Interim Analyses..................................................................................................45
11.
References ........................................................................................................................46
12.
Appendices .......................................................................................................................47


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
List of Tables
Table
Page
Table GPGR.1.
Objectives and Endpoints .......................................................................18
Table GPGR.2.
Treatments Administered........................................................................28


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
List of Figures
Figure
Page
Figure GPGR.1.
Illustration of study design for Protocol I8F-MC-GPGR.........................20


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Tirzepatide (LY3298176)
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................48
Appendix 2.
Clinical Laboratory Tests........................................................................51
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................52
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............55
Appendix 5.
Blood Sampling Summary......................................................................56
Appendix 6.
Classification of Contraceptive Methods.................................................57
Appendix 7.
Pancreatic Monitoring ............................................................................58
Appendix 8.
Protocol Amendment I8F-MC-GPGR (b) Summary 
Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics in 
Healthy Female Subjects ........................................................................61


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
1. Protocol Synopsis
Title of Study:
Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics in Healthy Female Subjects
Rationale: 
Study I8F-MC-GPGR will assess the effect of a 5 mg subcutaneous (SC) dose of tirzepatide administered using a 
pre-filled syringe on the pharmacokinetics (PK) of an oral contraceptive (OC) in healthy female subjects.  This study 
will evaluate the potential effect of tirzepatide mediated delay in gastric emptying (GE) on the PK of an OC, as 
premenopausal women with diabetes could take oral contraceptives concomitantly with tirzepatide.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To evaluate the effect of a single SC dose of tirzepatide 
on the pharmacokinetics (PK) of a combination OC in 
healthy female subjects.
AUC(0-tau), AUC(0-tlast), Cmax
Secondary
To evaluate the safety and tolerability of a single 
subcutaneous dose of tirzepatide when coadministered 
with an OC in healthy female subjects.  
Incidence of adverse events (AEs)
Summary of Study Design:
This is a single-center, open-label, 2-period, fixed sequence study with a lead-in period, in healthy female subjects.  
Subjects may already have been on OC medication prior to screening or be OC naïve.  Each subject will participate 
in 2 treatment periods and a lead-in period.
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to Day 1 of the 
lead-in period.  On Day -1 of the lead-in period and of Periods 1 and 2, subjects will receive a single 28-day packet 
of the study OC (21 days of active treatment and 7 days of non-active treatment) and will be instructed to 
self-administer a once-daily (QD) dose of OC tablet at approximately the same time each day.
In Period 1, subjects will be admitted to the clinical research unit (CRU) on Day 20.  Subjects will undergo blood 
sampling for assessment of OC PK on Day 21 until 48 hours postdose.  Subjects may be permitted to leave the CRU 
once the 48 hour OC PK blood assessment has been performed on Day 23.
In Period 2, subjects will be admitted to the CRU on Day 19.  Subjects will also receive a single SC 5 mg tirzepatide 
dose on Day 20, approximately 15 minutes after they have taken the OC.  Subjects will undergo blood sampling for 
the assessment of tirzepatide PK on Day 20 until 96 hours postdose on Day 24, and for the assessment of OC PK on 
Day 21 until 48 hours post OC dose on Day 23.  Subjects may be permitted to leave the CRU once the 96 hour
tirzepatide PK blood assessment has been performed on Day 24.


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
Treatment Arms and Planned Duration for an Individual Subject:
The study duration for individual subjects, inclusive of screening is expected to be approximately 20 weeks, divided 
as follows:

Screening:  up to 28 days prior to Day 1 of the lead-in period

Lead-in Period and Period 1:  Day 1 to Day 28, including QD dosing with an OC (21 days of active 
treatment [Days 1 to 21] and 7 days of non-active treatment [Days 22 to 28])

Period 2:  Day 1 to Day 28, including QD dosing with an OC (21 days of active treatment [Days 1 to 21] 
and 7 days of non-active treatment [Days 22 to 28]), and single dosing with tirzepatide on Day 20

Follow-up:  Final follow-up will occur 28 ± 1 days after tirzepatide dosing
Number of Subjects:
Approximately 42 subjects will be enrolled so that a minimum of 28 subjects complete the study.
Statistical Analysis:
The primary PK parameters for analysis will be AUC(0-tau), AUC(0-tlast), and Cmax.
Pharmacokinetic parameters will be evaluated to estimate the effect of tirzepatide on the PK of the OC (norgestimate 
[NGM], norelgestromin [NGMN], and ethinyl estradiol [EE]).  
Log-transformed Cmax and AUC parameters of NGM, NGMN, and EE will be evaluated.  The differences in Cmax 
and AUC between OC + tirzepatide (Test) and OC alone (Reference) will be back-transformed to present the ratios 
of geometric means and the corresponding 90% confidence interval (CI). The tmax will be analyzed using a Wilcoxon 
signed rank test.  Estimates of the median difference based on the observed medians, 90% CIs from the Wilcoxon 
test will be calculated.
Planned PK parameters will also be summarized with descriptive statistics.
All Investigational product (IP) and protocol procedure AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology.
Safety parameters that will be assessed include safety lab parameters (including amylase, lipase, and blood glucose), 
and vital signs.  The parameters will be listed, and summarized using standard descriptive statistics, where 
appropriate.
Physical examinations and 12-lead electrocardiograms (ECGs) will be performed for safety monitoring purposes and 
will not be presented. 
Additional analysis will be performed if warranted upon review of the data.


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
2. Schedule of Activities


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
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Tirzepatide (LY3298176)
Study Schedule Protocol I8F-MC-GPGR
Screening
Lead-In
Period 1
FU/
EDa
Comments
Procedure
D-28 to -2 D-1
D1-27
D-1 
(D28)
D1-
13
D14
D15-
19
D20
D21
D22-27
D28
(D-1)
Note that Day-1 of Period 1 corresponds to Day 28 of 
lead-in period.
Informed Consent
X
Subject Admission 
to CRU
X
OC Dosing
D1-27
X
X
X
X
X
X
X
X
OC active treatment on Days 1 to 21; non-active 
treatment on Days 22 to 28. To be taken prior to 
breakfast at approximately the same time every 
morning. A light breakfast may be taken about 1 hour 
after dosing.
Subject Discharge 
from CRU
Day 23
Subjects’ CRU stay may be extended at the 
investigator’s discretion for safety monitoring.
Outpatient Visit
X
X
D21
X
X
X
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Physical Exam
/Medical Assessment
X
X
X
X
X
X
X
Full physical examination during first CRU check-in. 
For all other study visits, assessments performed to 
include medical review and targeted examination, as 
appropriate.
Weight
X
X
X
X
Height
X
Temperature
X
X
Ethanol and urine 
drug screen testing
X
X
Safety 12-lead ECG 
(hours)
X
X
X
X
X
X
Single safety 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
D21
X
X
X
X
Additional time points may be added, if warranted and 
agreed upon between Lilly and the investigator.
Clinical Laboratory 
Tests
X
X
X
X
See Appendix 2 for details.
Pregnancy Test
X
X
X
X
See Appendix 2 for details.
Serum Progesterone
D21
Local lab assessment of compliance to OC.
Urine Cotinine Test
X
X
AEs/Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X


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Tirzepatide (LY3298176)
Screening
Lead-In
Period 1
FU/
EDa
Comments
Procedure
D-28 to -2 D-1
D1-27
D-1 
(D28)
D1-
13
D14
D15-
19
D20
D21
D22-27
D28
(D-1)
Note that Day-1 of Period 1 corresponds to Day 28 of 
lead-in period.
Pharmacogenetic 
Sample
X
Single sample during lead-in only.
OC PK Sampling 
(hours)
Predose,
0.25, 
0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 10, 
12, 16
24 (Day 
22), 48 
(Day 23)
The exact time of sampling must be recorded. A 10% 
time allowance variance will be considered acceptable.
OC sampling is relative to actual time of dosing 
(0 hours) on Day 21.


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Tirzepatide (LY3298176)
Study Schedule Protocol I8F-MC-GPGR
Period 2
FU/
EDa
Comments
Procedure
D-1 
(D28)
D1-
13
D14
D15-
18
D19
D20
D21
D22-27
D28
Note that Day-1 of Period 2 corresponds to Day 28 
of Period 1
Subject Admission to CRU
X
OC Dosing
X
X
X
X
X
X
X
X
X
OC active treatment on Days 1 to 21; non-active 
treatment on Days 22 to 28.  To be taken prior to 
breakfast at approximately the same time every
morning.  A light breakfast may be taken about 
1 hour after dosing.
Tirzepatide SC 5 mg Dosing
X
To be administered approximately 15 minutes after 
OC dosing.
Subject Discharge from CRU
Day 24
Subjects’ CRU stay may be extended at the 
investigator’s discretion for safety monitoring.
Outpatient Visit
X
X
X
X
Physical Exam /Medical 
Assessment
X
X
Predose
X
X
Assessments performed to include medical review 
and targeted examination, as appropriate.
Weight
X
X
X
Height
Temperature
X
Safety 12-lead ECG (hours)
X
X
X
Single safety 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
X
X
Additional time points may be added, if warranted 
and agreed upon between Lilly and the 
investigator.
Clinical Laboratory Tests
X
X
X
X
See Appendix 2 for details.
Pregnancy Test
X
X
X
AEs/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
OC PK Sampling (hours)
Predose, 0.25, 
0.5, 1, 1.5, 2, 
2.5, 3, 4, 6, 8, 
10, 12, 16
24 (Day 
22), 48 
(Day 23)
The exact time of sampling must be recorded. A 
10% time allowance variance will be considered 
acceptable. Time of PK sampling of OC and 
tirzepatide will be referenced to actual dosing time 
of OC (Day 21 – 0 hours) and tirzepatide (Day 20 
– 0 hours) respectively. Time of immunogenicity 
sampling on Day 20 will be matched to tirzepatide 
predose sample. Predose samples should be 
collected within 1 hour prior to actual dosing.
In the event of immediate or non-immediate drug 
hypersensitivity reactions, unscheduled samples 
will be collected as detailed in Section 9.4.6.
Tirzepatide PK Sampling (hours)
Predose,  
8, 12
24
48 (Day 
22), 72
(Day 23), 
96 (Day 
24)
X
X
Immunogenicity Samples (hours)
Predose
X


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Tirzepatide (LY3298176)
Abbreviations:  AE = adverse event; CRU = clinical research unit; D or d = day; ECG = 12-lead electrocardiogram; ED = early discontinuation; OC = oral contraceptive; PK = pharmacokinetic(s). Note 
that OC PK sampling times are given relative to Day 21 dosing (Time 0 hour).  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, PK sample (record of actual PK sampling time is the priority), immunogenicity and pharmacogenetic sample.
a
Final follow-up will occur on Day 49 ± 1 day (i.e., 28 days ± 1 day after tirzepatide dosing). Early discontinuation visit should take place within 14 days upon confirmation of early discontinuation. 
Tirzepatide PK and immunogenicity samples need not be drawn if the subject discontinues prior to receiving a dose of tirzepatide.


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Tirzepatide (LY3298176)
3. Introduction
3.1.
Study Rationale
Study I8F-MC-GPGR will assess the effect of a 5 mg subcutaneous (SC) dose of tirzepatide 
administered using a pre-filled syringe on the pharmacokinetics (PK) of an oral contraceptive
(OC) in healthy female subjects.
3.2.
Background
Tirzepatide (LY3298176) is being developed for the treatment of type 2 diabetes mellitus 
(T2DM) as an adjunct to diet and exercise.  In addition, it is being developed as a therapy for the 
indications of chronic weight management and nonalcoholic steatohepatitis (NASH).  It is 
administered once weekly by SC injection.
The available preclinical and clinical data indicate that co-simulation of glucose-dependent 
insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) receptors may enhance 
insulin secretion, improve insulin sensitivity, and reduce body weight beyond the effect of 
selective GLP-1R simulation (Frias et al. 2018; Coskun et al. 2018).
Tirzepatide, a dual agonist of GIP and GLP-1, is a 39-amino acid synthetic peptide.  Its structure 
is based on the GIP sequence and includes a C20 fatty di-acid moiety that prolongs the duration 
of action.  It has a chemical structure and pharmacologic profile that is distinct from the GLP-1 
receptor agonists due to the addition of GIP, which is unique among the marketed incretin 
mimetics.
In a Phase I study (Coskun et al.  2018) that included single and multiple ascending dose (SAD, 
MAD) parts, tirzepatide has been administered as single SC doses up to 8 mg in healthy subjects.  
In the MAD part, higher doses up to 10 mg were attained in healthy subjects via dose escalation.  
Doses up to 15 mg were achieved in patients with T2DM via dose escalation.  In this study, 
gastrointestinal (GI) adverse events (AEs) (nausea, vomiting, diarrhea, abdominal distension) 
and decreased appetite were the most frequently reported events by both healthy subjects and 
also by patients with T2DM and were dose related.  Most AEs were mild in severity, a few were 
moderate, and none were reported as severe.  During the single ascending dose study, the high 
incidence of GI AEs, notably vomiting, were considered to be dose limiting at the 8-mg dose; 
therefore, the 5-mg dose was considered the maximum tolerated dose.  A dose-dependent 
increase in heart rate was detected for both healthy subjects and patients with T2DM who 
received tirzepatide, similar to what was observed with selective GLP-1 receptor agonists.
Immunogenicity assessment in Phase I showed low treatment-emergent antidrug antibody 
(TE-ADA) rate in tirzepatide-treated subjects (2.6%). Highest ADA titers in TE-ADA+ subjects 
ranged from 1:40 to 1:160 and showed no impact on tolerability or PK profile of tirzepatide.  A 
few subjects experienced transient elevations in lipase and/or amylase levels, but these episodes 
were not associated with any relevant outcomes.  Once-weekly doses of 1, 5, 10, and 15 mg have 
been further investigated in a Phase 2 study (Frias et al, 2018).  An additional dose level of 
12 mg and alternate dose escalation schemes were investigated in a 12-week Phase 2 study.  The 


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Tirzepatide (LY3298176)
Phase 1 and 2 clinical data have not shown AEs different from that of available GLP- receptor 
agonists currently marketed.
The effect of tirzepatide on gastric emptying (GE) has been assessed in healthy subjects and in 
patients with T2DM using acetaminophen pharmacokinetics (PK) as a surrogate (Study GPGA). 
In healthy subjects and patients with T2DM, changes in the mean concentration-time profiles of 
acetaminophen suggested a dose-dependent delay in GE following a single dose of tirzepatide. 
The delay in GE resulted in a 50 % decrease in Cmax and approximately a 1-hour delay in tmax. 
The overall AUC was not affected. The delay in GE was greatest following the first dose of 
tirzepatide (at dose level ≥1.5 mg) and appeared to show tachyphylaxis after repeated dosing.
Overall, the safety and tolerability, and PK/PD profiles of tirzepatide support further 
development of tirzepatide in patients with T2DM.  Further details can be found in the 
Investigator’s Brochure (IB).  
A combination OC consisting of norgestimate (NGM) and ethinyl estradiol (EE) will be used in 
this study. Norgestimate and EE are rapidly absorbed following oral administration.
Norgestimate is rapidly and completely metabolized by first pass (intestinal and/or hepatic) 
mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active 
metabolites of NGM. Serum concentrations of NGM following single or multiple dosing were 
generally below assay detection within 5 hours; whereas NGMN appears rapidly in serum with 
concentrations greatly exceeding that of NGM and has a serum t1/2 ranging from 12 to 30 hours.
Peak serum concentrations of NGMN and EE are generally reached by 2 hours after
administration of the combination OC. Accumulation following multiple dosing of the 0.25 mg
NGM/0.035 mg EE dose is approximately 2-fold for NGMN and EE compared with single dose
administration. The PK of NGMN is dose proportional following NGM doses of 0.18 mg to
0.25 mg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle.
Steady state concentrations of NGMN and NG are achieved by Day 21. The elimination t1/2 of 
EE ranged from approximately 6 to 14 hours.
The following adverse reactions have been reported in patients receiving OCs and are believed to 
be drug-related: nausea, vomiting, gastrointestinal symptoms (such as abdominal cramps and 
bloating), breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, temporary 
infertility after discontinuation of treatment, edema, melasma which may persist, breast changes: 
tenderness, enlargement, secretion, change in weight (increase or decrease), change in cervical 
erosion and secretion, diminution in lactation when given immediately postpartum, cholestatic 
jaundice, migraine, allergic reaction, including rash, urticaria, angioedema, mental depression, 
reduced tolerance to carbohydrates, vaginal candidiasis, change in corneal curvature 
(steepening), intolerance to contact lenses. An increased risk of the following serious adverse 
reactions has been associated with the use of OCs: thrombophlebitis and venous thrombosis with 
or without embolism; arterial thromboembolism, pulmonary embolism, myocardial infarction, 
cerebral hemorrhage, cerebral thrombosis, hypertension, gallbladder disease, hepatic adenomas 
or benign liver tumors. There is evidence of an association between the following conditions and 
the use of OCs: deep vein thrombosis, retinal thrombosis (Orthocyclin USPI).


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Tirzepatide (LY3298176)
3.3.
Benefit/Risk Assessment
Risks of tirzepatide have been consistent with risks associated with other GLP-1 receptor 
agonists currently marketed.  Potential risks include, but are not limited to, gastrointestinal (GI) 
effects, acute pancreatitis, increases in heart rate, and hypoglycemic events (GLP-1 receptor 
agonist class effect).
No clinically significant safety or tolerability concerns have been identified during clinical 
investigation of tirzepatide up to the highest single dose level of 8 mg or multiple weekly doses, 
when escalated up to 15 mg.  Based on this information, the 5-mg dose to be administered in 
Study GPGR is reasonably anticipated to be tolerable in this group of healthy subjects.
There is no anticipated therapeutic benefit in these healthy subjects.
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated AEs of tirzepatide are to be found in the IB.


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4. Objectives and Endpoints
Table GPGR.1 shows the objectives and endpoints of the study.
Table GPGR.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effect of a single SC dose of tirzepatide 
on the pharmacokinetics (PK) of a combination OC in 
healthy female subjects.
AUC(0-tau), AUC(0-tlast), Cmax
Secondary
To evaluate the safety and tolerability of a single 
subcutaneous dose of tirzepatide when coadministered 
with an OC in healthy female subjects.  
Incidence of AEs
Abbreviations:  AE = adverse event; AUC(0-tau) = area under the concentration versus time curve within 1 dosing 
interval; AUC(0-tlast), Cmax = maximum observed drug concentration; OC = oral contraceptive; 
PK = pharmacokinetics; SC = subcutaneous; tmax = time to maximum observed drug concentration.


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5. Study Design
5.1.
Overall Design
This is a single-center, open-label, 2-period, fixed sequence study with a lead-in period, in 
healthy female subjects.  Subjects may already have been on OC medication prior to screening or 
be OC naïve.  Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to Day 1 of the lead-in period. A final follow-up visit will occur on 
Day 49 ± 1 day (i.e., 28 days ± 1 day after tirzepatide dosing). During each treatment period, the 
PK of individual components of the OC combination will be assessed on Day 21 to enable 
evaluation of OC PK alone. During Period 2, tirzepatide will be administered on Day 20 such 
that peak exposure by Day 21 (tirzepatide tmax ~ 24 hours postdose) can be attained when OC
PK is evaluated on Day 21 (NGM and EE are rapidly absorbed after oral administration). This 
will permit studying the influence of tirzepatide on OC PK, in the presence of maximum 
tirzepatide exposure; i.e., with greatest impact on GE.
Study governance considerations are described in detail in Appendix 3.
Figure GPGR.1 illustrates the study design.


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Abbreviations:  Adm = admission to the clinical research unit; CRU = clinical research unit; Dis = discharge from 
the clinical research unit; OC = oral contraceptive; PK = pharmacokinetic
Figure GPGR.1.
Illustration of study design for Protocol I8F-MC-GPGR.
5.2.
Number of Participants
Approximately 42 subjects will be enrolled so that a minimum of 28 subjects complete the study.  
For purposes of this study, a subject completes the study when all scheduled procedures shown 
in the Schedule of Activities 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 study to evaluate the potential effect of tirzepatide mediated delay in GE on the PK of an OC 
is warranted, as premenopausal women with diabetes could take oral contraceptives 
concomitantly with tirzepatide. Tirzepatide is not expected to interact with the metabolism of 
either NGM or EE. However, due to the GE delay effect of tirzepatide, the PK (and thus the 
effectiveness) of an orally administered OC may be affected.
The lead-in period is intended to stabilize the PK of EE and NGM for all subjects and to 
synchronize their menstrual cycles, allowing all subjects to be dosed on the same day.  The 


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washout period of 7 days (non-active tablets from OC packet) is that conventionally used in 
normal dosing of the OC tablet and will allow regular menstrual cycling.  
A 28-day packet of a combination OC containing 21 days of tablets containing active ingredients 
(0.035 mg EE and 0.25 mg NGM), and 7 days of non-active tablets is being used in this study, as 
it is a commonly prescribed OC that has been used in previous clinical studies to assess the 
impact of drugs on the PK of OCs.  The PK of EE, NGMN and NGM will be assessed in this 
study.
In addition to OC PK, the PK of tirzepatide will also be assessed, to ensure that tirzepatide 
exposures are per the expectation following a single SC dose of 5 mg tirzepatide.  These data 
may be used to compare with historical data where the impact of GE is greatest following a 
single SC dose of 5 mg tirzepatide.
Women taking OCs may show ECG changes associated with drug-induced torsade de pointes, 
such as increased corrected QT prolongation (Sedlak et al. 2013).  In addition, T-wave alteration 
frequency can also be observed.  QTc prolongation and T-wave morphological can be associated 
with the anti-androgenic potency of the progestin taken, although absolute QTc prolongation is 
usually noted to be modest. Multiple ECGs pre-tirzepatide administration will be done so as to 
monitor such possible OC-induced changes at baseline.
5.5.
Justification for Dose
Data from Phase 1 study GPGA have shown that a 5 mg dose of tirzepatide was well tolerated by 
healthy subjects and patients with T2DM and is also planned as 1 of the doses to be investigated 
in Phase 3 studies.  Doses higher than 5 mg were achieved via escalation since a 5 mg dose was 
considered the maximum tolerated dose when administered as a single dose. Additionally, based 
on data from Study GPGA, evaluating the effect of tirzepatide on GE using acetaminophen as a 
probe substrate, we have observed that the delay in GE is greatest following the first 5 mg dose 
of tirzepatide and following repeated doses of tirzepatide, the effect on GE appears to show 
tachyphylaxis. Hence conducting this study GPGR using a single 5 mg dose of tirzepatide will 
provide the necessary data to evaluate the impact of tirzepatide mediated GE delay on OC PK, if 
any. 


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6. Study Population
Eligibility of subjects for the study will be largely based on the results of medical history, 
physical examination, vital signs, clinical laboratory tests and 12-lead electrocardiogram (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 enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
If the investigator decides not to administer the dose to a subject or not to enroll a subject on a 
particular day, the subject’s visit may be rescheduled, and any assessments or procedures 
performed up to that point may be repeated to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria:
[1]
are overtly healthy females of childbearing potential, as determined through
medical history and physical examination.
[1a] GLP-RAs do not change the PK parameters of oral contraceptives (Kapitza 
et al. 2015; Trulicity USPI; Victoza USPI; Byetta USPI). However, as a 
precaution, the participant must agree to the following contraceptive 
requirements, as this study is designed to test if tirzepatide may cause the
OC tablet to be less effective than usual: to either remain abstinent (if this is 
their preferred and usual lifestyle), or to use 1 additional highly effective
method of contraception (less than 1% failure rate; such as an interuterine 
device) and 1 additional effective method of contraception (such as 
diaphragm with spermicide or cervical sponge), or 2 additional effective
methods of contraception from the screening visit until 2 months after the
post study follow-up visit.
Subjects reporting abstinence who become sexually active while on the 
study must agree to use other effective additional methods of contraception
(such as diaphragm with spermicide or cervical sponge).
A full list of permitted highly effective and effective methods of 
contraception is presented in Appendix 6.
[1b] must have a negative pregnancy test result at screening and at Day -1 of the 
lead-in period.
[1c] must not be intending to start a family within 2 months after the post study 
follow-up visit.
[2]
are between 18 years and 45 years of age, inclusive, at the time of screening.


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[3]
have a body mass index of ≥18.5 kg/m2 at screening.
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling per the protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.
[8]
have blood pressure, pulse rate, and an ECG reading that are considered to be 
within normal limits as determined by the investigator.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria:
[9]
are investigative site personnel directly affiliated with this study or their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[10] are Lilly employees or are employees of a third party organization involved 
with the study.
[11] are currently enrolled in a clinical trial involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study.  
[12] have received treatment with a drug that has not received regulatory approval 
for any indication within 5 half-lives or 30 days of screening, whichever is 
longer.
[13] have previously completed or withdrawn from this study or any other study 
investigating tirzepatide, and have previously received the IP. 
[14] have known allergies to EE, NMG, tirzepatide, or to related compounds or to 
any components of either formulation.
[15] have 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.
[16] have a significant history of or current cardiovascular (e.g., myocardial 
infarction, congestive heart failure, cerebrovascular accident, venous 
thromboembolism, etc.), respiratory, hepatic, renal, GI, endocrine, 
hematological (including history of thrombocytopenia), or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs, or of constituting a risk when taking the study 
medication, or interfering with the interpretation of data.


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[17] have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis) or gastrointestinal disorder, for example relevant 
esophageal reflux or gall bladder disease, or any gastrointestinal disease 
which impacts GE (e.g., gastric bypass surgery, pyloric stenosis, with the 
exception of appendectomy) or could be aggravated by GLP-1 analogs. 
Subjects who had an uncomplicated appendectomy, 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 screening physician.
[18] regularly use known drugs of abuse and/or show positive findings on drug 
screening.
[19] have evidence of human immunodeficiency virus (HIV) infection and/or are 
positive for HIV antibodies.
[20] have evidence of hepatitis C and/or are positive for hepatitis C antibodies.
[21] have evidence of hepatitis B and/or are positive for hepatitis B surface antigen
and/or test positive for hepatitis B core antibody in the absence of hepatitis B 
surface antigen.
[22] are unable or unwilling to refrain from nicotine during the study.  Any use 
within the 6 months prior to Day -1 of the lead-in period, and/or a positive
cotinine test at screening or Day -1 of the lead-in period is exclusionary.
[23] have used or plan to use over-the-counter or prescription medication, and/or 
herbal supplements (with the exception of vitamin/mineral supplements, 
and/or thyroid replacement therapy) within 14 days prior to dosing and for the 
duration of the study, including any medications that reduce GI motility, 
including, but not limited to, anticholinergics, antispasmodics, 
5-hydroxytryptamine-3 receptor antagonists, dopamine antagonists, and 
opiates.
[24] have had a blood donation of 450 mL or more in the last 3 months, or have 
had any blood donation within the last month prior to screening. 
[25] have an average weekly alcohol intake that exceeds 14 units per week, OR are 
unwilling to stop alcohol consumption from 24 hours prior to each CRU visit,
while they are resident in the CRU, and from 24 hours prior to planned 
tirzepatide dosing until discharge from the study or completion of all study 
procedures (1 unit of alcohol = 12 oz or 360 mL of beer; 5 oz or 150 mL of 
wine; 1.5 oz or 45 mL of distilled spirits).
[26] are women with a positive pregnancy test or women who are lactating.
[27] have taken injectable contraceptives or have used hormonal implants within 
12 months of enrollment to this study or topical controlled delivery 
contraceptives (transdermal patch) or hormonal intrauterine devices 
(e.g., Mirena® device) within 3 months prior to enrollment of this study.


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[28] have a contraindication to taking hormonal contraceptives, or have a history of 
clinically significant intolerance to hormone therapy that would limit study 
participation or interfere with interpretation of the data, including thrombosis 
and a history of thromboembolic disease, recurrent jaundice, acute or chronic 
liver disease, migraines, undiagnosed vaginal bleeding, significant 
hyperlipidemia, hepatic adenoma, and mammary, endometrial, or hepatic 
carcinoma or any other estrogen-dependent neoplasia (known or suspected).
[29] have a serum triglyceride (TG) ≥3.4 mmol/L (300 mg/dL) at screening.
[30] are deemed unsuitable by the investigator for any other reason.
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [9] and [10] prevent conflict of interest in study participants.  Criteria [11] through [30] 
exclude medical conditions, medication intolerance, concomitant medication use that may 
confound the assessment of study endpoints, and subjects not willing to adhere to the lifestyle 
requirements of the study.
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
A light breakfast might be taken about 1 hour after OC dosing.
Subjects will be required to fast overnight for at least 9 hours before being given a SC dose of 
tirzepatide on Day 20 of Period 2, and when clinical laboratory test samples are taken (see 
Schedule of Activities [Section 2]).  On Day 20 of Period 2, tirzepatide will be administered
approximately 15 minutes after OC dosing, and a light breakfast may be provided about 1 hour 
after OC dosing.
Subjects may not consume any food other than that provided by the CRU during all inpatient 
stays.  Water may be consumed freely.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed from 24 hours prior to each CRU visit, while subjects are resident in 
the CRU, and from 24 hours prior to planned tirzepatide dosing until discharge from the study or 
completion of all study procedures.  No nicotine use will be permitted during the 6 months prior 
to Day -1 of the lead-in period or during the study.
Subjects will be allowed to maintain their regular caffeine consumption throughout the study 
period (except during specific fasting time periods).
6.3.3. Activity
No strenuous physical activity will be allowed for 48 hours prior to dosing until discharge from 
the study or completion of all study procedures.


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6.4.
Screen Failures
Screening tests such as clinical laboratory tests, additional medical assessments and vital 
signs/ECGs may be repeated at the discretion of the investigator.  As this is a healthy subject 
only study, individuals who do not meet the criteria for participation in this study (screen failure) 
may not be re-screened.


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7. Treatment
7.1.
Treatment Administered
Each subject will receive 1 dose of tirzepatide on Day 20 of Period 2, administered via pre-filled 
syringe (PFS), comprised of 1 SC injection of 5 mg tirzepatide into the abdomen.  In addition, 
each subject will receive one 28-day packet of the study OC (containing 21 days of active tablets
[0.035 mg EE and 0.25 mg NGM] and 7 days of non-active tablets) on Day -1 of the lead-in 
period and of Periods 1 and 2.  Subjects will be instructed to take 1 tablet (beginning on Day 1) 
at approximately the same time each day.
While resident at the CRU, OC tablets will be administered orally with approximately 240 mL of 
room temperature water in the morning in a sitting position.  Subjects will not be allowed to lie 
supine for 2 hours after dosing while resident at the CRU, unless clinically indicated or for study 
procedures.  The administration of OC should be followed by a light breakfast about 1 hour after
dosing.  On Day 20 of Period 2, tirzepatide will be administered approximately 15 minutes after 
OC dosing.  A light breakfast may be provided about 1 hour after OC dosing.
Subjects will be asked to take the OC tablets with a full glass of water in the sitting or standing 
position when self-administering at home.  If a subject forgets to take an OC tablet, it should be 
taken as soon as the subject remembers, with the next one taken at the normal time, and with all 
timings recorded in the dosing diary (or equivalent).  In addition, if an OC tablet is not taken 
within 12 hours of the stated time, the subject must contact the CRU staff.  No medication should 
be discarded, even if, for whatever reason, the medication was not taken.  All empty containers 
and/or blister cards will be returned to the CRU at the end of the lead-in period and each 
treatment period so that a full drug reconciliation can be performed.  After receipt by the sponsor 
of the final data listings, the empty containers will be discarded.
The pharmacy will record all OC dispensed to subjects on a drug accountability log.  All unused 
medications will be returned to the pharmacy and destroyed only upon receiving the sponsor's 
written permission.  
The actual time of all dose administrations will be recorded in the subject’s case report form 
(CRF) for inpatient dosing days and in the diary card (or equivalent) provided by the CRU on 
outpatient or self-administration days.  All doses of tirzepatide will be administered inpatient by 
clinical site staff.
Table GPGR.2 shows the treatment regimens.
Prior to injection, the investigator or designee will clean the subject’s skin.  Each SC injection 
will be administered to the lower abdominal region approximately 5 cm from the umbilicus 
(i.e., left lower quadrant and right lower quadrant), with the PFS needle applied at an appropriate 
angle.  Detailed instructions for administration will be provided by the sponsor.  
Only a limited number of individuals will perform SC administration for consistency reasons.


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Table GPGR.2.
Treatments Administered
Treatment Name
Tirzepatide
Oral Contraceptive
Dosage Formulation
Prefilled syringe
Tablet
Dosage strength
5 mg / 0.5 mL
EE 0.035 mg / NGM 0.25 mg (active) × 21 days
0 mg (non-active) × 7 days
Route of Administration
Subcutaneous
Oral
Dosing Instructions
Single injection into lower abdominal 
quadrant on Day 20 in period 2
Once daily × 12 weeks
The investigator or designee is responsible for:

explaining the correct use of the Investigational product (IP) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, the site 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
Tirzepatide will be supplied by the sponsor or its designee in accordance with current good 
manufacturing practice.
Each syringe of tirzepatide is designed to deliver 5 mg of tirzepatide.
Tirzepatide, in 5 mg single-dose, disposable manual PFS, will be supplied by Lilly, with 
study-specific labels, for use in the study.
Oral contraceptive will be sourced locally as tablets for oral administration and will be provided 
to subjects in its commercial blister pack.  The OC tablets in this study will have the same 
concentration of the required active ingredients:  21 days of active tablets (0.035 mg EE and 
0.25 mg NGM), and 7 days of non-active tablets.  Each subject will receive the same lot number 
of packets (if possible).
The IP will be dispensed by CRU pharmacy staff in accordance with the instructions provided by 
the sponsor.
The IP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
All subjects will receive the same treatment.


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7.2.1. Selection and Timing of Doses
The OC doses will be administered at approximately the same time on each day. Tirzepatide 
will be administered on Day 20 of Period 2.
7.3.
Blinding
This study is open-label.
7.4.
Dose Modification
Dose modification is not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
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 is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
On Day -1 of the lead-in period, subjects will receive a dosing diary (or equivalent) to record 
their compliance with the OC dosing during the outpatient phase.  The actual time of all dose 
administrations will be recorded in the dosing diary (or equivalent) provided by the CRU on 
outpatient or self-administration days.  If a subject forgets to take an OC tablet, it should be 
taken as soon as the subject remembers, with the next one taken at the normal time, and with all 
timings recorded in the dosing diary (or equivalent).  In addition, if an OC tablet is not taken 
within 12 hours of the stated time, the subject must contact the CRU staff.  No medication should 
be discarded, even if, for whatever reason, the medication was not taken.
Compliance with the OC during the lead-in period will be assessed by serum progesterone 
testing on Day 21 of the lead-in period.  Subjects with progesterone levels ≥3 ng/mL on Day 21 
of the lead-in period will not continue in the study.
If the PI is concerned with compliance, the PI will discuss with the Lilly CP or CRP to determine 
if the subject should continue with the study or be discontinued for non-compliance.
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.  The actual time of all dose administrations will be recorded in the subject’s 
CRF for inpatient dosing days.


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7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (1 g 
maximum/dose or 3 g/24 hours) may be administered at the discretion of the investigator for 
treatment of headaches etc.  If the need for concomitant medication (other than acetaminophen) 
arises (for example, to treat an AE), inclusion or continuation of the subject may be at the 
discretion of the investigator, preferably after consultation with a Lilly Clinical Pharmacologist 
(CP) or CRP or designee.  Any medication used during the course of the study must be 
documented.
7.8.
Treatment After the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the study and treatment prematurely for any reason should complete 
adverse event and other follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the OC for abnormal liver tests should be considered by the investigator 
when a subject meets 1 of the following conditions after consultation with the Lilly-designated 
medical monitor:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of 
normal (ULN)

ALT or AST >3 × ULN sustained for more than 2 weeks or

ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or INR >1.5 or

ALT or AST >3 × ULN the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3 × ULN

ALP >2.5 × ULN and TBL >2 × ULN

ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
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 (GCP)

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 the study indication, 
discontinuation from the study occurs prior to introduction of the new agent


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
Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
Subjects may be discontinued due to clinically significant AEs related to the OC (as described in 
Section 3.2) at the discretion of the investigator.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if 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.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the CRF.  Failure or delays 
(i.e., outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (e.g., equipment technical problems, venous access difficulty, or subject 
defaulting or being late on an agreed scheduled procedure) will not be considered as protocol 
deviations but the CRU will still be required to raise a file note for data reconciliation purpose.
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.
The investigator will record all relevant AE and SAE information in the CRF.  After the
informed consent form (ICF) is signed, study site personnel will record, via CRF, the occurrence 
and nature of each subject’s preexisting conditions, including clinically significant signs and 


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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, the PFS, 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, PFS 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.
If a subject’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via CRF.
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 (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the PFS necessitates medical or surgical intervention to 
preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned
Study site personnel must alert the Lilly CRP/CP, or its 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.
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 


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been discharged from the study, and she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal exposure to IP) does not meet the definition of an adverse event.  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 guidance’s.
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 she has a 
complaint or problem with the IP or PFS so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
dose.
Refer to the IB.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.1.1.
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 7) 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.
9.4.2. Glucose Monitoring
Blood glucose monitor measurements may be taken during the study as deemed necessary by the 
investigator where clinically indicated.


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9.4.2.1.
Hyperglycemia and Hypoglycemia Reporting
Episodes of hyperglycemia (fasting plasma glucose >270 mg/dL [15 mmol/L]) or hypoglycemia 
(plasma 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 glucose during Periods 1 and 2, 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 
glucose continues to exceed the acceptable level, treatment with an appropriate antidiabetic agent 
may be initiated by the investigator.
Hypoglycemia episodes will be recorded on specific CRF pages. Hypoglycemia will be treated 
appropriately by the investigator and additional monitoring of plasma 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) ≤70 mg/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. Plasma glucose measurements may not be available during 
such an event, but neurological recovery attributable to the restoration of blood glucose 


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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 (e.g., 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

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).
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.
Hypoglycemic events will be recorded in the hypoglycemia module of the CRF to allow for the 
collection of comprehensive safety information relating to these events.  All episodes of severe 
hypoglycemia will additionally be reported as SAEs (see Section 9.2.1 for details regarding SAE 
reporting).
9.4.3. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).
Blood pressure and pulse rate should be measured after at least 5 minutes’ supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between Lilly and the investigator.
9.4.4. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee.


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For each subject, a single 12-lead digital electrocardiogram (ECG) will be collected according to 
the Schedule of Activities.  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(s) and for immediate subject management, should any clinically relevant findings be 
identified.
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 
adverse event.
9.4.5. Injection-site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

itching

pain
All injection-site reactions reported as AEs will be closely monitored until resolution.  The report 
of a clinically significant AE of injection-site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation and consideration of a skin biopsy 
and additional unscheduled laboratory evaluations (such as ALT, AST, complete blood count 
with percent eosinophils, and additional immunogenicity testing).
Investigational site staff will be provided with separate instructions/training on how to evaluate 
injection-site reactions and their severity in a consistent manner.  Photographs of injection-site 
reactions may be taken in a standardized manner for record keeping purposes if deemed 


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necessary by the investigator; however, the photographs will not be used to evaluate the severity 
of injection-site reaction.
9.4.6. Hypersensitivity Reactions
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.
In the event of suspected drug hypersensitivity reactions (immediate or non-immediate) in 
subjects who experience moderate to severe injection reactions as assessed by the investigator, 
unscheduled blood samples will be collected for PK and antidrug antibody (ADA) analyses at the 
following timepoints:

as close as possible to the onset of the event

at the resolution of the event

30 (±3) days following the event
Additionally, unscheduled serum samples for immune safety laboratory testing (including, but 
not limited to β tryptase, total IgE, complement and cytokine panel testing) should also be 
collected at approximately 60 to 120 minutes and 4 to 6 weeks after the onset of the event in 
these subjects.
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock) of each sampling will be recorded.
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.
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 (asper the 
algorithm for the monitoring of pancreatic events in Appendix 7) and, if pancreatitis is suspected, 
the case will be further defined using 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.


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9.4.7.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or elevated total 
bilirubin ≥2 × ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatinine 
kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If the 
abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator 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 a SAE.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 3 mL will be collected to determine the plasma concentrations of tirzepatide, and 
6 mL will be collected to determine the plasma concentrations of EE, NGMN and NGM. 
A maximum of 3 unscheduled 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 time (24-hour clock time) of each sampling will be recorded.
Failure or being late (i.e., outside stipulated time allowances) to perform procedures or obtain 
samples due to legitimate clinical issues (i.e., equipment technical problems, venous access 
difficulty, or subject defaulting or turning up late on an agreed scheduled procedure) will not be 
considered as protocol deviations but the CRU will have to notify the sponsor in writing via a 
file note.
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 tirzepatide will be assayed using a validated liquid chromatography tandem 
mass spectrometry method.  Concentrations of EE, NGMN and NGM will be assayed using 
validated liquid chromatography with tandem mass spectrometry (LC/MS) methods.


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Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism work, protein binding, or 
bioanalytical method cross-validation.
9.6.
Pharmacodynamics
Not applicable.
9.6.1. Immunogenicity Assessments 
At the visit and time specified in the Schedule of Activities, a venous blood sample be collected 
to determine antibody production against the tirzepatide. Antibodies may be further 
characterized for cross-reactive binding to native GIP and GLP-1 and their ability to neutralize 
the activity of tirzepatide. To interpret the results of immunogenicity, a venous blood sample 
will be collected at the same time point to determine the plasma concentrations of tirzepatide. 
All samples for immunogenicity should be taken predose when applicable and possible.
Treatment-emergent (TE) ADAs are defined in Section 10.3.5. If the immunogenicity sample at 
the last scheduled assessment or discontinuation visit is TE ADA positive (titer >1280), 
additional samples may be taken until the signal returns to baseline (i.e., no longer TE ADA 
positive) or for up to 1 year after last dose.   
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 tirzepatide.  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, where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to IP 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 tirzepatide or after tirzepatide 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 


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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
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 42 subjects will be enrolled so that a minimum of 28 subjects complete the study.
For EE AUC and Cmax, the intra-subject variability (coefficient of variation [CV]) was estimated 
to be 14.2% (derived from Study H9X-MC-GBCQ). Based on this assumption, 28 subjects will 
provide a precision of 0.08 on a log-scale. This would result in a 90% probability that the half-
width of the 90% confidence interval (CI) of the ratio of the geometric least square means for 
AUC and Cmax is no larger than 7.3%.
For NGMN AUC and Cmax, the intra-subject variability (CV) was estimated to be 11.3% and 
20.0%, respectively (derived from Study H9X-MC-GBCQ). Based on this assumption, 
28 subjects will provide a precision of 0.06 and 0.11 on a log-scale for AUC and Cmax, 
respectively. This would result in a 90% probability that the half-width of the 90% CI of the 
ratio of the geometric least square means for AUC and Cmax is no larger than 5.9% and 10.2%, 
respectively.
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, weight, height, body mass index (BMI), or other demographic characteristics 
will be reported, and may be used in the PK analyses and safety summaries as quantitative of 
classification variables.  Subject age, weight, height, and BMI will be summarized as 
appropriate.
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 summaries will be produced for all subjects who received at least 1 dose of OC or
tirzepatide, whether or not they completed all protocol requirements.
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.  


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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 period will be presented by severity and by 
association with IP as perceived by the investigator.  Symptoms reported to occur prior to 
enrollment 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 investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety lab parameters (including amylase, lipase, 
and blood glucose), and vital signs.  The parameters will be listed, and summarized using 
standard descriptive statistics, where appropriate.
Physical examinations and ECGs will be performed for safety monitoring purposes and will not 
be presented.  Additional analysis will be performed if warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for NGM, NGMN and EE will be calculated by standard 
noncompartmental methods of analysis.  Planned PK parameters will be summarized with 
descriptive statistics.
The primary parameters for analysis estimated for NGM, NGMN and EE will be maximum drug 
concentration (Cmax) and area under the concentration versus time curve (AUC).  Other 
noncompartmental parameters, such as half-life (t1/2), apparent clearance (CL/F), and apparent 
volume of distribution (V/F) may be reported.
Plasma concentrations of tirzepatide will be listed and summarized.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to estimate the effect of tirzepatide on the PK of 
the OC (NGM, NGMN, and EE).  Log-transformed Cmax and AUC parameters of NGM, 
NGMN, and EE will be evaluated.  The differences in Cmax and AUC between OC + tirzepatide 
(Test) and OC alone (Reference) will be back-transformed to present the ratios of geometric 
means and the corresponding 90% CI.
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs from the Wilcoxon test will be calculated.
10.3.3. Pharmacodynamic Analyses 
Not applicable.


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10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.5. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TE ADA to tirzepatide 
may be tabulated.  Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) 
greater than the minimum required dilution if no ADAs were detected at baseline (treatment-
induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs 
were detected at baseline (treatment-boosted ADA).
The frequency of cross-reactive binding to native GIP and GLP-1 and neutralizing antibodies 
may also be tabulated in TE ADA+ subjects, when available.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to tirzepatide may be assessed.
10.3.6. Data Review During the Study
This section is not applicable for this study.
10.3.7. Interim Analyses
No interim analyses are planned for this study.  If an 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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11.
References
American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes—
2018. Diabetes Care. 2018;41(suppl 1):S55–S64.
Byetta (exenatide) USPI, 2018.
Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA,
Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D’Alessio DA,
Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2
diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z,
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active
comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193.
International Hypoglycemia 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.
Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a Once-Weekly 
Human GLP-1 Analog, Does Not Reduce the Bioavailability of the Combined Oral 
Contraceptive, Ethinylestradiol/Levonorgestrel. J Clin Pharmacol. 2015;55(5):497–504.  
Ortho-Cyclen USP, Oct 2013.
Sedlak T, Shufelt C, Iribarren C, Lyon LL, Bairey Merz N. Oral Contraceptive Use and the 
ECG: Evidence of an Adverse QT Effect on Corrected QT Interval. Ann Noninvasive 
Electrocardiol. 2013;18(4):389-398.
Trulicity (dulaglutide) USPI, 2019.
Victoza (liraglutide) USPI, 2019.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a subject 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.
CIOMS
Council for International Organizations of Medical Sciences
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
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.
CV
coefficient of variation
ECG
12-lead electrocardiogram
EE
ethinyl estradiol
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
GCP
good clinical practice
GE
gastric emptying
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization


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Tirzepatide (LY3298176)
informed consent
A process by which a subject voluntarily confirms 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.  
Investigational 
Product (IP)
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.
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.
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
NGM
norgestimate
Non-
investigational 
Product (Non-IP)
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
OC
oral contraceptive
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.
PK/PD
pharmacokinetic/pharmacodynamic
SAE
serious adverse event
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
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistry (fasting)a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Glucose (fasting)
Leukocytes (WBC)
Blood urea
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubinh
Lymphocytes
Alkaline phosphatase
Monocytes
Aspartate aminotransferase
Eosinophils
Alanine aminotransferase
Basophils
Creatinine
Platelets
Amylase
Lipase
Urinalysisa
Triglyceride
Specific gravity
pH
Hepatitis B surface antigenc,d,e
Protein
Hepatitis C antibodyc,d,e
Glucose
HIVc,d,e
Ketones
Progesterone testing (serum)f
Bilirubin
Lipid Panel (Fasting)a,d
Urobilinogen
Triglycerides 
Blood
LDL-C
Nitrite
HDL-C
Total cholesterol
Leukocytes (WBC)
Ethanol and urine drug screen testingc,g
Microscopic examination of sedimentb
Urine cotininea,g
Abbreviations:  HDL = high density lipoprotein cholesterol; HIV = human immunodeficiency virus; LDL = low 
density lipoprotein cholesterol; RBC = red blood cells; WBC = white blood cells.
a
Performed by local laboratory.  Results will be validated by the laboratory at the time of initial testing.
b
Test only if dipstick result is abnormal (i.e., positive for blood, protein, or nitrites).
c
Performed by local laboratory.
d
At screening only.
e
Tests may be waived if they have been performed within 6 months before screening with reports available for 
review.
f
Day 21 of the lead-in period only.
g
Screening and Day -1 of the lead-in period only.
h
If total bilirubin is >upper limit of normal, reflect and indirect bilirubin should be measured.


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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 ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

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 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 ERB was properly constituted and convened as 
required by 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.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study site’s ERB should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:


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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
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 investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
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 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.

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, 


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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 CRP.
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 bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
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-GPGR Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Estimated Number 
of Blood Samples
Total 
Volume (mL)
Screening tests (local laboratory)a
24
1
24
Clinical laboratory tests (local laboratory)a
10
6
60
OC Pharmacokinetics (central / referral laboratory)b

Study visits (2 periods)
6
16 × 2 periods (+ 3 
unscheduled) = 35
210
Tirzepatide Pharmacokinetics (central / referral 
laboratory)
3
9
27
Immunogenicity (central or referral laboratory)
10 
2
20
Pharmacogenetics (stored sample)
10
1
10
Total
351
Total for clinical purposes rounded up to nearest 10 mL
360
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Classification of Contraceptive Methods
Highly Effective (Less Than 1% Failure Rate) Methods of Contraception:

Intrauterine device (such as ParaGard®)

Bilateral tubal ligation

Bilateral tubal occlusion (such as Essure)

Hysterectomy without bilateral oophorectomy

Bilateral salpingectomy

Total abstinence or in a same-sex relationship (if this is their preferred and usual 
lifestyle).  Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception

Vasectomy – for male partners of women in clinical trials
Effective Methods of Contraception:

Male condom with spermicide*

Female condom with spermicide*

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
* The use of male and female condoms as a double-barrier method is not considered acceptable.


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Appendix 7.
Pancreatic Monitoring
Glucagon-like peptide-1 agonists have been associated with a possible risk of acute pancreatitis.  
In 2006, the United States prescribing information for exenatide was revised to include the event 
of pancreatitis.  In 2007, the United States 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 T2DM.
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and, in order to assess for any potential effects of tirzepatide on the exocrine 
pancreas, amylase and lipase values will be monitored in all current and future clinical trials with 
tirzepatide.
Additional monitoring will be requested for amylase and/or lipase values ≥3 × ULN at any visit, 
even in asymptomatic subjects (see figure below).  Lipase and amylase values may also be 
obtained at any time during the clinical trials for any subject suspected of having symptoms 
suggestive of exenatide pancreatitis (such as severe GI signs and/or symptoms), at the 
investigator’s discretion.
Acute pancreatitis is an AE 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 CT scan or magnetic resonance 
imaging
Most subjects with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium, and radiates to the back in approximately one-half of the cases.  The pain is often 
associated with nausea and vomiting.  However, experience with GLP-1 agonists has 
demonstrated that some subjects asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  For 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 subjects safely and to quickly reach (or not reach) a 
diagnosis of pancreatitis.


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Abbreviations:  CT = computed tomography; MRI = magnetic resonance imaging; 
ULN = upper limit of normal.


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Subjects diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate healthcare option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as SAEs.  For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to study 
drug.


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Appendix 8.
Protocol Amendment I8F-MC-GPGR (b) 
Summary 
Effect of Tirzepatide on Oral Contraceptive 
Pharmacokinetics in Healthy Female Subjects
Overview
Protocol I8F-MC-GPGR ‘Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics in 
Healthy Female Subjects’ 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.  This 
amendment is considered to be substantial since one of the primary objective endpoint 
measurements has been changed.
The overall changes and rationale for the changes made to this protocol are as follows:

Exclusion criterion [29] was updated to exclude healthy participants with a serum 
triglyceride level ≥3.4 mmol/L (300 mg/dL) at screening. This update ensures that 
participants with CTCAE Grade 2 hypertriglyceridemia (i.e., >300 mg/dL) will not be 
enrolled.

The primary endpoints were changed from AUC(0-∞), AUC(0-tlast) and Cmax to 
AUC(0-tau), AUC(0-tlast) and Cmax. AUC(0-tau) at steady state approximates AUC(0-∞) 
after a single dose, and hence AUC(0-tau) is a more suitable endpoint than AUC(0-∞)
for this study, where PK of the OC is measured only at steady state.

Sample size calculations were adjusted based on the change of the primary objective 
endpoint from AUC(0-∞) to AUC(0-tau).  

The length of the overnight fast prior to Period 2 Day 20 and prior to when clinical 
laboratory samples are collected was extended from 8 hours to 9 hours.  

The full physical examination was moved from screening to prior to the first CRU 
check-in.  This update reduces subject contacts from full physical examinations and 
limits it only to those who have passed preliminary inclusion/exclusion criteria. This is 
part of the site effort to reduce potential COVID-19 exposures.  

Minor editorial changes and formatting corrections were made but are not necessarily 
documented in the revision below.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1 Protocol Synopsis
Objectives/Endpoints:
Objectives
Endpoints
Primary
To evaluate the effect of a single SC dose of tirzepatide 
on the pharmacokinetics (PK) of a combination OC in 
healthy female subjects.
AUC(0-∞)(0-tau), AUC(0-tlast), Cmax
Secondary
To evaluate the safety and tolerability of a single 
subcutaneous dose of tirzepatide when coadministered 
with an OC in healthy female subjects.  
Incidence of adverse events (AEs)
Statistical Analysis:
The primary PK parameters for analysis will be AUC(0-∞)(0-tau), AUC(0-tlast), and Cmax.
Pharmacokinetic parameters will be evaluated to estimate the effect of tirzepatide on the PK of the OC (norgestimate 
[NGM], norelgestromin [NGMN], and ethinyl estradiol [EE]).  
Log-transformed Cmax and AUC parameters of NGM, NGMN, and EE will be evaluated.  The differences in Cmax 
and AUC between OC + tirzepatide (Test) and OC alone (Reference) will be back-transformed to present the ratios 
of geometric means and the corresponding 90% confidence interval (CI). The tmax will be analyzed using a Wilcoxon 
signed rank test.  Estimates of the median difference based on the observed medians, 90% CIs from the Wilcoxon 
test will be calculated.
Planned PK parameters will also be summarized with descriptive statistics.
All Investigational product (IP) and protocol procedure AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology.
Safety parameters that will be assessed include safety lab parameters (including amylase, lipase, and blood glucose), 
and vital signs.  The parameters will be listed, and summarized using standard descriptive statistics, where 
appropriate.
Physical examinations and 12-lead electrocardiograms (ECGs) will be performed for safety monitoring purposes and 
will not be presented. 
Additional analysis will be performed if warranted upon review of the data.
2 Schedule of Activities


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Study Schedule Protocol I8F-MC-GPGR
Screening
Lead-In
Period 1
FU/
EDa
Comments
Procedure
D-28 to -2 D-1
D1-27
D-1 
(D28)
D1-
13
D14
D15-
19
D20
D21
D22-27
D28
(D-1)
Note that Day-1 of Period 1 corresponds to Day 28 of 
lead-in period.
Informed Consent
X
Subject Admission 
to CRU
X
OC Dosing
D1-27
X
X
X
X
X
X
X
X
OC active treatment on Days 1 to 21; non-active 
treatment on Days 22 to 28. To be taken prior to 
breakfast at approximately the same time every 
morning. A light breakfast may be taken about 1 hour 
after dosing.
Subject Discharge 
from CRU
Day 23
Subjects’ CRU stay may be extended at the 
investigator’s discretion for safety monitoring.
Outpatient Visit
X
X
D21
X
X
X
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Physical Exam
/Medical Assessment
X
X
X
X
X
X
X
Full physical examination at screening during first CRU 
check-in. Thereafter For all other study visits, 
assessments performed to include medical review and 
targeted examination, as appropriate.
Weight
X
X
X
X
Height
X
Temperature
X
X
Ethanol and urine 
drug screen testing
X
X
Safety 12-lead ECG 
(hours)
X
X
X
X
X
X
Single safety 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
D21
X
X
X
X
Additional time points may be added, if warranted and 
agreed upon between Lilly and the investigator.
Clinical Laboratory 
Tests
X
X
X
X
See Appendix 2 for details.
Pregnancy Test
X
X
X
X
See Appendix 2 for details.
Serum Progesterone
D21
Local lab assessment of compliance to OC.
Urine Cotinine Test
X
X
AEs/Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X


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Screening
Lead-In
Period 1
FU/
EDa
Comments
Procedure
D-28 to -2 D-1
D1-27
D-1 
(D28)
D1-
13
D14
D15-
19
D20
D21
D22-27
D28
(D-1)
Note that Day-1 of Period 1 corresponds to Day 28 of 
lead-in period.
Pharmacogenetic 
Sample
X
Single sample during lead-in only.
OC PK Sampling 
(hours)
Predose, 
0.25, 
0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 10, 
12, 16
24 (Day 
22), 48 
(Day 23)
The exact time of sampling must be recorded. A 10% 
time allowance variance will be considered acceptable. 
OC sampling is relative to actual time of dosing 
(0 hours) on Day 21.


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Study Schedule Protocol I8F-MC-GPGR
Period 2
FU/
EDa
Comments
Procedure
D-1 
(D28)
D1-
13
D14
D15-
18
D19
D20
D21
D22-27
D28
Note that Day-1 of Period 2 corresponds to Day 28 
of Period 1
Subject Admission to CRU
X
OC Dosing
X
X
X
X
X
X
X
X
X
OC active treatment on Days 1 to 21; non-active 
treatment on Days 22 to 28.  To be taken prior to 
breakfast at approximately the same time every 
morning.  A light breakfast may be taken about 
1 hour after dosing.
Tirzepatide SC 5 mg Dosing
X
To be administered approximately 15 minutes after 
OC dosing.
Subject Discharge from CRU
Day 24
Subjects’ CRU stay may be extended at the 
investigator’s discretion for safety monitoring.
Outpatient Visit
X
X
X
X
Physical Exam /Medical 
Assessment
X
X
Predose
X
X
Full physical examination at screening. Thereafter, 
assessments performed to include medical review 
and targeted examination, as appropriate. 
Assessments performed to include medical review 
and targeted examination, as appropriate.
Weight
X
X
X
Height
Temperature
X
Safety 12-lead ECG (hours)
X
X
X
Single safety 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
X
X
Additional time points may be added, if warranted 
and agreed upon between Lilly and the 
investigator.
Clinical Laboratory Tests
X
X
X
X
See Appendix 2 for details.
Pregnancy Test
X
X
X
AEs/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
OC PK Sampling (hours)
Predose, 0.25, 
0.5, 1, 1.5, 2, 
2.5, 3, 4, 6, 8, 
10, 12, 16
24 (Day 
22), 48 
(Day 23)
The exact time of sampling must be recorded. A 
10% time allowance variance will be considered 
acceptable. Time of PK sampling of OC and 
tirzepatide will be referenced to actual dosing time 
of OC (Day 21 – 0 hours) and tirzepatide (Day 20 
– 0 hours) respectively. Time of immunogenicity 
sampling on Day 20 will be matched to tirzepatide 
predose sample. Predose samples should be 
collected within 1 hour prior to actual dosing.
Tirzepatide PK Sampling (hours)
Predose,  
8, 12
24
48 (Day 
22), 72 
(Day 23), 
96 (Day 
24)
X
X


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Period 2
FU/
EDa
Comments
Procedure
D-1 
(D28)
D1-
13
D14
D15-
18
D19
D20
D21
D22-27
D28
Note that Day-1 of Period 2 corresponds to Day 28 
of Period 1
Immunogenicity Samples (hours)
Predose
X
In the event of immediate or non-immediate drug 
hypersensitivity reactions, unscheduled samples 
will be collected as detailed in Section 9.4.6.
Abbreviations:  AE = adverse event; CRU = clinical research unit; D or d = day; ECG = 12-lead electrocardiogram; ED = early discontinuation; OC = oral contraceptive; PK = pharmacokinetic(s). Note 
that OC PK sampling times are given relative to Day 21 dosing (Time 0 hour).  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, PK sample (record of actual PK sampling time is the priority), immunogenicity and pharmacogenetic sample.
a
Final follow-up will occur on Day 49 ± 1 day (i.e., 28 days ± 1 day after tirzepatide dosing).  Early discontinuation visit should take place within 14 days upon confirmation of early discontinuation.  
Tirzepatide PK and immunogenicity samples need not be drawn if the subject discontinues prior to receiving a dose of tirzepatide.


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
Page 67
Tirzepatide (LY3298176)
4 Objectives and Endpoints
Table GPGR.1
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effect of a single SC dose of tirzepatide 
on the pharmacokinetics (PK) of a combination OC in 
healthy female subjects.
AUC(0-∞)(0-tau), AUC(0-tlast), Cmax
Secondary
To evaluate the safety and tolerability of a single 
subcutaneous dose of tirzepatide when coadministered 
with an OC in healthy female subjects.  
Incidence of AEs
Abbreviations:  AE = adverse event; AUC(0-∞) (0-tau)= area under the concentration versus time curve from zero 
to infinity within 1 dosing interval; AUC(0-tlast), Cmax = maximum observed drug concentration; OC = oral 
contraceptive; PK = pharmacokinetics; SC = subcutaneous; tmax = time to maximum observed drug concentration.
6.2 Exclusion Criteria
[29] have a serum triglyceride (TG) ≥5 3.4 mmol/L (442.5 300 mg/dL) at 
screening. 
6.3.1.
Meals and Dietary Restrictions
A light breakfast might be taken about 1 hour after OC dosing.
Subjects will be required to fast overnight for at least 8 9 hours before being given a SC dose of 
tirzepatide on Day 20 of Period 2, and when clinical laboratory test samples are taken (see 
Schedule of Activities [Section 2]).  On Day 20 of Period 2, tirzepatide will be administered 
approximately 15 minutes after OC dosing, and a light breakfast may be provided about 1 hour 
after OC dosing.
10.1 Sample Size Determination
Approximately 42 subjects will be enrolled so that a minimum of 28 subjects complete the study.
For EE AUC and Cmax, the intra-subject variability (coefficient of variation [CV]) was estimated 
to be 18.2% and 14.2%, respectively (derived from Sstudy H9X-MC-GBCQ).  Based on this 
assumption, 28 subjects will provide a precision of 0.10 and 0.08 on a log-scale for AUC and 
Cmax, respectively.  This would result in a 90% probability that the half-width of the 90% 
confidence interval (CI) of the ratio of the geometric least square means for AUC and Cmax is no 
larger than 9.3% and 7.3%, respectively.
For NGMN AUC and Cmax, the intra-subject variability (CV) was estimated to be 16.3%11.3% 
and 20.0%, respectively (derived from Sstudy H9X-MC-GBCQ).  Based on this assumption, 
28 subjects will provide a precision of 0.090.06 and 0.11 on a log-scale for AUC and Cmax, 
respectively.  This would result in a 90% probability that the half-width of the 90% CI of the 


I8F-MC-GPGR Clinical Pharmacology Protocol (b)
Page 68
Tirzepatide (LY3298176)
ratio of the geometric least square means for AUC and Cmax is no larger than 8.3%5.9% and 
10.2%, respectively.  


Leo Document ID = 885eeb45-8122-4e6f-824a-605feb7b056e
Approver:
Approval Date & Time: 14-May-2020 02:27:54 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan:  I8F-MC-GPGR  
 
Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics in Healthy Female Subjects 
 
NCT04172987 
 
Approval Date: 31-Jan-2020 


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             Page 1 of 18
STATISTICAL ANALYSIS PLAN
Effect of Tirzepatide on Oral Contraceptive Pharmacokinetics in Healthy Female Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 29 January 2020
Study Drug: Tirzepatide (LY3298176)
Sponsor Reference: I8F-MC-GPGR
Covance CRU Study: 1001215-8399709
Clinical Phase I
Approval Date: 31-Jan-2020 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399709
Sponsor Reference: I8F-MC-GPGR
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary .........................................................................................................................6
4.2
Secondary......................................................................................................................6
5.
STUDY DESIGN.................................................................................................................6
6.
TREATMENTS...................................................................................................................7
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................8
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................8
9.
STATISTICAL METHODOLOGY .....................................................................................8
9.1
General..........................................................................................................................8
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
Hypoglycemia ....................................................................................................15
9.4.3
Concomitant Medication.....................................................................................16
9.4.4
Clinical Laboratory Parameters...........................................................................16
9.4.5
Serum Progesterone............................................................................................16
9.4.6
Vital Signs..........................................................................................................16
9.4.7
Body Weight and Height ....................................................................................16
9.4.8
Electrocardiogram (ECG)...................................................................................16
9.4.9
Immunogenicity Assessments.............................................................................16
9.4.10
Hepatic Monitoring ............................................................................................17
9.4.11
Hypersensitivity Reactions .................................................................................17
9.4.12
Injection-Site Reactions......................................................................................17
9.4.13
Other Assessments .............................................................................................18
9.4.14
Safety and Tolerability Statistical Methodology..................................................18


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10. INTERIM ANALYSES .....................................................................................................18
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............18
12. REFERENCES ..................................................................................................................18
13. DATA PRESENTATION ..................................................................................................18
13.1 Derived Parameters .....................................................................................................18
13.2 Missing Data ...............................................................................................................18
13.3 Insufficient Data for Presentation ................................................................................18


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ADA
Anti-drug antibody
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-τ)
Area under the concentration versus time curve during one dosing 
interval
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
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
BQL
Below the lower limit of quantitation
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
EE
Ethinyl Estradiol
GE
Gastric emptying
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography


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Statistical Analysis Plan 
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Covance Clinical Study No.: 1001215-8399709
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NGM
Norgestimate
NGMN
Norelgestromin
OC
Oral contraceptive
PG
Plasma glucose
PK
Pharmacokinetic(s)
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
TBL
Total bilirubin
TE ADA
Treatment-emergent antidrug antibody
TFLs
Tables, Figures, and Listings
t½  
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
WHO
World Health Organization


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Statistical Analysis Plan 
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Covance Clinical Study No.: 1001215-8399709
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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
18 October 2019) and Protocol Amendment (a) (final version dated 06 December 2019).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) 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 with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. For open-label 
studies, this SAP must be signed off prior to first subject visit 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 with
Eli Lilly and Company 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 
Conference 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
To evaluate the effect of a single subcutaneous (SC) dose of tirzepatide on the PK of a 
combination oral contraceptive (OC) in healthy female subjects.
4.2
Secondary
To evaluate the safety and tolerability of a single SC dose of tirzepatide when coadministered 
with an OC in healthy female subjects.
5. STUDY DESIGN
This is a single-center, open-label, 2-period, fixed sequence study with a lead-in period, in 
healthy female subjects. Subjects may already have been on OC medication prior to screening or 
be OC naïve. Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to Day 1 of the lead-in period. A final follow-up visit will occur on Day 49 
± 1 day (i.e. 28 days ± 1 day after tirzepatide dosing). During each treatment period, the PK of 
individual components of the OC combination will be assessed on Day 21 to enable evaluation 


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Covance Clinical Study No.: 1001215-8399709
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of OC PK alone. During period 2, tirzepatide will be administered on Day 20 such that peak 
exposure by Day 21 (tirzepatide time of maximum observed drug concentration [tmax] ~ 24 hours 
postdose) can be attained when OC PK is evaluated on Day 21 (norgestimate [NGM] and ethinyl 
estradiol [EE] are rapidly absorbed after oral administration). This will permit studying the 
influence of tirzepatide on OC PK, in the presence of maximum exposure; i.e. with greatest 
impact on gastric emptying (GE). 
Figure GPGR.1 illustrates the study design.
Abbreviations: Adm = admission to the clinical research unit; CRU = clinical research unit; 
Dis = discharge from the clinical research unit; OC = oral contraceptive; PK = pharmacokinetic
Figure GPGR.1. Illustration of study design
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Abbreviation
Treatment order in 
TFL
0.035 mg EE / 0.25 mg NGM
OC
1
0.035 mg EE / 0.25 mg NGM + 5 mg tirzepatide SC
OC + 5 mg tirzepatide SC
2


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7. SAMPLE SIZE JUSTIFICATION
Approximately 42 subjects will be enrolled so that a minimum of 28 subjects complete the study. 
For EE area under the concentration versus time curve (AUC) and maximum observed drug 
concentration (Cmax), the intra-subject variability (coefficient of variation [CV]) was estimated to 
be 18.2% and 14.2%, respectively (derived from study H9X-MC-GBCQ). Based on this 
assumption, 28 subjects will provide a precision of 0.10 and 0.08 on a log-scale for AUC and 
Cmax, respectively. This would result in a 90% probability that the half-width of the 90% 
confidence interval (CI) of the ratio of geometric least square means for AUC and Cmax is no 
larger than 9.3% and 7.3%, respectively. 
For norelgestromin (NGMN) AUC and Cmax, the intra-subject variability (CV) was estimated to 
be 16.3% and 20.0% respectively (derived from study H9X-MC-GBCQ). Based on this 
assumption, 28 subjects will provide a precision of 0.09 and 0.11 on a log-scale for AUC and 
Cmax, respectively. This would result in a 90% probability that the half-width of the 90% CI of 
the ratio of the geometric least square means for AUC and Cmax is no larger than 8.3% and 
10.2%, respectively. 
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of OC or 
tirzepatide, whether or not they completed all protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
OC or tirzepatide 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.
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 subjects’ 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 


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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, race, ethnicity, body weight, 
height and body mass index will be summarized and listed.
All other demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 8.1 or later).
Plasma concentrations of NGM, NGMN and EE will be used to determine the following PK 
parameters, when possible:  
Parameter
Units
Definition
AUC(0-τ)
h*pg/mL
Area under the concentration versus time curve during one dosing 
interval
Cmax
pg/mL
Maximum observed drug concentration
tmax
h
Time of maximum observed drug concentration
t½
h
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
Apparent total body clearance of drug calculated after extra-vascular 
administration
Vz/F
L
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Plasma concentrations of tirzepatide 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.: 1001215-8399709
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Parameter
Units
Definition
AUC(0-tlast)
h*ng/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(0-∞)
h*ng/mL
Area under the concentration versus time curve from time zero to infinity
%AUC(tlast-)
%
Percentage of AUC(0-∞) extrapolated
Cmax
ng/mL
Maximum observed drug concentration
tmax
h
Time of maximum observed drug concentration
t½
h
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
Apparent total body clearance of drug calculated after extra-vascular 
administration
Vz/F
L
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
Apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate. Plasma concentrations of 
tirzepatide will be listed and summarized.
The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL 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 pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one 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 three 
consecutive concentrations above the lower limit of quantification (LLOQ), with at least 
one of these concentrations following Cmax.


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
AUC(0-) values where the 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.

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. Half-life 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 
quantitation (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 non-endogenous.
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 two 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 it is considered to be a true characteristic of the profile of the drug.

For multiple-dosing data, when pre-dose concentrations are missing, the value to be 
substituted will be Cmin for the dosing interval.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.


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
The terminal point selections will be indicated on a semi-logarithmic plot.
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 pre-dose average concentration for single-dose data from non-endogenous 
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 single dosing of non-endogenous compounds, the concentration in 
a pre-dose 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.


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Statistical Analysis Plan 
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Data between Individual Profiles
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 one 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
PK parameters will be evaluated to estimate the effect of tirzepatide on the PK of OC (NGM, 
NGMN and EE); OC administered alone will be the reference treatment and OC coadministered 
with tirzepatide will be the test treatment. Log-transformed AUC(0-τ) and Cmax of NGM, NGMN 
and EE will be analyzed using a paired t-test. The treatment differences between the test and 
reference arm will be back-transformed to present the ratio of geometric means, corresponding 
90% CI, and p-value from the paired t-test.
Example SAS code:
proc ttest data=<data in> alpha=0.1;
    by analyte param;
    paired test*ref;
run;


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The tmax will be analyzed using a Wilcoxon signed rank test for the same comparison. Estimates 
of the median of differences, the 90% CI for the median of differences, and p-value from the 
Wilcoxon signed rank test will be calculated.
The PK parameters for each treatment and analyte will be summarised and listed. Furthermore, 
the geometric mean and 90% CI of AUC(0-τ) and Cmax of NGM, NGMN and EE will be plotted, 
along with the individual values, against treatment. For tmax, the median and individual values 
will be plotted against treatment.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse Events
A pre-existing condition is defined as an adverse event (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 which starts after informed consent but prior to OC dosing in the lead-in phase. 
A treatment-emergent AE is defined as an AE which occurs postdose or which is present prior to 
dosing and becomes more severe postdose. 
The assignment of TEAEs to treatments will be as follows:

A TEAE occurring during or after Day 1 dosing in the lead-in phase and prior to 
tirzepatide dosing on Day 20 in Period 2 will be assigned to OC.

A TEAE occurring during or after tirzepatide dosing on Day 20 in Period 2 will be 
assigned to OC + 5 mg tirzepatide SC.
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings. The following rules will be applied in summary tables:

If an AE increases in severity, the AE will only be counted once at the maximum severity 
with the exception of the following: 
o
If an AE occurs during or after Day 1 dosing in the lead-in phase and increases in 
severity during or after tirzepatide dosing on Day 20 in Period 2; the AE will be 
counted twice (at the maximum severity for each treatment).

If an AE decreases in severity at any time, the AE will be counted once at the maximum 
severity.
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment (including 
overall), 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 treatment, Medical Dictionary for Regulatory
Activities (MedDRA) version 22.1 system organ class and preferred term. The summary and 
frequency AE tables will be presented for all causalities and those considered related to the study 
drug by the investigator. Any serious AEs will be listed. AEs by day of onset will be presented. 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399709
Sponsor Reference: I8F-MC-GPGR
Discontinuations due to AEs will be listed.
9.4.2
Hypoglycemia
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 events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows:

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70 mg/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 hypoglycaemia 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 the 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. Plasma glucose 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 (≤70 mg/dL [3.9 mmol/L]).
o
Severe hypoglycemia requiring medical attention:  a severe hypoglycemic 
event when subjects require therapy by health care providers (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

Relative hypoglycemia:  an event during which typical symptoms of hypoglycemia, 
which do not require the assistance of another person, are accompanied by PG 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399709
Sponsor Reference: I8F-MC-GPGR
>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 
counted only 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 PG ≤70 mg/dL (3.9 mmol/L).
Investigator review of glucose results clinically indicative of hypoglycemia will be required.
9.4.3
Concomitant Medication
Concomitant medication will be coded using the WHO drug dictionary (Version 
September 2019). Concomitant medication will be listed.
9.4.4
Clinical Laboratory Parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Changes from baseline (Day -1 in the lead-in phase) will 
also be presented. Additionally, clinical chemistry, hematology and urinalysis data outside the 
reference ranges will be listed and flagged on individual subject data listings.
9.4.5
Serum Progesterone
Compliance with the OC during the lead-in period will be assessed by serum progesterone
testing on Day 21 of the lead-in period. These data will be listed.
9.4.6
Vital Signs
Vital signs data will be summarized by treatment and timepoint. Values for individual subjects 
will be listed.
Temperature will be listed only.
9.4.7
Body Weight and Height
Body weight and height will be listed.
9.4.8
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.9
Immunogenicity Assessments
Immunogenicity data will be listed and frequency tables will be presented. The frequency and 
percentage of subjects with pre-existing anti-drug antibody (ADA) and with treatment-emergent 


Final, 29 January 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399709
Sponsor Reference: I8F-MC-GPGR
ADAs (TE ADAs) will be presented. TE ADAs are those that are boosted or induced by 
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 (1:10) if no 
ADAs were detected at baseline, where baseline is defined as Day 20 predose in Period 2.
If cross-reactivity with native GLP-1 and GIP or a neutralization assay is performed, the 
frequency of each will be determined. 
The relationship between the presence of antibodies and PK parameters of tirzepatide may be 
assessed if deemed appropriate.
9.4.10 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant that have potential for hepatotoxicity, including acetaminophen will be listed.
Results from any hepatic monitoring procedures, such as a magnetic resonance elastography 
(MRE) scan, and biopsy assessments 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.
9.4.11 Hypersensitivity Reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to 
assess the subject’s medical history, alternative causes, and symptoms.
These data will be listed.
9.4.12
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Injection site assessment data (erythema, induration, categorical pain, pruritus, and edema) will 
be listed.


Final, 29 January 2020
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399709
Sponsor Reference: I8F-MC-GPGR
9.4.13
Other Assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.14
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim analyses are planned for this study.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three 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 center of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = ec030875-e054-4ffd-8738-d02e4c6b07dd
Approver: 
Approval Date & Time: 30-Jan-2020 13:18:13 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Jan-2020 14:16:44 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Jan-2020 16:43:22 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-Jan-2020 18:33:11 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD