A Master Protocol to Investigate the Efficacy and Safety of Tirzepatide Once Weekly in Participants Who Have Obstructive Sleep Apnea and Obesity: A Randomized, Double-Blind, Placebo-Controlled Trial
Phase: PHASE3
Conditions: Obstructive Sleep Apnea, Obesity
Sponsor: Eli Lilly and Company

Protocol I8F-MC-GPIF (c) 
A Master Protocol to Investigate the Efficacy and Safety of Tirzepatide Once Weekly in 
Participants who have Obstructive Sleep Apnea and Obesity: A Randomized, Double-Blind, 
Placebo-Controlled Trial (SURMOUNT-OSA) 
NCT05412004    
Approval Date: 02-JUN-2023

CONFIDENTIAL 
Master Protocol I8F-MC-GPIF(c) 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of 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 (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Master Protocol Title: A Master Protocol to Investigate the Efficacy and Safety of Tirzepatide 
Once Weekly in Participants who have Obstructive Sleep Apnea and Obesity: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-OSA)
Protocol Number: I8F-MC-GPIF 
Amendment Number: c 
List of Intervention-Specific Appendices (ISAs): 
I8F-MC-GPI1: Participants with OSA unwilling or unable to use PAP therapy 
I8F-MC-GPI2: Participants with OSA on PAP therapy 
Compound: Tirzepatide (LY3298176) 
Brief Title: A Master Protocol for Tirzepatide in Participants with Obstructive Sleep Apnea and 
Obesity 
Study Phase: 3 
Acronym: SURMOUNT-OSA 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number: 
IND: 157090 
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-116270 
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Master Protocol I8F-MC-GPIF(c) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
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Master Protocol I8F-MC-GPIF(c) 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Amendment b 
30-Sep-2022 
Amendment a 
10-Feb-2022 
Original Protocol 
27-Jan-2022 
Amendment [c] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
This amendment includes changes made to the primary and key secondary endpoints for change 
in AHI and clarification around timing of the PHQ-9 assessment. Revisions were made to clarify 
the role of central reading of PSG scores. 
 
Protocol changes have been made as outlined in the following table. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis  
and  
3. Objectives, Endpoints, and 
Estimands 
 
Primary Objective: 
Removed “percent” 
To align with change made 
to primary endpoint. Note, 
the current sample size is 
deemed adequate for the 
assessment of the updated 
primary endpoint and all key 
secondary endpoints 
Primary Endpoints: 
Updated primary endpoint from 
“Percent change in AHI from 
baseline to Week 52” to 
“Change in AHI from baseline 
to Week 52 (events per hour)” 
In response to regulatory 
recommendation 
Key Secondary Endpoints: 
Updated first endpoint from 
“Change in AHI” to “Percent 
change in AHI” 
Changed to reflect revisions 
in endpoint hierarchy   
1.3. Schedule of Activities 
(SoA) 
 
“PHQ-9” row: 
Added additional information to 
Comments: “PHQ-9 at V7 and 
V11 may be scheduled for any 
day +/- 14 days.” 
Clarification 
5.2 Exclusion Criteria 
EC#44: Added glucose-lowering 
medication, including metformin 
Clarification 
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Master Protocol I8F-MC-GPIF(c) 
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Section # and Name 
Description of Change 
Brief Rationale 
to the list of medications 
prohibited within 3 months of 
Visit 1 
6.8.2 Prohibited Concomitant 
Medications 
Added glucose-lowering 
medication, including metformin 
to the list of prohibited 
concomitant medications 
Clarification 
8.1.1.1 Polysomnography 
Added text, “The eligibility 
criteria and AHI related 
endpoints of the study will be 
assessed based on central 
reading of the PSG.” 
Clarification that PSG based  
endpoints are based on result 
determined from central 
reading of PSG 
9.1 Statistical Hypotheses 
“Percent” has been removed 
from the description of the 
treatment effect definition 
To align with changes made 
in Section 1.1 and Section 3 
9.3.1 General Considerations 
A statement was added to clarify 
that efficacy analyses will be 
conducted on all participants 
meeting study eligibility criteria  
Clarifications added to 
ensure consistency of text in 
Section 9.3.1  with the table 
in Section 9.2  
The first intercurrent event has 
been updated to include 
incorrect study procedures 
leading to invalid measurements 
Clarifying how invalid 
measurements will be 
handled in the analysis. 
9.3.2 Primary Analysis 
“Percent” has been removed 
when describing the primary 
endpoint 
To align with changes made 
in Section 1.1 and Section 3 
9.3.3 Analysis of Key 
Secondary Endpoints 
“Percent” has been added when 
describing the analysis 
To align with changes made 
in Section 1.1 and Section 3 
Throughout 
Editorial corrections 
Minor, therefore not 
described 
 
 
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Master Protocol I8F-MC-GPIF(c) 
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Table of Contents  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
2. 
Introduction ...................................................................................................................24 
2.1. 
Study Rationale ...............................................................................................................24 
2.2. 
Background .....................................................................................................................24 
2.3. 
Benefit/Risk Assessment ................................................................................................25 
3. 
Objectives, Endpoints, and Estimands .......................................................................26 
4. 
Study Design ..................................................................................................................29 
4.1. 
Overall Design ................................................................................................................29 
4.2. 
Scientific Rationale for Study Design ............................................................................29 
4.3. 
Justification for Dose ......................................................................................................30 
4.4. 
End of Study Definition ..................................................................................................30 
5. 
Study Population ...........................................................................................................31 
5.1. 
Inclusion Criteria ............................................................................................................31 
5.2. 
Exclusion Criteria ...........................................................................................................32 
5.3. 
Lifestyle Considerations .................................................................................................36 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................36 
5.3.2. 
Physical Activity .............................................................................................................36 
5.4. 
Screen Failures ................................................................................................................37 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................37 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................38 
6.1. 
Study Interventions Administered ..................................................................................38 
6.1.1. 
Medical Devices..............................................................................................................39 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................39 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................39 
6.4. 
Study Intervention Compliance ......................................................................................40 
6.5. 
Dose Modification ..........................................................................................................40 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms .......................................40 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................41 
6.7. 
Treatment of Overdose ...................................................................................................41 
6.8. 
Concomitant Therapy .....................................................................................................41 
6.8.1. 
Management of Incident Diabetes ..................................................................................42 
6.8.2. 
Prohibited Concomitant Medications .............................................................................43 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................44 
7.1. 
Discontinuation of Study Intervention ............................................................................44 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................46 
7.1.2. 
Temporary Discontinuation ............................................................................................46 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................47 
7.3. 
Lost to Follow up ............................................................................................................48 
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8. 
Study Assessments and Procedures.............................................................................49 
8.1. 
Efficacy Assessments .....................................................................................................49 
8.1.1. 
Primary Efficacy Assessment .........................................................................................49 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................49 
8.1.3. 
Exploratory Efficacy Assessments .................................................................................51 
8.2. 
Safety Assessments .........................................................................................................53 
8.2.1. 
Physical Examinations ....................................................................................................53 
8.2.2. 
Vital Signs .......................................................................................................................53 
8.2.3. 
Electrocardiograms (ECG)..............................................................................................53 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................53 
8.2.5. 
Pregnancy Testing ...........................................................................................................54 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................54 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................55 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................55 
8.3.2. 
Pregnancy ........................................................................................................................57 
8.3.3. 
Adverse Events of Special Interest .................................................................................58 
8.4. 
Pharmacokinetics ............................................................................................................59 
8.4.1. 
Bioanalytical Methods ....................................................................................................59 
8.5. 
Pharmacodynamics .........................................................................................................59 
8.6. 
Genetics ..........................................................................................................................59 
8.7. 
Biomarkers ......................................................................................................................60 
8.8. 
Immunogenicity Assessments.........................................................................................60 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................60 
9. 
Statistical Considerations .............................................................................................61 
9.1. 
Statistical Hypotheses .....................................................................................................61 
9.1.1. 
Multiplicity Adjustment ..................................................................................................61 
9.2. 
Analyses Sets ..................................................................................................................61 
9.3. 
Statistical Analyses .........................................................................................................62 
9.3.1. 
General Considerations ...................................................................................................62 
9.3.2. 
Primary Analysis .............................................................................................................64 
9.3.3. 
Analysis of Key Secondary Endpoints ...........................................................................64 
9.3.4. 
Treatment Group Comparability .....................................................................................65 
9.3.5. 
Safety Analyses ...............................................................................................................65 
9.3.6. 
Evaluation of Immunogenicity .......................................................................................66 
9.3.7. 
Other Analyses ................................................................................................................67 
9.4. 
Interim Analysis ..............................................................................................................67 
9.5. 
Sample Size Determination ............................................................................................68 
10. 
Supporting Documentation and Operational Considerations ..................................69 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................69 
10.1.1. Regulatory and Ethical Considerations ...........................................................................69 
10.1.2. Financial Disclosure........................................................................................................69 
10.1.3. Informed Consent Process ..............................................................................................70 
10.1.4. Data Protection................................................................................................................70 
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Master Protocol I8F-MC-GPIF(c) 
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10.1.5. Committees Structure......................................................................................................70 
10.1.6. Dissemination of Clinical Study Data.............................................................................71 
10.1.7. Data Quality Assurance ..................................................................................................72 
10.1.8. Source Documents ..........................................................................................................73 
10.1.9. Study and Site Start and Closure ....................................................................................74 
10.1.10. Publication Policy ...........................................................................................................74 
10.1.11. Investigator Information .................................................................................................74 
10.1.12. Sample Retention ............................................................................................................75 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................76 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................78 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................80 
10.3.1. Definition of AE .............................................................................................................80 
10.3.2. Definition of SAE ...........................................................................................................81 
10.3.3. Definition of Product Complaints ...................................................................................82 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................83 
10.3.5. Reporting of SAEs ..........................................................................................................84 
10.3.6. Regulatory Reporting Requirements ...............................................................................85 
10.3.7. Special Safety Topics ......................................................................................................85 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................88 
10.4.1. Definitions.......................................................................................................................88 
10.4.2. Contraception Guidance..................................................................................................89 
10.5. 
Appendix 5: Genetics......................................................................................................91 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................92 
10.6.1. Hepatic Evaluation Testing .............................................................................................92 
10.6.2. Close Hepatic Monitoring ...............................................................................................94 
10.6.3. Comprehensive Hepatic Evaluation ................................................................................94 
10.7. 
Appendix 7: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................96 
10.8. 
Appendix 8: Protocol GPIF Standardized Protocols for the 
Measurement of Height, Weight, Neck Circumference, Waist 
Circumference, Vital Signs, and Electrocardiogram ......................................................97 
10.8.1. Measuring Height............................................................................................................97 
10.8.2. Measuring Weight ...........................................................................................................97 
10.8.3. Measuring Hip and Waist Circumference.......................................................................97 
10.8.4. Measuring Neck Circumference .....................................................................................98 
10.8.5. Vital Sign Measurements (Blood Pressure and Heart Rate) ...........................................98 
10.8.6. Electrocardiogram ...........................................................................................................99 
10.9. 
Appendix 9: Provisions for Changes in Study Conduct Due to the 
COVID-19 Pandemic ....................................................................................................100 
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Master Protocol I8F-MC-GPIF(c) 
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10.10. 
Appendix 10: Abbreviations and Definitions ...............................................................104 
10.11. 
Appendix 11: Country-Specific Requirements .............................................................108 
10.11.1. Germany ........................................................................................................................108 
10.12. 
Appendix 12: Protocol Amendment History ................................................................112 
11. 
References ....................................................................................................................122 
 
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Master Protocol I8F-MC-GPIF(c) 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Master Protocol Title: A Master Protocol to Investigate the Efficacy and Safety of Tirzepatide 
Once Weekly in Participants who have Obstructive Sleep Apnea and Obesity: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-OSA) 
Brief Title: A Master Protocol for Tirzepatide in Participants with Obstructive Sleep Apnea and 
Obesity 
Rationale: 
Obstructive sleep apnea (OSA) is a breathing disorder associated with significant comorbidity 
and mortality. Currently available therapeutic approaches have shown moderate success in 
treating the clinical signs and symptoms of OSA (that is, snoring and excessive daytime 
sleepiness) but have failed to address the underlying pathophysiology of the disease and, more 
importantly, the cardiovascular (CV) morbidity and mortality associated with OSA. 
Tirzepatide is a dual GIP/GLP-1R agonist that has demonstrated statistically significant and 
clinically relevant lowering in HbA1c and dose-dependent weight loss in 5 Phase 3 trials that 
enrolled patients with type 2 diabetes mellitus (T2DM) (Dahl et al. 2021; Frias et al. 2021; Lilly 
2021; Ludvik et al. 2021; Rosenstock et al. 2021). Data from clinical studies show that a large 
proportion of participants have significant body weight reduction with tirzepatide treatment, 
suggesting that this agent may represent a promising pharmacologic treatment option that could 
reduce the frequency of apnea and hypopnea events as well as reduce weight, decrease blood 
pressure, and improve insulin resistance and dyslipidemia, which are all features associated with 
the increase in CV morbidity and mortality as seen in people living with OSA. 
 
 
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Master Protocol I8F-MC-GPIF(c) 
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Objectives, Endpoints, and Estimands: 
The following objectives and endpoints apply to both intervention-specific appendices (ISAs). 
Primary Objective  
Endpoints  
To demonstrate that tirzepatide at the MTD (10 mg or 15 mg) 
QW is superior to placebo for mean decrease in AHI.  
Change in AHI from baseline to Week 52 (events per 
hour). 
Key Secondary Objectives (controlled for type I error) 
Endpoints 
To demonstrate that tirzepatide at the MTD (10 mg or 15 mg) 
QW is superior to placebo for 
From baseline to Week 52 
 
Change in AHI 
 
A hierarchical assessment of PROs 
 
Percent change in AHI 
 
A hierarchical combination of the following: 
o 
Change in FOSQ-10 score 
o 
Change in FOSQ (30 items) Vigilance 
domain score 
o 
Change in FOSQ (30 items) Activity Level 
domain score 
 
Clinically meaningful change in AHI 
 
Percent of participants with ≥50% AHI 
reduction 
 
Achieving OSA remission or mild nonsymptomatic 
OSA 
 
Percent of participants with 
o 
AHI <5 or 
o 
AHI 5-14 with ESS ≤10  
 
Change in body weight 
 
 
Percent change in body weight 
 
 
 
Change in inflammatory status 
 
 
Change in SBP 
 
Change in hsCRP concentration 
From baseline to Week 48a 
 
Change in SBP 
Abbreviations: AHI = Apnea-Hypopnea Index; ESS = Epworth Sleepiness Scale; FOSQ = Functional Outcomes of 
Sleep Questionnaire; hsCRP = high-sensitivity C reactive protein; MTD = maximum-tolerated dose; 
OSA = obstructive sleep apnea; PROs = patient-reported outcomes; SBP = systolic blood pressure; QW = once 
weekly. 
a BP will be assessed at Week 48 because PAP suspension at Week 52 may confound BP assessment. 
For estimands guiding statistical analyses, see Section 9.3.1. 
Overall Design: 
The overall study design consists of 2 components: 
 Master Protocol: defines study elements common for both populations. 
 ISAs: provide detailed population-specific information. 
Study I8F-MC-GPIF (GPIF) is multicenter, randomized, parallel-arm, double-blind, placebo-
controlled, Phase 3 study with 52-week treatment duration conducted under a basket-design, 
which will investigate the effects of treatment with weekly (QW) tirzepatide at the maximum 
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Master Protocol I8F-MC-GPIF(c) 
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tolerated dose (MTD) (10 mg or 15 mg), compared with placebo in participants who have 
moderate-to-severe OSA and obesity. 
One master protocol will support 2 studies/ISAs. 
 ISA 1 (GPI1) will include participants who are unwilling or unable to use PAP therapy. 
 ISA 2 (GPI2) will include participants who are on PAP therapy for at least 3 months at 
time of screening and plan to continue PAP therapy during the study. 
Participants will be assigned to the ISA which reflects their current PAP usage. The participant 
will then be randomly assigned 1:1 to treatment or placebo. 
Number of Participants: 
Approximately 412 participants will be randomly assigned to study intervention across the entire 
master protocol, with approximately 206 participants randomly assigned to study intervention in 
each ISA. See Section 9.5 for additional information. 
An upper limit of approximately 70% enrollment of male participants will be used to ensure a 
sufficiently large sample of female participants. 
Intervention Groups and Duration: 
The study interventions are: 
 tirzepatide at the MTD (10 mg or 15 mg) SC QW, or 
 placebo. 
The expected total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is 60 weeks across the following study periods: 
 Screening: 4 weeks 
 Treatment: 52 weeks 
 Post-treatment follow-up: 4 weeks 
The maximum duration of treatment is 52 weeks. 
Data Monitoring Committee: Yes 
 
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Master Protocol I8F-MC-GPIF(c) 
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1.2. 
Schema  
Master Protocol and ISA Schema 
 
Abbreviations: ISA = intervention-specific appendix; MTD = maximum-tolerated dose; PAP = positive airway pressure. 
 
 
 
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Master Protocol I8F-MC-GPIF(c) 
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Dose Escalation and Visit Schema 
 
Abbreviations: MTD = maximum-tolerated dose; QW = once weekly. 
 
 
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Master Protocol I8F-MC-GPIF(c) 
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1.3. 
Schedule of Activities (SoA)  
If Study Period I - Screening takes longer or shorter than 4 weeks to complete, it will not be considered a protocol deviation. Study 
Period I - Screening should not exceed 6 weeks unless approval from the sponsor is received. 
Visit procedures may be conducted over more than 1 day as long as all activities are completed within the allowable visit tolerance 
period of each visit. 
Study Period II - Treatment: For early discontinuations (ED) from study that occur before the last visit in treatment period, see the 
activities listed for ED in this table. 
 
 
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Master Protocol I8F-MC-GPIF(c) 
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Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
Informed consent  
X 
  
 
 
 
 
 
 
 
 
 
 
 
The informed consent must be signed before any 
protocol-specific tests/procedures are performed.  
Inclusion and 
exclusion criteria, 
review and confirm 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria should be confirmed prior 
to drug assignment and administration of first dose of 
study intervention.  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Includes ethnicity, year of birth, gender (sex), and 
race. 
Preexisting 
conditions and 
medical history, 
including relevant 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
All conditions ongoing and relevant past surgical and 
medical history should be collected. 
Prespecified 
medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Should include, but not be limited to, collecting 
diagnosis of OSA and obesity-related health 
problems. 
Prior treatments for 
indication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Include OSA and obesity.  
Substance use 
(alcohol, caffeine, 
tobacco use)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Any events that occur after signing the informed 
consent are considered AEs as defined in Section 
8.3.1. Additional data are collected for certain AEs. 
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Master Protocol I8F-MC-GPIF(c) 
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Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
Physical Evaluation 
 
Height  
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight measurements should be obtained per the 
instructions in Section 10.8.  
Waist 
circumference 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Waist circumference should be obtained per the 
instructions in Section 10.8.  
Hip circumference 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Hip circumference should be obtained per the 
instructions in Section 10.8. 
Neck circumference 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Neck circumference should be obtained per the 
instructions in Section 10.8. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes PR and BP. Measured after participant has 
been sitting at least 5 minutes. Vital-sign 
measurements should be taken before obtaining an 
ECG tracing and before collection of blood samples 
for laboratory testing. See Sections 8.2.2 and 10.8. 
Complete physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
The complete physical examination is performed 
(excludes pelvic, rectal, and breast examinations 
unless clinically indicated).  
Symptom-directed 
physical assessment  
 
X (refer to Comment) 
 
Symptom-directed physical assessment from V2 
through V11 and ED will be conducted at the 
discretion of the PI, as indicated based on participant 
status and standard of care.  
 
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Master Protocol I8F-MC-GPIF(c) 
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Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
May be performed by qualified personnel per local 
regulations. 
12-lead ECG (local) 
X 
 
 
 
 
 
 
 
 
 
X  
X 
 
ECG measurements should be obtained per the 
instructions in Section 8.2.3.  
Wearable Devices and PSG Assessments 
 
Schedule Sleep 
Center Study for 
PSG 
X 
 
 
 
 
X 
 
  
 
X 
 
 
 
PSG results must be reviewed to confirm eligibility 
prior to randomization. 
Sleep Center Study 
for PSG  
X 
 
 
 
 
 
X 
 
  
 
X 
 
 
PSG at V7 and 11 may be scheduled for any day +/- 
14 days. 
Participant wears 
the WatchPat300  
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
Applicable only to participants in GPI1 (off PAP). 
Training documents will detail information on the 
dispensation, wearing, and return process. 
Participant wears 
actigraphy (AX6) 
device  
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
Training documents will detail information on the 
dispensation, wearing, and return process. 
Participant Education and Supplies 
eDiary education 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Additional training can be repeated, as needed. 
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Master Protocol I8F-MC-GPIF(c) 
18 
 
Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
Train participant on 
study intervention 
administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Re-training is available anytime.  
Review Lifestyle 
Program 
instructions 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
 
Diet and exercise goals established during the lifestyle 
consultation and the importance of adherence to the 
lifestyle component of the trial will be reinforced at 
each trial contact by study staff.  
Participant Diary  
Participant diary 
dispensed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Includes the following:  
Electronic diaries: Sleep diary; Dosing diary; 
Hypoglycemic events (when applicable), PAP 
adherence (for GPI2 only). 
Paper diary: Patient Diet and Exercise diary  
Diary compliance 
check 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Diary return 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Patient-Reported Outcomes (Electronic) 
Complete prior to any clinical-administered assessments 
 
ESS  
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
When the PROs are scheduled for visits at which the 
PSG will be done, they should be completed on the 
same day as PSG and in the following order (FOSQ, 
ESS, PROMIS Short Form v1.0 Sleep Disturbance 8b, 
PROMIS Short Form v1.0 Sleep-related Impairment 
8a, PGIS, PGIC, SF-36v2 acute form, and EQ-5D-
EQ-5D-5L 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
FOSQ 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
PGIS (OSA 
Symptom Scales) 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
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Master Protocol I8F-MC-GPIF(c) 
19 
 
Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
5L). Completing the PRO assessments on the next day 
after PSG is not considered a protocol violation. 
PGIC (OSA 
Symptom Scales) 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
PROMIS Short 
Form v1.0 Sleep 
Disturbance 8b 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
PROMIS Short 
Form v1.0 Sleep-
related Impairment 
8a 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
SF-36v2, acute 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
PHQ-9 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
The PHQ-9 should be administered after assessment 
of AEs, if both collected on the same day. 
PHQ-9 at V7 and V11 may be scheduled for any day 
+/- 14 days. 
Clinician-Administered Assessments (Paper) 
 
C-SSRS 
screening/baseline 
X 
  
 
 
 
 
 
 
 
 
 
 
 
The C-SSRS should be administered after assessment 
of AEs, if both collected on the same day. 
The C-SSRS since last visit is adapted for the 
assessment of the ideation and behavior categories 
only. The Intensity of Ideation and Lethality of 
Behavior sections are removed. 
C-SSRS (since last 
visit version) 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
Laboratory Tests and Sample Collections 
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Master Protocol I8F-MC-GPIF(c) 
20 
 
Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
Hematology 
X 
 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
HbA1c 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
Clinical chemistry 
(includes glucose) 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
Lipid panel 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Only for WOCBP and females with a history of tubal 
ligation. See Section 10.4, Appendix 4. 
Urine pregnancy 
(local) 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
A urine pregnancy test must be performed at V2 with 
the result available prior to first dose/injection of 
study intervention for WOCBP only. Additional 
pregnancy tests (beyond those required per the SoA) 
should be performed at any time during the trial if a 
menstrual period is missed, there is clinical suspicion 
of pregnancy, or as required by local law or 
regulation. 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Optional; performed as needed to confirm 
postmenopausal status. See Section 10.4, Appendix 4. 
Insulin 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
C-Peptide 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Free fatty acids 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
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Master Protocol I8F-MC-GPIF(c) 
21 
 
Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
Cystatin-C 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Calcitonin 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Pancreatic amylase 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Lipase 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
Calculated using CKD-EPI method. 
UACR 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
X 
 
PK samples 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
PK samples to be collected predose and close to ADA 
samples. 
Immunogenicity 
(ADA) samples 
 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
In the event of systemic drug hypersensitivity 
reactions (immediate or nonimmediate), additional 
unscheduled samples should be collected as detailed 
in Section 10.3.7.2 (Hypersensitivity Reactions). 
Immunogenicity samples and PK samples for 
immunogenicity must be predose. 
Stored Samples 
Genetics sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Sample can be obtained at or after the specified visit. 
Exploratory 
biomarker samples  
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
Randomization and Dosing 
Register visit with 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Master Protocol I8F-MC-GPIF(c) 
22 
 
Study 
Period I - 
Screening 
Study Period II - Treatment  
Study 
Period III 
- Post-
Treatment 
Follow-up 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
 
Weeks from 
randomization  
-4 
0 
4 
8 
12 
16 
20 
24 
36 
48 
52 
- 
See 
footnote a 
 
Visit interval 
tolerance (days) 
-14 to +21 
– 
±3 
±3 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
±3 
 
Fasting Visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnote b. 
ISA assignment via 
IWRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ISA treatment 
randomization via 
IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Observe participant 
administer study 
intervention 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Participants should administer their first dose of study 
intervention at the end of the V2, after other study 
procedures are completed. 
Dispense study 
drug via IWRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dispense study 
drug to participant 
(for at home 
dosing) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dispense ancillary 
supplies to 
participant 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of ancillary supplies may vary beyond 
V2 based on expiry dating of applicable supplies 
and/or participant needs. 
Participant returns 
all unused study 
intervention  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess study 
intervention 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Master Protocol I8F-MC-GPIF(c) 
23 
Abbreviations: ADA = antidrug antibody; AEs = adverse events; AX6 = Axivity 6; CKD EPI = Chronic Kidney Disease Epidemiology; hsCRP = high sensitivity 
C-reactive protein; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; eGFR = estimated glomerular 
filtration rate; EQ-5D-5L = EuroQol - 5 Dimension - 5 Level; ESS = Epworth Sleepiness Scale; FOSQ = Functional Outcomes of Sleep Questionnaire; FSH = 
follicle-stimulating hormone; HbA1c = hemoglobin A1c; ISA = intervention-specific appendix; IWRS = interactive web-response system; OSA = obstructive 
sleep apnea; PHQ = Patient Health Questionnaire-9; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Status; 
PK = pharmacokinetic; PSG = polysomnography; PR = pulse rate; PRO = patient reported outcome; PROMIS = Patient-Reported Outcomes Measurement 
Information System; SF-36v2 = Short-Form 36 version 2; SoA = schedule of activities; TSH = thyroid-stimulating hormone; UACR = urinary 
albumin/creatinine ratio; V = visit; WOCBP = woman of childbearing potential. 
a Post-treatment follow-up occurs approximately 4 weeks after the participant’s final treatment period visit. 
b Fasting visit: On all office visits, study participants should be reminded to report to the site before taking study intervention in a fasting condition, after a 
period of approximately 8 hours without eating, drinking (except minimal amount of water, as needed), or any significant physical activity. 
 
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Master Protocol I8F-MC-GPIF(c) 
 
24 
2. 
Introduction  
2.1. 
Study Rationale  
Obstructive sleep apnea is a breathing disorder associated with significant comorbidity and 
mortality. Currently available therapeutic approaches have shown moderate success in treating 
the clinical signs and symptoms of OSA (that is, snoring and excessive daytime sleepiness) but 
have failed to address the underlying pathophysiology of the disease and, more importantly, the 
CV morbidity and mortality associated with OSA. 
Tirzepatide is a dual GIP/GLP-1R agonist that has demonstrated statistically significant and 
clinically relevant lowering in HbA1c and dose-dependent weight loss in 5 Phase 3 trials that 
enrolled patients with T2DM (Dahl et al. 2021; Frias et al. 2021; Lilly 2021; Ludvik et al. 2021; 
Rosenstock et al. 2021). Data from clinical studies show that a large proportion of participants 
have significant body weight reduction with tirzepatide treatment, suggesting that this agent may 
represent a promising pharmacologic treatment option that could reduce the frequency of apnea 
and hypopnea events as well as reduce weight, decrease BP, and improve insulin resistance and 
dyslipidemia, which are all features associated with the increase in CV morbidity and mortality 
as seen in people living with OSA. 
2.2. 
Background  
Obstructive sleep apnea is a serious medical condition with a limited number of therapeutic 
options and high unmet need. OSA is a well-established risk factor for morbidity and mortality 
from CV and other metabolic diseases; further, it negatively affects daily life of patients 
(Tietjens et al. 2019; Gottlieb and Punjabi 2020). 
Treatments for OSA include behavioral measures like weight loss programs, medical devices 
such as PAP, oral appliances or hypoglossal nerve stimulation, and surgery, including bariatric 
surgery in people living with obesity and OSA. Weight loss through caloric restriction and 
lifestyle interventions improves AHI, cardiometabolic comorbidities, and quality of life. 
Although a limited number of studies have investigated the effect of pharmacological weight-
loss therapy, their results support that adding weight-loss medication to lifestyle intervention 
reduces AHI and improves sleep quality and possibly other OSA-related outcomes. As such, 
standard of care recommends a prioritization of weight loss for patients with OSA and obesity or 
who are overweight, including consideration for FDA-approved antiobesity pharmacotherapy 
(Hudgel et al. 2018). Bariatric surgery is available for patients with severe obesity and can 
dramatically improve OSA (Currie et al. 2021). However, such surgical procedures are 
associated with greater risk for perioperative and postoperative complications (Opperer et al. 
2016). 
Positive airway pressure is the first-line treatment for moderate-to-severe and symptomatic mild 
OSA. Despite good clinical efficacy for the signs and symptoms of OSA, randomized controlled 
studies in PAP therapy have failed to show improvements in nonsleep-related outcomes linked to 
OSA such as stroke, heart attack, diabetes and depression (AHRQ 2021). It is thought inadequate 
PAP therapy adherence may explain why randomized clinical trials have failed to demonstrate 
benefit (Gottlieb and Punjabi 2020). Nonadherence to PAP therapy is a major clinical challenge 
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Master Protocol I8F-MC-GPIF(c) 
 
25 
and studies have shown wide variability in adherence, ranging from 29% to 83% (Weaver and 
Grunstein 2008). Currently, there are only few pharmacologic alternatives indicated for 
symptoms in patients with OSA and none are disease modifying. 
There is significant unmet need in treatment of patients with OSA. Tirzepatide, a GIP and 
GLP-1R dual agonist, has the potential to provide benefit to patients with OSA who have obesity 
by reducing weight, which may reduce the frequency of apnea and hypopnea events, decreasing 
BP, and improving insulin resistance and dyslipidemia.  
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tirzepatide may be found in the IB. 
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Master Protocol I8F-MC-GPIF(c) 
 
26 
3. 
Objectives, Endpoints, and Estimands  
The following objectives and endpoints apply to both ISAs. 
Primary Objective  
Endpoints  
To demonstrate that tirzepatide at the MTD (10 mg or 15 mg) 
QW is superior to placebo for mean decrease in AHI.  
Change in AHI from baseline to Week 52 (events per 
hour). 
Key Secondary Objectives (controlled for type I error) 
Endpoints 
To demonstrate that tirzepatide at the MTD (10 mg or 15 mg) 
QW is superior to placebo for 
From baseline to Week 52 
 
Change in AHI 
 
A hierarchical assessment of PROs 
 
Percent change in AHI 
 
A hierarchical combination of the following: 
o 
Change in FOSQ-10 score 
o 
Change in FOSQ (30 items) Vigilance 
domain score 
o 
Change in FOSQ (30 items) Activity Level 
domain score 
 
Clinically meaningful change in AHI 
 
Percent of participants with ≥50% AHI 
reduction 
 
Achieving OSA remission or mild nonsymptomatic 
OSA 
 
Percent of participants with 
o 
AHI <5 or 
o 
AHI 5-14 with ESS ≤10  
 
Change in body weight 
 
 
Percent change in body weight 
 
 
 
Change in inflammatory status 
 
 
Change in SBP 
 
 
Change in hsCRP concentration 
 
From baseline to Week 48a 
 
Change in SBP 
Other Secondary Objectives 
 
Endpoints 
To demonstrate that tirzepatide at the MTD (10 mg or 15 mg) 
QW is superior to placebo for 
From baseline to Week 52 
 
Change in excessive daytime sleepiness 
 
Change in ESS score 
 
Change in patient-reported functional status as 
assessed by FOSQ (30 items) 
 
Change in all other FOSQ domain scores 
 
Change in body weight 
 
Percent of participants who achieve 
o 
≥10% body weight reduction 
o 
≥15% body weight reduction 
o 
≥20% body weight reduction  
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Master Protocol I8F-MC-GPIF(c) 
 
27 
 
Change in lipid parameters 
 
Change in 
o 
HDL-cholesterol 
o 
non-HDL-cholesterol 
o 
triglycerides  
 
 
 
Change in PROs 
 
 
Change in: 
o 
PROMIS Sleep-related impairment 
short form 8a score 
o 
PROMIS Sleep disturbance short form 
8b score 
o 
SF-36v2 acute form domain scores 
 
Percent of participants with improved 
categorical shift in: 
o 
PGIS-OSA Sleepiness 
o 
PGIS-OSA Fatigue 
o 
PGIS-OSA Snoring  
 
Insulin 
 
Hypoxic burden 
 
Change in DBP 
 
Change in fasting insulin 
 
Change in SASHB (% min/hour) 
From baseline to Week 48a 
 
Change in DBP 
Exploratory Objectives  
Endpoints 
To demonstrate that tirzepatide at the MTD (10 mg or 15 mg) 
QW is superior to placebo for 
From baseline to Week 52 
 
Change in PROs 
 
Change in 
o 
EQ-5D-5L utility index 
o 
EQ-VAS scores 
 
Percent of participants with improved 
categorical shift in: 
o 
PGIC-OSA Sleepiness 
o 
PGIC-OSA Fatigue 
o 
PGIC-OSA Sleep quality 
o 
PGIC-OSA Snoring 
 
To evaluate the effect of tirzepatide on sleep 
parameters as measured by Actigraphy (AX6) 
 
Mean change from baseline to endpoint 
assessment in 
o 
Daytime sleep duration 
o 
Daily step counts 
o 
Average acceleration 
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Master Protocol I8F-MC-GPIF(c) 
 
28 
Abbreviations: AHI = Apnea-Hypopnea Index; AX6 = Axivity 6; DBP = diastolic blood pressure; ESS = Epworth 
Sleepiness Scale; EQ-5D-5L = EuroQol - 5 Dimension - 5 Level; EQ-VAS = EuroQol Visual Analogue Scale; 
FOSQ = Functional Outcomes of Sleep Questionnaire; HDL = high-density lipoprotein; hsCRP = high-sensitivity 
C reactive protein; MTD = maximum-tolerated dose; OSA = obstructive sleep apnea; PGIC-OSA = Patient 
Global Impression of Change – Obstructive Sleep Apnea; PGIS-OSA = Patient Global Impression of Status – 
Obstructive Sleep Apnea; PROs = patient-reported outcomes; PROMIS = Patient-Reported Outcomes 
Measurement Information System; SBP = systolic blood pressure; SF-36v2 = Short-Form 36 version 2, SASHB 
= sleep apnea-specific hypoxic burden; QW = once weekly. 
a BP will be assessed at Week 48 because PAP suspension at Week 52 may confound BP assessment. 
 
For estimands guiding statistical analyses, see Section 9.3.1. 
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Master Protocol I8F-MC-GPIF(c) 
 
29 
4. 
Study Design  
4.1. 
Overall Design  
Study I8F-MC-GPIF (GPIF) is a multicenter, randomized, parallel-arm, double-blind, placebo-
controlled Phase 3 study to evaluate the efficacy and safety of tirzepatide at the MTD (10 mg or 
15 mg) QW versus placebo in participants who have obesity and moderate-to-severe OSA. 
This basket-type master protocol will investigate 2 participant populations, described in 2 ISAs: 
 GPI1 will include participants who are unwilling or are unable to use PAP therapy. 
 GPI2 will include participants who are on PAP therapy for at least 3 months at time of 
screening and plan to continue PAP therapy during the study. 
Participants to be assigned to whichever ISA they qualify for. Participants will then be randomly 
assigned to: 
 tirzepatide at the MTD (10 mg or 15 mg) SC QW, or 
 placebo. 
The expected total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is 60 weeks across the following study periods: 
 Screening: 4 weeks 
 Treatment: 52 weeks 
 Post-treatment follow-up: 4 weeks 
The maximum duration of treatment is 52 weeks. Procedures and assessments for each visit are 
presented in the SoA, Section 1.3. 
4.2. 
Scientific Rationale for Study Design  
The basket trial design employs a single overarching trial structure as a means to implement 
multiple investigations (Woodcock and LaVange 2017). Such approaches often allow for more 
streamlined and coordinated clinical trial logistics and consistency in data collection methods. 
The 2 studies associated with the master protocol, also called “Intervention-Specific 
Appendices” (ISAs), will describe any objectives, endpoints and efficacy assessments specific to 
each study population. ISA refers to specific population and background intervention, as defined 
by inclusion criteria. Used together, the master protocol and the 2 ISAs will describe the 
investigations to be conducted. 
ISA 1 and ISA 2 represent different populations with different treatment needs, and it is 
anticipated that tirzepatide may meet the needs of each participant group. 
Inclusion of a placebo treatment arm is acceptable because there are no currently effective 
disease-modifying treatments for OSA; this approach is in agreement with the use of placebo 
described in the Declaration of Helsinki (WMA 2013). The use of a placebo comparator in Study 
GPIF is needed to determine the efficacy and safety of tirzepatide therapy. 
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Master Protocol I8F-MC-GPIF(c) 
 
30 
4.3. 
Justification for Dose  
Tirzepatide doses of up to 15 mg administered SC QW will be evaluated in this study. 
Participants may be treated with lower maintenance dose of 10 mg if they do not achieve full 
dose escalation to 15 mg and/or do not tolerate 15 mg. 
These doses and associated escalation schemes were selected based on assessment of safety, 
efficacy (weight loss), and GI tolerability data in Phase 1, 2, and 3 studies in patients with 
T2DM, followed by exposure-response modeling of the data that predicted weight loss in 
patients with overweight or obesity.  
Dosing algorithms starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5 mg 
increments every 4 weeks should permit time for development of tolerance to GI events and are 
predicted to minimize GI tolerability concerns. 
Similar to the GLP-1RA class, most of the tirzepatide AEs were dose-dependent and GI-related, 
consisting mainly of nausea, vomiting, and diarrhea. In general, these events were mild or 
moderate in severity, with few severe episodes, and transient. 
Tirzepatide doses of 10 mg and 15 mg as MTD were selected based principally on the following 
criteria: 
 each dose provides robust weight loss relative to placebo 
 the percent of participants achieving ≥10% weight loss is higher with 15 mg than 10 mg, 
and 
 safety and tolerability were supported by Phase 3 results in T2DM. 
The proposed tirzepatide maintenance dose of up to 15 mg using a dose-escalation regimen is 
expected to safely maximize the potential for weight loss while minimizing GI tolerability 
concerns as has been achieved for approved GLP-1 RA drugs. The subsequent benefit of weight 
loss should result in clinically meaningful improvements in AHI. 
4.4. 
End of Study Definition  
A participant is considered to have completed the study if they have completed all required 
phases of the study including the last visit or the last scheduled procedure shown in the SoA. The 
end of the study for each ISA is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial globally. 
The end of study timing for each ISA is independent of the other ISA end of study timing. 
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Master Protocol I8F-MC-GPIF(c) 
 
31 
5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be at least 18 (or the legal age of consent in the jurisdiction in which the 
study is taking place) years of age, inclusive, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Previously diagnosed moderate-to-severe OSA with an AHI ≥15, as diagnosed with PSG, 
home sleep apnea test (HSAT), or other method that meets local guidelines prior to Visit 
1. See Section 10.10 for definitions of apnea and hypopnea. 
3. AHI ≥15 on PSG as part of the trial at Visit 1. 
4. In the investigator’s opinion, are well-motivated, capable, and willing to 
 learn how to self-inject study intervention, as required for this protocol (visually 
impaired persons who are not able to perform the injections must have the assistance 
of a sighted individual trained to inject study intervention; persons with physical 
limitations who are not able to perform the injections must have the assistance of an 
individual trained to inject study intervention) 
 inject study intervention (or receive an injection from a trained individual if visually 
impaired or with physical limitations), and 
 follow study procedures for the duration of the study, including, but not limited to: 
follow lifestyle advice (for example, dietary restrictions and exercise plan), maintain 
a study diary, and complete required questionnaires. 
Weight 
5. BMI ≥30 kg/m2. 
6. Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight. 
Sex and Contraceptive/Barrier Requirements 
7. Males and females may participate in this trial. 
Female participants must not be pregnant, intending to be pregnant, breastfeeding, or 
intending to breastfeed. 
Contraceptive use by participants should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. For definitions 
and the contraception requirements of this protocol, see Appendix 4 (Section 10.4) . 
Informed Consent 
8. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
Diabetes-related 
9. Have T1DM or T2DM, history of ketoacidosis, or hyperosmolar state/coma. 
10. HbA1c ≥ 6.5% (≥ 48 mmol/mol) at Visit 1. 
OSA-related 
11. Any previous or planned surgery for sleep apnea or major ear, nose or throat surgery, 
including tonsillectomy and adenoidectomy that still may affect breathing at time of Visit 
1. Inclusion of a participant with more minor ear, nose or throat surgery (for example, 
deviated septum) will be at the investigator’s discretion. 
12. Significant craniofacial abnormalities that may affect breathing at time of Visit 1. 
13. Diagnosis of Central or Mixed Sleep Apnea with % of mixed or central 
apneas/hypopneas ≥50%, or diagnosis of Cheyne Stokes Respiration. 
14. Diagnosis of Obesity Hypoventilation Syndrome or daytime hypercapnia. 
15. Active device treatment of OSA other than PAP therapy (for example, dental appliance), 
or other treatment, that in the opinion of the investigator, may interfere with study 
outcomes, unless willing to stop treatment at Visit 1 and throughout the study. 
16. Respiratory and neuromuscular diseases that could interfere with the results of the trial in 
the opinion of the investigator. 
Obesity-related 
17. Have a self-reported change in body weight >5 kg within 3 months prior to screening. 
18. Have a prior or planned surgical treatment for obesity (excluding liposuction or 
abdominoplasty if performed more than 1 year prior to screening). 
19. Have or plan to have endoscopic and/or device-based therapy for obesity or have had 
device removal within the last 6 months (for example, mucosal ablation, gastric artery 
embolization, intragastric balloon, and duodenal-jejunal bypass sleeve). 
Other medical 
20. History of clinically relevant medical, behavioral, or psychiatric disorder, other than 
OSA, that is associated with insomnia or excessive sleepiness. 
21. Impaired renal function, defined as eGFR <30 mL/min/1.73 m2. 
22. Have a known clinically significant gastric emptying abnormality (for example, severe 
gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI 
motility. 
23. History of chronic or acute pancreatitis. 
24. Thyroid-stimulating hormone outside of the range of 0.4 to 6.0 mIU/L at the screening 
visit. 
Note: Participants receiving treatment for hypothyroidism may be included, provided 
their thyroid hormone replacement dose has been stable for at least 3 months. 
Note: TSH values above the normal range can, in some patients, suggest subclinical 
hypothyroidism. If, in the investigator’s opinion, the participant has subclinical 
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hypothyroidism and may require initiation of thyroid hormone replacement during the 
course of the study, the participant should be excluded from the study. 
25. Have obesity induced by other endocrinologic disorders (for example, Cushing 
Syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, 
Melanocortin 4 Receptor deficiency or Prader-Willi Syndrome). 
26. Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at 
significant risk for suicide. 
27. Have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS or 
have answered “yes” to any of the suicide-related behaviors on the “suicidal behavior” 
portion of the C-SSRS, 
and the ideation or behavior occurred within the past month. 
28. PHQ-9 score of 15 or more at Visit 1 or 2, prior to randomization. 
29. Uncontrolled hypertension (SBP ≥160 mmHg and/or DBP ≥100 mmHg) at Visit 1. 
30. Any of the following CV conditions less than 3 months prior to randomization: acute MI, 
cerebrovascular accident (stroke), unstable angina, or hospitalization due to congestive 
heart failure. 
31. History of (less than 3 months prior to Visit 1) or planned CV procedure. 
32. Heart failure, including New York Heart Association Functional Classification Class IV 
33. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than 
nonalcoholic fatty liver disease, or any of the following, as determined by the central 
laboratory during screening: 
 ALT level >3.0X the ULN for the reference range 
 ALP level >1.5X the ULN for the reference range, or 
 TBL level >1.2X the ULN for the reference range (except for cases of known 
Gilbert’s Syndrome). 
Note: Participants with nonalcoholic fatty liver disease are eligible to participate in 
this trial if their ALT level is ≤3.0X the ULN for the reference range. 
34. Have a calcitonin level (at Visit 1) of: 
a. ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2 
b. ≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2 
35. Have a family or personal history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2. 
36. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy (other than basal- or squamous-cell skin cancer, in situ 
carcinomas of the cervix, or in situ prostate cancer) for less than 5 years. 
37. Have any other condition not listed in this section (for example, hypersensitivity or 
intolerance) that is a contraindication to GLP-1R agonists. 
38. Have a history of any other condition (such as known drug or alcohol abuse, diagnosed 
eating disorder, or other psychiatric disorder) that, in the opinion of the investigator, may 
preclude the participant from following and completing the protocol. 
39. Have history of use of marijuana less than 3 months of V1 and unwillingness to abstain 
from marijuana use during the trial. Participants should also refrain from use of 
cannabidiol oil for the duration of the study. 
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40. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an 
organ transplant. 
41. Requires the use of supplemental oxygen. 
 
Prior/Concomitant Therapy 
42. Are receiving or have received within 3 months prior to screening chronic (>2 weeks or 
14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra- 
articular, or inhaled preparations) or have evidence of a significant, active autoimmune 
abnormality (for example, lupus or rheumatoid arthritis) that has required (within the last 
3 months) or is likely to require, in the opinion of the investigator, concurrent treatment 
with systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular, or 
inhaled preparations) in the next 12 months.  
43. Have current or history of (less than 3 months prior to Visit 1) treatment with 
medications that may cause significant weight gain, including but not limited to: tricyclic 
antidepressants, atypical antipsychotic and mood stabilizers, for example: 
 imipramine 
 amitriptyline 
 mirtazapine 
 paroxetine 
 phenelzine 
 chlorpromazine 
 thioridazine 
 clozapine 
 olanzapine 
 valproic acid and its derivatives 
 lithium 
Note: Selective serotonin reuptake inhibitors are permitted, except for paroxetine. 
44. Have taken, less than 3 months prior to Visit 1, medications (prescribed or over-the-
counter) or alternative remedies intended to promote weight loss. Examples include, but 
are not limited to: 
 Saxenda® (liraglutide 3.0 mg) 
 Xenical®/Alli® (orlistat) 
 Meridia® (sibutramine) 
 Acutrim® (phenylpropanolamine) 
 Sanorex® (mazindol) 
 Adipex® (phentermine) 
 BELVIQ® (lorcaserin) 
 Qsymia® (phentermine/topiramate combination) 
 Contrave® (naltrexone/bupropion) 
 Pramlintide 
 Zonisamide 
 Topiramate 
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 Wegovy® 
 Any glucose-lowering medication, including metformin 
Note: Use of metformin or any other glucose-lowering medication, whether prescribed 
for polycystic ovary syndrome or diabetes prevention is not permitted. 
45. Use of stimulants less than 3 months prior to Visit 1 (for example, modafinil, 
armodafinil, solriamfetol, pitolisant, amphetamine, dextroamphetamine, 
dexmethylphenidate, methylphenidate, and lisdexamfetamine). 
46. Use of hypnotics, mirtazapine, opioids, trazodone less than 3 months prior to Visit 1. 
47. Use of GLP-1 RA less than 3 months prior to Visit 1. 
48. Criterion 48 is deleted. 
49. Use of any over-the-counter or prescription medications that could affect the evaluation 
of excessive sleepiness, per investigator discretion. 
50. Unwillingness to discontinue over-the-counter (herbal or supplemental) medication that, 
in the opinion of the investigator, can interfere with the study. 
Prior/Concurrent Clinical Study Experience 
51. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
52. Previously randomly assigned to study intervention in this study or any other study 
investigating tirzepatide. 
53. Have participated, within the last 30 days in a clinical trial involving a study intervention. 
If the previous study intervention is scientifically or medically incompatible with this 
study and has a long half-life, 3 months or 5 half-lives (whichever is longer) should have 
passed prior to screening (participation in observational studies may be permitted upon 
review of the observational study protocol and approval by the sponsor). 
54. Are Lilly employees or employees of third-party organizations involved with the study. 
55. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
56. Have any medical condition that, in the opinion of the investigator, would be a 
contraindication to participation in the trial 
 
 
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5.3. 
Lifestyle Considerations  
Per the SoA (Section 1.3), participants will consult with study personnel experienced in diet and 
exercise counseling to receive lifestyle program instructions at timepoints indicated in the SoA. 
Diet and exercise goals and the importance of adherence to the lifestyle program will be 
reinforced at each trial contact by study staff. 
5.3.1. 
Meals and Dietary Restrictions  
At Visit 2 and subsequent visits, participants will consult with study personnel experienced in 
diet and exercise counseling to receive lifestyle program instructions at timepoints indicated in 
the SoA. Dietary counseling will consist of advice on healthy food choices and focus on calorie 
restriction using a hypocaloric diet with macronutrient composition of: 
 maximum 30% of energy from fat 
 approximately 20% of energy from protein 
 approximately 50% of energy from carbohydrates 
 an energy deficit of approximately 500 kcal/day compared to the participant’s estimated 
TEE 
To encourage adherence, it is recommended that a 3-day diet and exercise diary be completed 
prior to each counseling visit. During each visit, the participant’s diet is reviewed and advice to 
maximize adherence is provided if needed. 
The hypocaloric diet is continued after randomization and throughout the treatment period. If a 
BMI ≤22 kg/m2 is reached, the recommended energy intake should be recalculated with no kcal 
deficit for the remainder of the trial. 
Total energy expenditure is calculated by multiplying the estimated Basal Metabolic Rate (BMR) 
(see table below) with a Physical Activity Level value of 1.3 (FAO/WHO/UNU 2004), which 
reflects an inactive lifestyle. This calculation provides a conservative estimate of caloric 
requirements: 
                        TEE (kcal/day) = BMR X 1.3 
 
Equations for estimating BMR in kcal/daya 
Sex 
Age 
BMR (kcal/day) 
Men 
18-30 years 
15.057 X actual weight in kg + 692.2 
 
31-60 years 
11.472 X actual weight in kg + 873.1 
 
>60 years 
11.711 X actual weight in kg + 587.7 
Women 
18-30 years 
14.818 X actual weight in kg + 486.6 
 
31-60 years 
8.126 X actual weight in kg + 845.6 
 
>60 years 
9.082 X actual weight in kg + 658.5 
Abbreviations: BMR = basal metabolic rate; WHO = World Health Organization. 
aRevised WHO equations (Adapted from: FAO/WHO/UNU 2004). 
5.3.2. 
Physical Activity  
At Visit 2 and all subsequent visits, participants will be advised to increase their physical activity 
to at least 150 minutes per week. 
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5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who have history of marijuana use less than 3 months of Visit 1 may be rescreened 
once provided the individual is willing to abstain from marijuana use during the trial. Rescreened 
participants should be assigned a new participant number for every screening/rescreening event. 
See Section 5.4 of the respective ISA’s for additional rescreening guidelines. 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant  
Not applicable. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Interventions Administered  
Intervention 
Name 
Tirzepatide (LY3298176) 
Placebo 
Type  
Drug 
Drug 
Dose 
Formulation 
Single-dose pen 
Single-dose pen 
Dosage 
Level(s) 
10 mg QW,  
15 mg QW 
Not applicable  
Route of 
Administration 
SC 
SC 
Use 
Experimental 
Placebo 
IMP and 
NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor and dispensed via IWRS 
Packaging and 
Labeling 
Study intervention will be provided in autoinjectors (single-dose 
pens), packaged in cartons to be dispensed. Clinical study materials 
will be labeled according to country regulatory requirements 
Abbreviations: IMP = investigational medicinal product; IWRS = interactive web-response system; NIMP = non-
investigational medicinal product; QW = once-weekly; SC = subcutaneous. 
There are no restrictions on the time of day each weekly dose of study intervention is given, but 
it is advisable to administer the SC injections on the same day and same time each week. The 
actual date, time, and injection details of all dose administrations will be recorded in the diary by 
the participant. If a dose of study intervention is missed, the participant should take it as soon as 
possible unless it is within 72 hours of the next dose, in which case that dose should be skipped, 
and the next dose should be taken at the appropriate time. The day of weekly administration can 
be changed if necessary, as long as the last dose was administered 72 or more hours before. 
All participants will inject study intervention subcutaneously in the abdomen or thigh using the 
injection supplies provided; a caregiver may administer the injection in the participant’s upper 
arm. A new autoinjector will be used for each injection. If study intervention is to always be 
injected in the same body region, participants should be advised to alternate injection sites each 
week. 
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6.1.1. 
Medical Devices  
The combination products provided for use in the study are tirzepatide autoinjector (or matching 
placebo). Any medical-device incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout the study (see 
Section 10.3). 
6.2. 
Preparation, Handling, Storage, and Accountability  
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized study personnel. 
 The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
 Further guidance and information for the final disposition of unused study interventions 
are in the provided instructions. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
All participants will be centrally randomly assigned to study intervention using an IWRS. Before 
the study is initiated, the log in information and directions for the IWRS will be provided to each 
site. 
Study intervention will be dispensed at the study visits summarized in SoA. 
Returned study intervention should not be re-dispensed to the participants. 
This is a double-blind study in which participants and study personnel, are blinded to study 
intervention. The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participants’ intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s intervention assignment unless this could delay emergency treatment for the 
participant. If a participant’s intervention assignment is unblinded, the sponsor must be notified 
immediately within 24 hours of this occurrence. The date and reason that the blind was broken 
must be recorded. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
clinical research physician (CRP) for the participant to continue in the study. 
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Stratification 
Participants will be stratified at randomization per ISA by country/geographic region, baseline 
AHI (moderate/severe), and gender. 
6.4. 
Study Intervention Compliance  
A record of the number of single-dose pens dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded. 
Treatment compliance for each visit interval is defined as taking at least 75% of the required 
doses of study intervention. Similarly, a participant will be considered significantly 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication (more than 125%). 
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol. 
6.5. 
Dose Modification  
Dose modification is permitted for management of intolerable GI symptoms during the first 24 
weeks of the treatment period (Section 6.5.1). 
Participants who do not tolerate at least 10 mg even after the described measures, including 1 de-
escalation and re-escalation attempt, will be discontinued from the study intervention but remain 
in the study for continued follow-up. 
Interventions to optimize study intervention tolerance and adherence may be employed 
throughout the study and include, but are not limited to, brief temporary interruptions 
(Section 7.1.2) and use of additional medications to manage GI symptoms (for example, nausea, 
vomiting, and diarrhea). 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms  
In participants who experience intolerable GI symptoms (for example, nausea, vomiting, or 
diarrhea) at any time during the study, the following measures are recommended: 
 counselling on dietary behaviors that may help mitigate nausea and vomiting, (for 
example, eating smaller meals, splitting 3 daily meals into 4 or more smaller ones, and 
stopping eating when they feel full). 
 if symptoms persist despite #1, prescribing symptomatic medication (for example, 
antiemetic or antidiarrheal medication), at the investigator’s discretion. 
 if symptoms persist despite #1 and #2, interrupting study intervention for 1 dose, 
provided the participant has taken the last 3 weekly doses. Study treatment should be 
resumed at the assigned dose immediately, either alone or in combination with 
symptomatic medication, which can also be utilized to manage symptoms (Section 6.8). 
During the first 24 weeks of the treatment period (20-week dose escalation plus 4 weeks), 
participants unable to tolerate 2.5 mg or 5 mg (despite the interventions mentioned above) will 
be discontinued from the study intervention but remain in the study.  
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For participants unable to tolerate any dose between 7.5 mg and 15 mg inclusive, despite the 
above measures, the investigator should contact Lilly to consider a dose de-escalation step with 
subsequent re-escalation by 2.5 mg every 4 weeks in a blinded fashion, to reach either the 10-mg 
or 15-mg dose as described below.  
Only 1 cycle of dose de-escalation and re-escalation is permitted during the first 24 weeks of the 
treatment period. MTD is either 10 mg or 15 mg. Dose modifications after the first 24 weeks of 
the treatment period are not permitted. For temporary study treatment discontinuation, see 
Section 7.1.2. 
Participants who tolerate 
 10 mg, but do not tolerate 12.5 mg or 15 mg even following the above measures, 
including 1 de-escalation and re-escalation attempt, will continue on 10 mg as their MTD 
dose. 
 12.5 mg, but do not tolerate 15 mg even after the above measures, including 1 de-
escalation and re-escalation attempt, will continue on 10 mg as their MTD dose. 
 15 mg will continue on 15 mg as their MTD dose. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
Tirzepatide will not be made available to participants after conclusion of the study. 
6.7. 
Treatment of Overdose  
Study intervention overdose (more than the specified number of injections in less than 72 hours) 
will be reported as an AE. 
In the event of an overdose, the treating physician should: 
● Contact the medical monitor immediately. 
● Evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
● Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until study intervention no longer has a clinical effect. 
6.8. 
Concomitant Therapy  
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications (Section 6.8.2) that may interfere with the assessment of efficacy and 
safety characteristics of the study treatments. 
Investigative-site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study. This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible. 
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Nonstudy medications taken by participants who are screened but not randomly assigned to 
study intervention will not be reported to Lilly unless an SAE or AE occurs that the investigator 
believes may have been caused by a study procedure. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, or other specific categories of interest) that the participant is 
receiving at the time of screening or receives during the study must be recorded along with: 
● Reason for use 
● Dates of administration including start and end dates 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1. 
Management of Incident Diabetes  
Incident diabetes is defined when any 1 of the following occur after randomization (American 
Diabetes Association 2020): 
 unequivocal hyperglycemia (random glucose ≥200 mg/dL) with signs or symptoms of 
hyperglycemia 
 within a 4-week period, any 2 of the following criteria are observed or 1 abnormal 
value is observed and confirmed: 
 HbA1c ≥6.5% (48 mmol/mol) 
 FG or 0-hour serum glucose from 2-hour OGTT ≥126 mg/dL (7.0 mmol/L) 
 2-hour glucose ≥200 mg/dL (11.1 mmol/L) by a 2-hour OGTT 
 initiation of any medication for the treatment of diabetes 
Participants who develop type 2 diabetes during the study will be 
 provided with and trained to use a glucometer 
 educated on the signs and symptoms of hypoglycemia and its treatment (see Section 
10.3.7.1), and 
 provided a diary to record hypoglycemic episodes per Section 10.3.7.1. 
Participants will be referred to their usual care provider and provided with a letter showing the 
study results indicative of diabetes. The decision to further evaluate, to initiate 
antihyperglycemic therapy, and the choice of antihyperglycemic medication will be at the 
discretion of the participant’s usual care provider, with the exception of use of DPP-4 inhibitors 
and open-label GLP-1R agonists, which are prohibited in the study (Section 6.8.2). Monitoring 
for hypoglycemia includes capture of events as defined in Section 10.3 (Appendix 3). Date of 
diabetes diagnosis will be captured in the AE CRF. 
Initiation of metformin for the treatment of diabetes is permitted, but metformin should not be 
initiated during the study for the treatment of other metabolic conditions (for example, polycystic 
ovary syndrome and diabetes prevention). 
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6.8.2. 
Prohibited Concomitant Medications  
The following medications are prohibited during the study: 
 DPP-4 inhibitors 
 Open-label GLP-1R agonists 
 Stimulants (for example, modafinil, armodafinil, solriamfetol, pitolisant, amphetamine, 
dextroamphetamine, dexmethylphenidate, methylphenidate, and lisdexamfetamine) 
 medications that may cause significant weight gain (such as, but not limited to, 
paroxetine, tricyclic antidepressants, atypical antipsychotic and mood stabilizers). 
 Medications that may cause weight loss (such as, but not limited to, liraglutide, 
semaglutide, orlistat, sibutramine, phenylpropanolamine, mazindol, phentermine, 
lorcaserin, naltrexone/bupropion, phentermine/topiramate combination, pramlintide, 
zonisamide, and topiramate) 
 OTC, herbal, or supplemental medications that, in the opinion of the investigator, may 
interfere with the study 
 hypnotics, mirtazapine, opioids, trazodone, pramlintide, sibutramine, orlistat, and 
zonisamide 
 Systemic glucocorticoid therapy, per discussion with sponsor 
 Use of any over-the-counter or prescription medications that could affect the evaluation 
of excessive sleepiness, per investigator discretion (such as, but not limited to, CBD oil, 
THC, etc.) 
 Any glucose-lowering medication, including metformin 
In addition,  
 Active device treatment of OSA other than PAP therapy (for example, dental appliance), 
or other treatment that, in the opinion of the investigator, may interfere with study 
outcomes.  
Participants who initiate and will not or cannot discontinue a prohibited medication, device, or 
other treatment will be permanently discontinued from study intervention per Section 7.1. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1, 
Appendix 1. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits, as 
shown in the SoA. 
A participant who prematurely discontinues study intervention is strongly encouraged to remain 
in the study for safety and efficacy assessments through the treatment period and post-treatment 
follow-up. 
If a participant who discontinues the double-blind study treatment prematurely declines to 
complete the remaining scheduled study visits, then the participant should complete the early ED 
procedures indicated in the SoA. Participants should be encouraged to come back for the last 
treatment visit (Visit 11) to complete the end-of-treatment phase procedures and return for the 
post-treatment follow-up Visit 801. 
Possible reasons leading to permanent discontinuation of study intervention: 
 participant decision 
o the participant requests to discontinue study intervention 
 clinical considerations 
o initiation of a prohibited medication (Section 6.8.2), if participants will not or 
cannot discontinue them 
o BMI ≤18.5 kg/m2 is reached at any time during the treatment period, study 
intervention discontinuation should be considered  
o TEAE 
▪ intolerable GI symptoms despite management (Section 6.5.1)  
Note: The investigator should contact the Sponsor CRP to discuss 
whether it is medically appropriate for the participant to continue study 
treatment. 
▪ significant elevation of calcitonin 
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▪ If the investigator determines that a systemic hypersensitivity reaction 
has occurred related to study intervention administration, the 
participant may be permanently discontinued from the study 
intervention, and the sponsor’s designated medical monitor should be 
notified. If the investigator is uncertain about whether a systemic 
hypersensitivity reaction has occurred and whether discontinuation of 
study intervention is warranted, the investigator may consult the 
sponsor 
▪ occurrence of any other TEAE, SAE, or clinically significant finding 
for which the investigator believes that permanent study intervention 
discontinuation is the appropriate measure to be taken 
o Diagnosis of 
▪ T1DM 
▪ Thyroid C-cell hyperplasia, MTC or MEN Syndrome type 2 after 
randomization 
▪ acute or chronic pancreatitis 
▪ an active or untreated malignancy (other than basal or squamous cell 
skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization 
o onset of pregnancy in a female participant (see Sections 7.2 and 8.3.2) 
o Suicidal Ideation and Behavior 
▪ PHQ-9 score ≥15 
 Participants should be referred to a Mental Health Professional 
(MHP) to assist in deciding whether the participant should be 
discontinued from study intervention. If a participant’s 
psychiatric disorder can be adequately treated with psycho- 
and/or pharmacotherapy, then the participant, at the discretion 
of the Investigator (in agreement with the MHP), may be 
continued in the trial on randomly assigned therapy. 
▪ in addition, study intervention may be discontinued if participants: 
 answered “yes” to Question 4 or Question 5 on the “Suicidal 
Ideation” portion of the C-SSRS, or 
 answered “yes” to any of the suicide-related behaviors on the 
Suicidal Behavior portion of the C-SSRS. 
A psychiatrist or appropriately trained professional may assist in the decision to discontinue the 
participant. The participant should be referred to a MHP for further evaluation and care. 
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7.1.1. 
Liver Chemistry Stopping Criteria  
The study intervention should be interrupted or discontinued if one or more of these conditions 
occur: 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for drug interruption/ discontinuation 
decisions rather than TBL>2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL > 2x ULN  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for drug interruption/ discontinuation 
decisions rather than TBL>2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA 2009 and other consensus guidelines, with minor modifications 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited non-drug etiology is identified. 
Participants who are discontinued from study intervention due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected as described in Section 10.6, 
Appendix 6. 
7.1.2. 
Temporary Discontinuation  
In certain situations, after randomization, the investigator may need to temporarily interrupt 
study intervention. Every effort should be made by the investigator to maintain participants on 
study intervention and to restart study intervention after any temporary interruption, as soon as it 
is safe to do so. Distribution of study intervention at the correct dose will be per IWRS 
instructions. 
Investigators should inform the sponsor that study intervention has been temporarily interrupted. 
The data related to temporary interruption of study treatment will be documented in source 
documents and entered on the CRF. 
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If study 
intervention 
interruption is… 
then… 
2 consecutive doses 
or less  
participant restarts study intervention at last 
administered dose, as per escalation 
schedule. 
3 consecutive doses 
or more  
participant restarts study intervention (at 5 
mg, managed by IWRS) and repeats dose 
escalation scheme. 
Due to an AE 
the event is to be documented and followed 
according to the procedures in Section 8.3 
of this protocol. 
Due to intolerable 
persistent GI AE 
participants should be treated as suggested 
in Section 6.5.1. 
Abbreviations: AE = adverse event; GI = gastrointestinal; IWRS = interactive web-response system. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
 at any time at the participant’s own request 
 at the request of the participant’s designee (for example, parents or legal guardian) 
 a participant will be withdrawn from the study in case of inadvertent enrollment  
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
o If the participant becomes pregnant during the study (see Section 8.3.2 for 
additional details) 
 if enrolled in any other clinical study involving an investigational product, or enrolled in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication. In this case, discontinuation from the study occurs prior to introduction 
of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an ED visit and post-treatment follow-up, if applicable, as shown in the SoA. If the 
participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
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7.3. 
Lost to Follow up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments  
8.1.1. 
Primary Efficacy Assessment  
8.1.1.1. 
Polysomnography  
The primary efficacy assessment in this study is AHI. AHI measurements will be collected via 
polysomnography. 
Polysomnography assessments (including AHI, blood oxygen saturation parameters, PR, sleep 
parameters) will be performed during 1-night, overnight clinic stays, per the SoA. Data from the 
PSGs will be read and scored centrally using the AASM 1B hypopnea scoring method (when 
there is ≥4% oxygen desaturation from pre-event baseline; see Section 10.10, Appendix 10 for 
definitions) (Hamilton et al. 2021). 
The eligibility criteria and AHI related endpoints of the study will be assessed based on central 
reading of the PSG. 
8.1.2. 
Secondary Efficacy Assessments  
8.1.2.1. 
Patient-Reported Outcomes  
8.1.2.1.1. Functional Outcomes of Sleep Questionnaire (FOSQ)  
The FOSQ will be included to assess change in FOSQ domains and total score from baseline to 
Week 52. The FOSQ is a 30-item sleep-specific, participant-completed questionnaire used to 
assess the effect of disorders associated with excessive daytime sleepiness (EDS) on daily 
functioning in adults. It assesses the following 5 domains of 
 General productivity (8 items) 
 Activity level (9 items) 
 Vigilance (7 items) 
 Social outcomes (2 items) 
 Intimate and sexual relationships (4 items) 
The FOSQ items assess participant’s current status with each item rated on a scale of 1 (extreme 
difficulty) to 4 (no difficulty), with an additional not applicable (0 = “I don’t do this activity for 
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other reasons”) also available. Individual domain scores are calculated by taking the mean of 
answered, non-zero items within each domain and a total score can be calculated by first 
computing the mean score for each domain, then multiplying the mean of the domain scores by 5 
(Weaver et al. 1997). The total score for the FOSQ 10-item short form (FOSQ-10) can also be 
calculated. 
8.1.2.1.2. PROMIS Short Form v1.0 Sleep-related Impairment 8a  
The PROMIS Short Form v1.0 Sleep-related Impairment 8a assesses self-reported perceptions of 
alertness, sleepiness, and tiredness during usual waking hours, and the perceived functional 
impairments associated with sleep problems or impaired alertness. The PROMIS Short Form 
v1.0 Sleep-related Impairment 8a consists of 8 items each rated on a 5-point scale ranging from 
“not at all” to “very much.” Items have a recall period of “in the past 7 days.” Individual item 
scores are totaled to obtain a raw score, with higher scores indicating more sleep-related 
impairment. Raw scores can be converted to a T-score, which is standardized with a mean of 50 
and a SD of 10. (Northwestern, 2016a) 
8.1.2.1.3. PROMIS Short Form v1.0 Sleep Disturbance 8b  
The PROMIS Short Form v1.0 Sleep Disturbance 8b assesses self-reported perceptions of sleep 
quality, sleep depth, and restoration associated with sleep, including perceived difficulties and 
concerns with getting to sleep or staying asleep, as well as perceptions of the adequacy of and 
satisfaction with sleep. The PROMIS Short Form v1.0 Sleep Disturbance 8b consists of 8 items 
each rated on a 5-point scale ranging from “not at all” to “very much, ” “never” to “always,” or 
“very poor” to “very good.” Items have a recall period of “in the past 7 days.” Individual item 
scores are totaled to obtain a raw score, with higher scores indicating more sleep disturbance. 
Raw scores can be converted to a T-score, which is standardized with a mean of 50 and a SD of 
10. (Northwestern, 2016b) 
8.1.2.1.4. Epworth Sleepiness Scale  
The ESS will be included to assess improvements in excessive daytime sleepiness from baseline 
to Week 52. The ESS is an 8-item participant-completed measure that asks the participant to rate 
on a scale of 0 (would never doze) to 3 (high chance of dozing), their usual chances of dozing in 
8 different daytime situations, with a recall period of “in recent times.” The ESS total score is the 
sum of the 8-item scores and ranges from 0 to 24, with higher scores indicating greater daytime 
sleepiness (Johns 1991).  
8.1.2.1.5. Short-Form 36 Version 2 Health Survey, Acute Form, 1-week Recall Version  
The SF-36v2 will be included to assess health-related quality of life from baseline to Week 52. 
The SF-36v2 acute form, 1-week recall version is a 36-item generic, participant-completed 
measure designed to assess the following 8 domains over “the past week.” 
 Physical functioning 
 Role-physical 
 Bodily pain 
 General health 
 Vitality 
 Social functioning 
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 Role-emotional, and 
 Mental health 
The Physical Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Each domain is scored individually and 
information from these 8 domains are further aggregated into 2 health component summary 
scores: Physical Component Summary and Mental Component Summary. Items are answered on 
Likert scales of varying lengths (3-point, 5-point, or 6-point scales). Scoring of each domain and 
both summary scores are norm based and presented in the form of T-scores, with a mean of 50 
and SD of 10; higher scores indicate better levels of function and/or better health (Maruish 
2011). 
8.1.2.1.6. Patient Global Impression of Status – Obstructive Sleep Apnea (PGIS-OSA) 
Symptoms Scales  
Three patient global impression of status scales will be included to assess categorical shift in 
participant self-rated assessment of their OSA symptom severity from baseline to Week 52. 
PGIS-OSA Fatigue 
This is a single-item, participant self-rated assessment of their overall level of fatigue due to 
OSA, “over the past 7 days.” The item is rated on a 4-point scale ranging from “No fatigue” to 
“Severe fatigue.” 
PGIS-OSA Sleepiness 
This is a single-item, participant self-rated assessment of their overall level of sleepiness due to 
OSA during waking hours, “over the past 7 days.” The item is rated on a 4-point scale ranging 
from “Not at all sleepy” to “Very sleepy.” 
PGIS-OSA Snoring 
The PGIS-OSA Snoring scale consists of two items. The first item is a participant self-rated 
assessment of their overall perception of the severity of their snoring due to OSA, “over the past 
7 days,” with respect to how much their snoring has affected their sleep. The item is rated on a 4-
point scale ranging from “Not at all affected” to “Very affected.” For the second item, 
participants will be asked on a 3-point scale (“Not at all” to “All the time”) if they have ever 
been told by someone else that they snore in their sleep. 
8.1.3. 
Exploratory Efficacy Assessments  
8.1.3.1. 
Actigraphy  
The actigraphy device (AX6) will be utilized in the OSA trial to objectively evaluate the effect of 
tirzepatide on various sleep and physical activity parameters including but not limited to change 
of daytime sleep time, sleep efficiency, and change in daytime physical activity from baseline. 
The actigraphy device is a data logger capable of recording raw data from a suite of integrated 
sensors and can be configured to collect movement-relevant data in an uninterrupted fashion for 
up to 2 months, thus is ideal for collecting longitudinal movement data (for example, physical 
activity, sleep, etc.) in real-world health research and well-defined clinical trials. The actigraphy 
device meets the CE (Conformite Europeenne) mark requirements. Participants should wear the 
actigraphy device for 7 consecutive days, 5 times during the study, per the SoA. 
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Lack of participation in actigraphy collections at any time is not considered a protocol deviation. 
8.1.3.2. 
Patient Global Impression of Change – Obstructive Sleep Apnea (PGIC-OSA) 
Symptoms Scales  
Four patient global impression of change scales will be included to assess categorical shift in 
participant self-rated assessment of change in their OSA symptom severity from baseline to 
Week 52. 
PGIC-OSA Fatigue 
This is a single-item, participant self-rated assessment of the change in their overall level of 
fatigue due to OSA, “since you started taking the study medication.” The item is rated on a 5-
point scale ranging from “Much worse” to “Much better.” 
PGIC-OSA Sleepiness 
This is a single-item, participant self-rated assessment of the change in their overall level of 
sleepiness due to OSA during waking hours, “since you started taking the study medication.” 
The item is rated on a 5-point scale ranging from “Much more sleepy” to “Much less sleepy.” 
PGIC-OSA Sleep Quality 
This is a single-item, participant self-rated assessment of the change in their overall sleep quality 
due to OSA, “since you started taking the study medication.” The item is rated on a 5-point scale 
ranging from “Much worse” to “Much better.” 
PGIC-OSA Snoring 
This is a single-item, participant self-rated assessment of the overall change in how their snoring 
has affected their sleep, “since you started taking the study medication.” The item is rated on a 5-
point scale ranging from “My sleep is much more affected” to “My sleep is much less affected.” 
8.1.3.3. 
EQ-5D-5L  
The EQ-5D-5L (EuroQol Research Foundation 2019) is a standardized 5-item self-administered 
instrument for use as a measure of health outcome. It provides a simple descriptive profile and a 
single index value for health status that can be used in the clinical and economic evaluation of 
health care as well as population health surveys. The EQ-5D-5L assesses 5 dimensions of health: 
 
mobility 
 
selfcare 
 
usual activities 
 
pain/discomfort, and 
 
anxiety/depression. 
The 5L version, scores each dimension at 5 levels: 
 
no problems 
 
slight problems 
 
moderate problems 
 
severe problems, and 
 
unable to perform/extreme problems. 
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A total of 3125 health states is possible. In addition to the health profile, a single health state 
index value can be derived based on a formula that attaches weights to each of the levels in each 
dimension. This index value ranges between less than 0 (where 0 is a health state equivalent to 
death; negative values are valued as worse than dead) to 1 (perfect health). In addition, the EQ 
Visual Analog Scale records the respondent’s self-rated health status on a vertical graduated (0 to 
100) visual analog scale. The participant rates his/her perceived health from 0 (the worst 
imaginable health) to 100 (the best imaginable health). In conjunction with the health state data, 
it provides a composite picture of the respondent’s health status. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
A complete physical examination will include, at a minimum, assessments of the CV, 
respiratory, gastrointestinal and neurological systems as well as a thyroid examination. Height, 
weight, and waist circumference will also be measured and recorded. 
A symptom-directed physical assessment will be performed as indicated in the SoA, as clinically 
indicated. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2. 
Vital Signs  
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3). 
8.2.3. 
Electrocardiograms (ECG)  
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 
A local single 12-lead ECG will be collected at designated visits. ECGs should be collected prior 
to collection of blood samples for laboratory testing, including PK samples. Participants should 
be supine for at least 5 minutes before ECG collections and remain supine but awake during the 
ECG collection. ECGs may be repeated at the investigator’s discretion at any visit. 
After enrollment, if a clinically significant increase in the QT/QTc interval from baseline or 
other clinically significant quantitative or qualitative change from baseline is identified, the 
participant will be assessed by the investigator for symptoms (for example, palpitations, near 
syncope, and syncope) and to determine whether the participant can continue in the study. The 
investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation from at least 1 of the replicate ECGs from each time point. 
8.2.4. 
Clinical Safety Laboratory Tests  
See Section 10.2, Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
for the timing and frequency. 
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The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results must be 
retained with source documents unless a Source Document Agreement or comparable document 
cites an electronic location that accommodates the expected retention duration. Clinically 
significant abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the participant’s 
condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
 If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Section 10.2, Appendix 2 
must be conducted in accordance with the SoA, standard collection requirements, and 
laboratory manual. 
If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or are 
considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE. 
8.2.5. 
Pregnancy Testing  
See the SoA (Section 1.3) for testing for pregnancy and timepoints. 
See Appendix 4 (Section 10.4) for additional information for pregnancy. 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring  
Patients with obesity may occasionally develop suicidal ideation or behavior. 
Participants should be monitored appropriately and observed closely for SIB or any other 
unusual changes in behavior, especially at the beginning and end of the course of intervention, or 
at the time of dose changes, either increases or decreases. Participants who experience signs of 
SIB should undergo a risk assessment. All factors contributing to SIB should be evaluated and 
consideration should be given to discontinuation of the study intervention. 
Baseline assessment of suicidal ideation and behavior/intervention emergent suicidal ideation 
and behavior will be monitored using the C-SSRS and PHQ-9. 
8.2.6.1. 
C-SSRS  
Columbia Suicide-Severity Rating Scale (C-SSRS) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and behavior during the assessment period via a 
questionnaire. The scale was developed by the National Institute of Mental Health (NIMH) trial 
group (TASA) for the purpose of being counterpart to the Columbia Classification Algorithm of 
Suicide Assessment (C-CASA) categorization of suicidal events. (The Columbia Lighthouse 
Project, 2013) 
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For this study, the C-SSRS is adapted for the assessment of the ideation and behavior categories 
only. The Intensity of Ideation and Lethality of Behavior sections are removed. 
8.2.6.2. 
PHQ-9  
The PHQ-9 is a validated self-report screening tool that assesses the presence and intensity of 
depressive symptoms. The PHQ-9, which incorporates the 9 Diagnostic and Statistical Manual-
IV depression criteria as “0” (not at all) to “3” (nearly every day), was developed for use in 
primary care settings (Kroenke et al. 2001). 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3, Appendix 3: 
 AEs 
 SAEs 
 PCs 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention before completing the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.3) will 
be followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3). For PCs, the investigator is responsible for ensuring 
that follow-up includes any supplemental investigations as indicated to elucidate the nature 
and/or causality. Further information on follow-up procedures is provided in Section 10.3, 
Appendix 3. 
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
AE 
AE 
Signing of 
the ICF 
participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
SAE 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
until 1 month 
after the last 
dose of study 
intervention 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
PCs 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = serious adverse event. 
a Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.3.1.1. 
Adverse Event Monitoring with a Systematic Questionnaire  
Nonleading AE collection should occur prior to the collection of the C-SSRS and PHQ-9, if AE 
and C-SSRS/PHQ-9 collections done on the same day. 
If a suicide-related event is discovered during the C-SSRS or PHQ-9 but was not captured during 
the nonleading AE collection, sites should not change the AE form. 
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
 The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
 After learning of a pregnancy in the female partner of a study participant, the investigator 
will 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor. 
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 The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of gestational 
age, fetal status (presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant’s pregnancy. 
 The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of gestational age, fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
 A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at ≥20 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 
 Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in protocol 
Section 8.3.1. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. If the participant is 
discontinued from the study, follow the standard discontinuation process and continue 
directly to the study follow-up phase. The follow-up on the pregnancy outcome should 
continue independent of intervention or study discontinuation. 
8.3.3. 
Adverse Events of Special Interest  
Adverse events of special interest are prospectively defined to include 
 severe hypoglycemia 
 MACE (adjudicated); includes, but not limited to CV death, nonfatal MI, nonfatal stroke, 
hospitalization for unstable angina, and hospitalization for heart failure 
 treatment-emergent arrhythmias and cardiac conduction disorders 
 hepatobiliary disorders; includes biliary colic, cholecystitis, and other gallbladder disease 
 severe GI events 
 acute renal events 
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 Major Depressive Disorder/suicidal behavior and ideation 
 pancreatitis (adjudicated) 
 c-cell hyperplasia and thyroid malignancies 
 allergic/hypersensitivity reactions; includes ISRs and ADA formation 
If these events are reported, investigators may be prompted to collect additional data about the 
event. Sections 10.1.5.1 and 10.1.5.2 (Appendix 1), outline additional information on CV and 
pancreatic adjudication. Section 10.3.7 (Appendix 3) outline additional information on 
hypoglycemia, hypersensitivity reactions, and ISRs. 
8.4. 
Pharmacokinetics  
Blood samples will be obtained from all participants enrolled in the 2 ISAs to enable the 
characterization of tirzepatide PK and exposure response relationships, as permissible. Samples 
will be collected with concurrent immunogenicity samples at timepoints indicated in the SoA 
(Section 1.3). 
Blood samples collected from participants in the placebo arms will not be included in the 
bioanalyses of drug concentrations. 
 Plasma samples will be collected for measurement of plasma concentrations of 
tirzepatide as specified in the SoA 
 Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel. 
8.4.1. 
Bioanalytical Methods  
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 mass spectrometry method. Analyses of samples collected from placebo-treated 
participants are not planned. Bioanalytical samples collected to measure tirzepatide 
concentrations will be retained for a maximum of 1 year following last participant visit for the 
study. During this time, samples remaining after the bioanalyses may be used for exploratory 
analyses such as metabolism work, protein binding, and/or bioanalytical method cross-
validation. 
8.5. 
Pharmacodynamics  
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section. 
8.6. 
Genetics  
A whole blood sample will be collected for pharmacogenetic analysis where local regulations 
allow. 
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8.7. 
Biomarkers  
Blood samples will be collected to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of study participant response (including 
safety), and clinical outcome. Biomarkers will include measurement of biomolecules including 
proteins, lipids, and other cellular elements. 
Samples will be collected according to the schedule described in the SoA and as detailed in the 
laboratory manual provided separately to sites. 
All samples will be coded with the study participant number. These samples and any data 
generated can be linked back to the study participant only by the investigator site personnel. 
Lilly may store samples after the end of the study to achieve study objectives. Additionally, with 
participant’s consent, samples may be used for further research by Lilly or others such as 
universities or other companies to contribute to the understanding of OSA, obesity, or other 
diseases, the development of related or new treatments, or research methods.  
See Section 10.1.12, Appendix 1 for details related to sample retention. 
8.8. 
Immunogenicity Assessments  
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be 
collected for analysis to determine antibody production against tirzepatide. Antibodies may be 
further characterized for: cross-reactive binding to native GIP and GLP-1, neutralizing activity 
of tirzepatide on the GIP and GLP-1 receptors, and neutralizing activity to native GIP and/or 
GLP-1. To interpret the results of immunogenicity, a venous blood sample will be collected at 
the same time points to determine the serum concentrations of tirzepatide. All samples for 
immunogenicity should be taken predose when applicable and possible. 
Treatment-emergent ADAs are defined in Section 10.3, Appendix 3. 
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of tirzepatide at a laboratory approved by the sponsor. The purpose of retention, the maximum 
duration of retention, and facility for long-term storage of samples is described in Section 10.2, 
Appendix 2. Samples may also be used for development and control of an immunogenicity 
assay. 
For details related to sample retention, see Section 10.1.12, Appendix 1. 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
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9. 
Statistical Considerations  
This section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints. The SAP will include more technical and 
detailed description of the statistical analyses described in this section. 
Unblinding details will be specified in the unblinding plan section of the SAP or in a separate 
unblinding plan document. 
9.1. 
Statistical Hypotheses  
For each ISA, the primary objective is to demonstrate that tirzepatide at the MTD (10 mg or 
15 mg) is superior to Placebo in treating participants with OSA with respect to AHI endpoint. 
Thus the null and alternative hypotheses will be defined as below. 
Null hypothesis: tirzepatide at the MTD (10 mg or 15 mg) is not different from the placebo with 
respect to the mean percent change from baseline in AHI at 52 weeks. 
Alternative hypothesis: tirzepatide at the MTD (10 mg or 15 mg) is superior to the placebo with 
respect to the mean percent change from baseline in AHI at 52 weeks. 
The treatment effect will be defined as the difference between the estimates of the mean change 
from baseline at 52 weeks for tirzepatide at the MTD (10 mg or 15 mg) and placebo. 
9.1.1. 
Multiplicity Adjustment  
The statistical comparisons for the primary efficacy endpoint and the key secondary endpoints 
will be carried out based on a graphical approach for multiple comparisons within each ISA 
(Bretz et al. 2011). The graphical approach is a closed testing procedure; hence, it strongly 
controls the familywise Type I error rate (2-sided alpha level of 0.05) across the primary and key 
secondary objectives (Alosh et al. 2014). Details about the graphical approach will be described 
in the SAP. 
9.2. 
Analyses Sets  
This table describes the populations that will be used for statistical analyses within each ISA of 
the master protocol. Additional intervention-specific populations for analyses may be described 
in the respective ISA. 
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Analysis Set or Population 
Description 
mITT population 
All randomly assigned participants who are exposed to at 
least 1 dose of study intervention.  
FAS 
Data obtained during treatment period from the mITT 
population excluding those discontinuing study due to 
inadvertent enrollment, regardless of adherence to study 
intervention 
EAS 
Data obtained during treatment period from the mITT 
population excluding those discontinuing study due to 
inadvertent enrollment, excluding data after 
discontinuation of study intervention (last dose + 7 days) 
SS 
Data obtained during treatment period plus safety follow-
up period from mITT population, regardless of adherence 
to study intervention 
Abbreviations: EAS = efficacy analysis set; FAS = full analysis set; mITT = modified intent-to-treat; SS = safety 
analysis set. 
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
Statistical analysis will be the responsibility of the sponsor or its designee. Statistical analysis for 
each ISA will be conducted individually and a combined analysis with both ISAs is not planned. 
The SAP will be finalized prior to the unblinding of the first ISA. 
Changes to the data analysis methods will require an amendment only if a principal feature of the 
master protocol is changed. Any other change to the data analysis methods, and the justification 
for making the change, will be described in the SAP or the CSR for each respective ISA. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
Efficacy analyses will be conducted on all participants meeting study eligibility criteria randomly 
assigned to study intervention according to the treatment to which the participants are assigned 
and were exposed to at least one dose. The primary and key secondary efficacy analysis will be 
guided by 2 estimands, the “treatment regimen” estimand and the “efficacy” estimand to support 
global regulatory submissions and publications. For the “treatment regimen” estimand, the 
analysis will be conducted using FAS. To minimize missing data, participants randomly assigned 
to study intervention who prematurely discontinue study treatment will be encouraged to remain 
in the study, however, some participants may choose to permanently discontinue from the study 
which will lead to missing endpoints. Details on handling missing values can be found in 
Missing Value Imputation section. For the “efficacy” estimand, the analysis will be conducted 
using the EAS. 
Safety analysis will be conducted using the SS. Selected safety analyses may be conducted after 
excluding the data after permanent discontinuation of the study intervention. 
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Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval will be calculated at 95%, 2-sided. In statistical summaries and 
analyses, participants will be analyzed as randomized. Countries in similar geographic regions 
with fewer than 10 participants, based on the all-randomized population, will be pooled to 
achieve a pooled country of at least 10 participants. All analyses using country in the model will 
use a pooled country, unless otherwise specified. The final pooling by country and geographic 
region will be finalized prior to data lock. 
Baseline is defined as the last non missing measurement at or before the randomization visit 
(Visit 2) unless otherwise specified. 
Analysis of covariance will be used to analyze continuous variables collected only at baseline 
and endpoint. The model will include treatment and strata (pooled country/geographic region, 
AHI stratum [moderate (AHI ≥15 and AHI <30), severe (AHI ≥ 30)] and gender) as fixed effects 
and baseline as a covariate. The ANCOVA model for AHI analysis will include baseline AHI 
instead of the AHI stratum as a fixed covariate. 
The MMRM analysis, a restricted-maximum-likelihood-based model, will be used to analyze 
continuous longitudinal variables. All the longitudinal observations at each scheduled 
postbaseline visit will be included in the analysis. The model will include the fixed class effects 
of treatment, strata (pooled country/geographic region and gender), visit, and treatment-by-visit 
interaction, as well as the continuous, fixed covariate of baseline value. For analyses of variables 
other than AHI, the AHI stratum will also be included in the model. Significance tests will be 
based on least-squares means and Type III tests. 
For continuous measures, summary statistics may include sample size, mean, standard deviation, 
median, minimum, and maximum for both the actual and the change from baseline 
measurements. Least-square means and standard errors derived from the analysis models will 
also be displayed for the change from baseline measurements. Treatment comparisons will be 
displayed showing the treatment difference least-square means and the 95% confidence intervals 
for the treatment differences, along with the p-values for the treatment comparisons. 
For categorical measures, summary statistics may include sample size, frequency, and 
percentages. Fisher’s exact test or Pearson’s chi-square test will be used for treatment 
comparisons unless otherwise specified. 
Missing values for the primary and multiplicity adjusted endpoints at Week 52 and at Week 48 
for SBP will be handled as follows. For efficacy analysis relative to the “efficacy” estimand, no 
explicit imputation will be performed. For efficacy analysis relative to the “treatment regimen” 
estimand, missing values will be imputed using multiple imputation based on the reason of 
intercurrent events. The statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987). The intercurrent events and the resulting missing values will 
be handled as follows: 
Intercurrent events 
Strategy to handle 
intercurrent events 
Assumptions for 
missing values 
Methods to handle 
missing values 
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Study DC due to the 
COVID-19 pandemic 
(after other reasons 
for missing data are 
ruled out) or incorrect 
study procedure 
leading to invalid 
measurements 
ascertained while on 
treatment  
Hypothetical 
MAR 
Use observed data 
without any 
imputation 
All other study 
discontinuations 
Treatment policy 
MNAR 
Multiple imputation. 
Details will be 
indicated in SAP 
Abbreviations: COVID-19 = coronavirus disease-2019; DC = discontinuation; MAR = missing at random; 
MNAR = missing not at random. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.2. 
Primary Analysis  
The primary objective of this study is to test the hypothesis that tirzepatide at the MTD (10 mg or 
15 mg) is superior to placebo for participants with moderate to severe OSA on the mean  AHI 
reduction from baseline to Week 52.  
The primary analysis guided by the “treatment regimen” estimand will use FAS. Missing values 
will be imputed based on the strategy to handle intercurrent events described in Section 9.3.1, 
and more details about the imputation methods will be provided in the SAP. After the 
imputation, the primary efficacy comparison will be based on the contrast between tirzepatide at 
the MTD (10 mg or 15 mg) and placebo from the ANCOVA analysis of mean change from 
baseline to Week 52 in AHI using FAS as described in Section 9.3.1. 
The primary analysis guided by the “efficacy” estimand will use EAS. The efficacy comparison 
will be based on the contrast between tirzepatide at the MTD (10 mg or 15 mg) and placebo at 
Week 52 (Visit 11) from the MMRM analysis of mean change from baseline in AHI using EAS 
as described in Section 9.3.1. More details about the model will be provided in the SAP. 
Analysis aligned to each estimand will be evaluated at the full significance level of 0.05. 
9.3.3. 
Analysis of Key Secondary Endpoints  
The analyses for key secondary endpoints as in Section 3 will be performed for both the 
“treatment regimen” and “efficacy” estimand as described in Section 9.3.1 using the graphical 
testing scheme. The details of graphical testing scheme will be described in the SAP. 
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The analysis of the hierarchical combination PRO endpoint will be performed with the 
Finkelstein-Schoenfeld method, and the win ratio (Pocock et al. 2012) will be reported as the 
measure of treatment effect. 
The last measurement prior to randomization for all three PRO endpoints will be used as 
baseline. For the “treatment regimen” estimand, missing values at Week 52 will be imputed 
through multiple imputations based on the reason of missingness as described in Section 9.3.1. 
Analysis of percent change in AHI, percent change from baseline in body weight, CRP at the 52-
week visit and change in SBP at the 48-week visit will be conducted in a manner similar to the 
primary efficacy analyses with baseline AHI stratum added in the model, and baseline of the 
corresponding variable as a covariate. Analysis of percent change in AHI will not include the 
baseline AHI stratum. 
Comparisons at the 52-week visit between the treatments relative to the proportion of 
participants achieving ≥ 50% AHI reduction and AHI< 5 or (AHI ≥ 5 and AHI ≤ 14 and ESS ≤ 
10) will be conducted using logistic regression analysis including terms for treatment, pooled 
country, gender, and baseline AHI as a covariate. 
Analysis aligned to each estimand will be evaluated at the full significance level of 0.05 
contingent on reaching statistical significance of the primary objective. 
9.3.4. 
Treatment Group Comparability  
9.3.4.1. 
 Participant Disposition  
Participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported for each ISA. A detailed description of participant 
disposition and the reasons for discontinuation will be summarized by treatment group for each 
ISA at the end of the study. Intervention-specific analyses will be detailed in each respective 
ISA. 
9.3.4.2. 
Participant Characteristics  
Participant characteristics and baseline clinical measures will be summarized for each treatment . 
For all participant characteristics, the summaries will include descriptive statistics for continuous 
measures (for example, sample size, mean, standard deviation, median, minimum, and 
maximum) and for categorical measures (for example, sample size, counts and percentages). 
Additional intervention-specific analyses will be specified in each respective ISA. 
9.3.4.3. 
Concomitant Therapy  
Concomitant medications used during the study will be summarized for each ISA. 
9.3.5. 
Safety Analyses  
Unless specified otherwise, safety assessments will compare safety of tirzepatide at the MTD (10 
mg or 15 mg) with placebo irrespective of adherence to study intervention. Thus, safety analyses 
will be conducted using the SS. 
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9.3.5.1. 
Adverse Events  
Adverse events will be classified by system organ class and preferred term as defined by the 
Medical Dictionary for Regulatory Activities. 
All conditions existing prior to randomization at Visit 2 will be used as baseline. The 
postbaseline visits during the placebo-controlled phase will be included as the postbaseline 
period for analysis. 
For events that are gender specific, the denominator and computation of the percentage will only 
include participants of the given gender. 
9.3.5.2. 
Hypoglycemic Events  
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia will be 
summarized and compared between tirzepatide at the MTD (10 mg or 15 mg) and placebo. Rate 
of hypoglycemic episodes will also be analyzed. Some analyses may be conducted excluding 
data after introducing another antihyperglycemic therapy. 
9.3.5.3. 
Gastrointestinal Events  
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
9.3.5.4. 
Adjudicated Cardiovascular Events  
Listings of deaths, myocardial infarctions, strokes, and hospitalizations for unstable angina or 
heart failure confirmed by an independent Clinical Endpoint Committee (CEC) will be provided. 
9.3.5.5. 
Central Laboratory Measures and Vital Signs  
Values and change from baseline to postbaseline values of central laboratory measures and vital 
signs will be summarized and compared between tirzepatide at the MTD (10 mg or 15 mg) and 
placebo at each scheduled visit. 
9.3.5.6. 
Analysis of C-SSRS Data  
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide (The 
Columbia Lighthouse Project, 2013). 
9.3.6. 
Evaluation of Immunogenicity  
The frequency and percentage of participants with preexisting ADA and with TE ADA+ to 
tirzepatide will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution (1:10) of the ADA assay if no ADAs 
were detected at baseline (treatment-induced ADA), or those with a 4-fold (2 dilutions) increase 
in titer compared with baseline if ADAs were detected at baseline (treatment-boosted ADA). For 
the TE ADA+ participants, the distribution of maximum titers will be described. The frequency 
of neutralizing antibodies may also be tabulated in TE ADA+ participants. The relationship 
between the presence of antibodies and the PK parameters and PD response including safety and 
efficacy to tirzepatide may be assessed. 
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9.3.7. 
Other Analyses  
9.3.7.1. 
Health Economics  
Analyses of actual and change from baseline in PRO scores will be conducted using linear 
models with baseline PRO scores, treatment, stratification factors and other factors that may be 
considered relevant. These variables will be specified in the SAP. 
9.3.7.2. 
Subgroup Analyses  
The following subgroups will be analyzed using the “efficacy” estimand on percent change in 
AHI values from baseline to 52 week visit if there are sufficient numbers of participants in each 
treatment by subgroup (for example, 10%): 
 Age (50 years, 50 years), 
 Baseline OSA severity (Moderate, Severe), 
 Race, 
 Ethnicity, 
 Country, 
 Gender (Male or Female), 
 Baseline BMI (<30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2), and 
 Baseline ESS (ESS≤10, ESS>10). 
Analyses for percent change from baseline in AHI will be performed using an MMRM model 
that includes the same fixed effects given for the primary analysis model plus factors of 
subgroup, 2-way interaction of subgroup and treatment, 2-way interaction of subgroup and visit, 
and 3-way interaction of treatment, visit and subgroup. The interaction of subgroup and 
treatment at the primary endpoint (Week 52) will be evaluated to assess the treatment by 
subgroup interaction. When analyzing OSA severity (Moderate, Severe) as a subgroup, the 
baseline AHI will be not be included as a covariate to avoid confounding. Additional subgroup 
analyses may also be performed. 
More details on other analyses will be described in the SAP. 
9.4. 
Interim Analysis  
Based on the projected enrollment, approximately 3 interim analyses of safety will be conducted. 
The first interim analysis is planned to occur when approximately 20% of the anticipated number 
of participants are randomly assigned to study intervention or 6 months after the first participant 
is randomly assigned to study intervention, whichever occurs later, from one of the ISAs. 
Subsequent reviews will follow approximately every 6 months throughout the study. 
Only the DMC is authorized to evaluate unblinded interim analyses. Study sites will receive 
information about interim results only if they need to know for the safety of their participants. 
Unblinding details are specified in SAP and/or a separate unblinding plan document. 
The DMC charter will describe the specific parameters of the planned interim analysis. 
See Section 10.1.5, Appendix 1 And the DMC Charter for details related to the DMC. 
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The timing of dissemination of data summaries based on interim analyses is addressed in Section 
10.1.6, Appendix 1. 
9.5. 
Sample Size Determination  
Approximately 206 participants per ISA will be randomly assigned to either tirzepatide or 
placebo in a 1:1 ratio (approximately 103 participants per treatment arm), and the statistical 
power is evaluated for the primary efficacy endpoint and key secondary combination PRO 
endpoint at a 2-sided significance level of 0.05. This sample size will provide 
 At least 90% power to demonstrate superiority of tirzepatide at the MTD (10 mg or 15 
mg) to placebo for the mean percent change from baseline in AHI, assuming 50% 
improvement, with a common standard deviation of 50%, and a dropout rate of 25% 
 at least 90% power to demonstrate superiority of tirzepatide at the MTD (10 mg or 15 
mg) to placebo for the hierarchical combination PRO endpoint using Finkelstein-
Schoenfeld method (Finkelstein and Schoenfeld 1999) with a dropout rate of 25% 
An upper limit of approximately 70% enrollment of male participants will be used to ensure a 
sufficiently large sample of female participants. 
The sample size and power for the key secondary hierarchical combination PRO endpoint is 
estimated through simulations under the following assumptions (Blackman et al. 2016, Weaver 
et al. 2021): 
Variable 
Placebo 
Tirzepatide at 
the MTD 
(10 mg or 
15 mg) 
Definition of Win 
FOSQ-10 – 
change from 
baseline (mean 
± SD) 
1.24 ± 1.84 
1.95 ± 1.84 
If the change from baseline FOSQ-10 
for TZP at MTD (10 mg or 15 mg) 
minus change from baseline FOSQ-10 
for placebo ≥2.2 
FOSQ 
Vigilance – 
change from 
baseline (mean 
± SD) 
0.3 ± 0.5 
0.5 ± 0.5 
If the change from baseline FOSQ 
Vigilance for TZP at MTD (10 mg or 
15 mg) minus change from baseline 
FOSQ Vigilance for placebo ≥0.44 
FOSQ Activity 
Level – change 
from baseline 
(mean ± SD) 
0.3 ± 0.5 
0.5 ± 0.5 
If the change from baseline FOSQ 
Activity Level for TZP at MTD (10 mg 
or 15 mg) minus change from baseline 
FOSQ Activity Level for placebo ≥0.44 
Abbreviations: FOSQ = Functional Outcomes of Sleep Questionnaire; FOSQ-10 = FOSQ 10-item short form; 
MTD = maximum tolerated dose; SD = standard deviation; TZP = tirzepatide. 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
 Applicable ICH GCP Guidelines 
 International Organization for Standardization (ISO) 14155 
 Applicable laws and regulations 
The protocol, protocol amendments, ICFs, IB, and other relevant documents (for example, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and approved 
by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 Code of Federal Regulations , ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
Investigator sites are compensated for participation in the study as detailed in the clinical trial 
agreement. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3. 
Informed Consent Process  
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or the participant’s legally authorized 
representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets the 
requirements of 21 Code of Federal Regulations 50, local regulations, ICH guidelines, privacy 
and data protection requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection  
Participants will be assigned a unique identifier by the sponsor. Any participant records, datasets 
or tissue samples that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that the participant’s personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor has processes in place to ensure data protection, information security and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach. 
10.1.5. 
Committees Structure  
Prospective adjudication of major adverse CV events and pancreatic AEs will be performed by 
the independent adjudication committees for this study. 
Sections 10.1.5.1 and 10.1.5.2, Appendix 1 outline additional information on pancreatic and CV 
adjudication. 
An independent DMC for the interim analysis (Section 9.4) will include members with no 
conflict of financial interest. An independent DMC with members all external to the sponsor will 
be used to monitor participant safety in an unblinded fashion. For details on the DMC, refer to 
the DMC charter. 
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10.1.5.1. Cardiovascular Adjudicated Events  
Deaths and nonfatal CV AEs will be adjudicated by a committee blinded to treatment 
assignment. The nonfatal CV AEs to be adjudicated include: 
 
myocardial infarction 
 
hospitalization for unstable angina 
 
hospitalization for heart failure 
 
coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 
 
cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack. 
10.1.5.2. Pancreatitis Adjudicated Event  
Acute pancreatitis is defined as an AE of special interest in this trial (Section 8.3.3). 
The diagnosis of acute pancreatitis requires 2 of the following 3 features: 
 abdominal pain, characteristic of acute pancreatitis (generally located in the epigastrium 
and radiates to the back in approximately half the cases) (Banks and Freeman 2006; 
Koizumi et al. 2006); the pain is often associated with nausea and vomiting 
 serum amylase (total and/or pancreatic) and/or lipase ≥3X ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
All suspected cases of acute or chronic pancreatitis will be adjudicated by a committee blinded to 
treatment assignment. In addition, AEs of severe or serious abdominal pain of unknown etiology 
will also be submitted to the adjudication committee to assess for possible pancreatitis or other 
pancreatic disease. Relevant data from participants with acute or chronic pancreatitis and those 
with severe or serious abdominal pain will be entered into a specifically designed CRF page. The 
adjudication committee representative will enter the results of adjudication in a corresponding 
CRF page. 
10.1.6. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
The publication policy for Study GPIF is outlined in Section 10.1.10, Appendix 1 and further 
described in the Clinical Trial Agreement. 
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Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
Data and documents, including the study protocol, SAP, CSR, and blank or annotated CRFs, will 
be provided in a secure data sharing environment for up to 2 years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance  
All participant data relating to the study will be recorded on printed or electronic CRFs unless 
transmitted to the sponsor or designee electronically (for example, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These pre-defined parameters will be 
monitored during the study and important excursions from the QTLs and remedial actions taken 
will be summarized in the CSR. 
Monitoring details describing strategy (for example, risk-based initiatives in operations and 
quality such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (for example, 
contract research organizations). 
Study monitors will perform ongoing source data verification to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement unless 
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local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
In addition, sponsor or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site. The study may be audited by sponsor or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An EDC system will be used in this study for the collection of CRF data. The investigator 
maintains a separate source for the data entered by the investigator or designee into the 
sponsor-provided EDC system. The investigator is responsible for the identification of any data 
to be considered source and for the confirmation that data reported are accurate and complete by 
signing the CRF. 
Additionally, COA data (clinician-reported outcome instrument) for suicidality assessments will 
be collected by the authorized study personnel, via a paper source document and will be 
transcribed by the authorized study personnel into the EDC system. 
Additionally, electronic COA data (participant-focused outcome instrument) will be directly 
recorded by the participant, into an instrument (for example, handheld smart phone or tablet). 
The electronic COA data will serve as the source documentation and the investigator does not 
maintain a separate, written or electronic record of these data. 
Data collected via the sponsor-provided data capture system(s) will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive or access 
an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse. 
Data collected on the actigraphy device will be transferred electronically to the sponsor data 
warehouse, via a third party. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global PC 
management system. 
10.1.8. 
Source Documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on or entered in the CRF and are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The investigator 
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may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definition of what constitutes source data can be found in Section 10.1.7, Appendix 1. 
10.1.9. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. The first act of recruitment is the first site open and will be the study start date. 
Study or Site Termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 For study termination: 
o Discontinuation of further study intervention development 
 For site termination: 
o Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
o Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
o Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
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10.1.12. 
Sample Retention  
Sample retention 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 becomes commercially available. 
Sample Type  
Custodian  
Retention Period After Last Participant 
Visita  
Exploratory Biomarker 
Samples 
Sponsor or 
Designee  
15 years  
PK Samples 
Sponsor or 
Designee  
2 years  
Genetics 
Sponsor or 
Designee  
15 years  
Immunogenicity (ADA) 
Samples 
Sponsor or 
Designee  
15 years  
Abbreviations: ADA = antidrug antibody; PK = pharmacokinetic. 
aRetention periods may differ locally. 
 
 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table below will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. 
In circumstances where the sponsor approves local laboratory testing in lieu of central laboratory 
testing (in the table below), the local laboratory must be qualified in accordance with applicable 
local regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel. 
Clinical Laboratory Tests  
Comments  
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs)  
  
Differential 
  
Percent and/or Absolutes Count of: 
  
  Neutrophils, segmented 
  
  Bands  
  
  Lymphocytes 
  
  Monocytes 
  
  Eosinophils 
  
  Basophils 
  
Platelets 
  
Cell morphology (RBCs and WBCs) 
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
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Clinical Laboratory Tests  
Comments  
Total bilirubin 
  
Direct bilirubin 
  
ALP 
  
ALT 
  
AST 
  
BUN 
  
Creatinine  
  
CK 
  
Uric acid 
  
Albumin 
  
Calcium 
  
Glucose 
  
Lipid Panel 
Assayed by Lilly designated laboratory. 
Cholesterol  
  
Triglycerides 
  
HDL-C 
.  
LDL-C 
Generated by Lilly-designated laboratory. 
If Triglycerides are >400; direct LDL will be 
measured. 
VLDL-C 
Generated by Lilly-designated laboratory. 
Hormones (female) 
  
Serum Pregnancy  
Assayed by Lilly-designated laboratory.  
Urine Pregnancy 
Assayed and Evaluated locally  
FSH  
Assayed by Lilly-designated laboratory.  
Urine Chemistry 
 Assayed by Lilly-designated laboratory. 
Albumin 
  
Creatinine 
  
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI)  
  
UACR 
  
PK Samples – Tirzepatide 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Immunogenicity (ADA) Samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
  Anti-tirzepatide antibodies OR Tirzepatide antibodies 
 
  Anti-tirzepatide antibodies neutralization OR Tirzepatide 
antibodies neutralization 
 
Additional Testing  
Assayed by Lilly-designated laboratory.  
HbA1c 
 
Calcitonin 
 
Pancreatic Amylase 
 
Lipase 
 
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Clinical Laboratory Tests  
Comments  
Insulin 
Results will not be provided to the investigative sites. 
C-Peptide 
Results will not be provided to the investigative sites. 
Free Fatty Acids 
Results will not be provided to the investigative sites. 
hsCRP 
Results will not be provided to the investigative sites. 
Cystatin-C 
 
TSH 
Stored Samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Genetics Sample 
Exploratory Biomarker Samples 
  Serum 
  
  Plasma (EDTA) 
  
  Plasma (P800)  
  
Abbreviations: ADA = antidrug antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase;; AST = 
aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatinine kinase, CKD-EPI = Chronic Kidney 
Disease-Epidemiology; EDTA = ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate; 
FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; 
hsCRP = C-Reactive Protein, high-sensitivity; IWRS = interactive web-response system; LDL-C = low-density 
lipoprotein cholesterol; PK = pharmacokinetics; RBC = red blood cells; TSH = thyroid-stimulating hormone; 
UACR = urine albumin/creatinine ratio; VLDL-C = very-low-density lipoprotein cholesterol; WBC = white 
blood cells. 
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event  
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory tests results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up pre-dose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
 
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Timing 
Sample Type 
Laboratory Test a 
Collect from 30 minutes to 4 hours 
after the start of the event. 
● Note: The optimal 
collection time is from 1 to 2 
hours after the start of event. 
Serum 
total tryptase 
Serum 
complements (C3, C3a, and C5a) 
Serum 
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine panel 
that includes these 3 cytokines)  
Collect only if not already collected 
on the same day as the event. 
● Note: If collecting, collect 
up to 12 hours after the start of 
the event. 
Serum 
Tirzepatide ADA 
Serum/plasma 
Tirzepatide concentration 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
 The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization (ISO) 14155. 
 Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list of 
sponsor medical devices). 
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This 
definition includes events related to the investigational medical device or comparator 
and events related to the procedures involved except for events in users or other 
persons, which only include events related to investigational devices.  
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of study intervention, including signs, symptoms, or 
clinical sequalae. 
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
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However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
 
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, 
the following are also PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 
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10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and PC Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and PC 
information is reported on the PC Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the PC Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories: 
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.  
 
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Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) in order to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
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 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on an SAE paper form (see next 
section) or to the sponsor or designee by telephone. 
 Contacts for SAE reporting can be found on the SAE form.  
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found on the SAE form.  
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
 Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements.  
10.3.7. 
Special Safety Topics  
10.3.7.1. Hypoglycemia  
Participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia and how to treat hypoglycemia, and how to collect appropriate information for 
each episode of hypoglycemia. 
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood glucose 
samples collected during study visits. 
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All participants who develop diabetes during the study will be provided with glucometers. 
Participants without diabetes may, at the investigator’s discretion, be given glucometers to assist 
in the evaluation of reported symptoms consistent with hypoglycemia. Participants receiving 
glucometers will be provided a diary to record relevant information (for example, glucose values, 
symptoms). 
Hypoglycemic episodes will be recorded in the eDiary and should not be recorded as AEs unless 
the event meets serious criteria. If a hypoglycemic event meets severe criteria (see definition 
below), it should be recorded as serious on the AE and SAE CRFs, and reported to Lilly as an 
SAE. 
Investigators should use the following classification of hypoglycemia (ADA 2020): 
 
Level 1 hypoglycemia: 
Glucose <70 mg/dL (3.9 mmol/L) and ≥ 54 mg/dL (3.0 mmol/L): Level 1 hypoglycemia 
can alert a person to take action such as treatment with fast-acting carbohydrates. Providers 
should continue to counsel participants to treat hypoglycemia at this glucose alert value. 
Level 2 hypoglycemia: 
Glucose <54 mg/dL (3.0 mmol/L): Level 2 hypoglycemia is also referred to as documented 
or blood glucose confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This 
glucose threshold is clinically relevant regardless of the presence or absence of symptoms of 
hypoglycemia. 
Level 3 hypoglycemia: 
Severe hypoglycemia (in adults): A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia. For example, 
participants had altered mental status, and could not assist in their own care, or were 
semiconscious or unconscious, or experienced coma with or without seizures, and the 
assistance of another person was needed to actively administer carbohydrate, glucagon, or 
other resuscitative actions. Glucose measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of glucose concentration to normal is 
considered sufficient evidence that the event was induced by a low glucose concentration. 
 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance. 
 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia:  
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep. 
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To avoid duplicate reporting, all consecutive BG values <70 mg/dL (<3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event 
(Weinberg et al. 2010; Danne et al. 2013). 
10.3.7.2. Hypersensitivity Reactions  
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory. 
10.3.7.3. Injection-Site Reactions  
Symptoms and signs of a local ISR may include erythema, induration, pain, pruritus, and edema. 
If an ISR is reported by a participant or parent or guardian or site staff, the ISR CRF will be used 
to capture additional information about this reaction, for example, injection site pain, degree and 
area of erythema, induration, pruritis and edema. 
At the time of AE occurrence, samples will be collected for measurement of tirzepatide ADAs 
and tirzepatide concentration. 
 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of child 
bearing potential 
Females are considered a WOCBP if 
 
they have had at least 1 cycle of menses, or 
 
they have Tanner 4 breast development. 
 
Any amount of spotting should be considered menarche. If Tanner Staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner staging. 
Women not of 
child bearing 
potential 
Females are considered women not of child bearing potential if 
 
they have a congenital anomaly such as Mullerian agenesis 
 
they are infertile due to surgical sterilization, or 
 
they are post-menopausal. 
 
Examples of surgical sterilization include: hysterectomy, bilateral oophorectomy, 
or tubal ligation. 
Post-menopausal 
state 
The post-menopausal state should be defined as: 
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or 
2. A woman at least 40 years of age and up to 55 years old with an intact 
uterus, not on hormone therapy, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, AND 
with a follicle-stimulating hormone >40 mIU/mL; or 
3. A woman 55 or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea; or 
4. A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy 
 
* Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
SERMs, or chemotherapy that could induce transient amenorrhea. 
Abbreviations: SERM = selective estrogen receptor modulators; WOCBP = woman of child bearing potential. 
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10.4.2. 
Contraception Guidance  
10.4.2.1. Females  
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same sex 
relationship, as part of their preferred and usual lifestyle 
Must… 
Must not… 
 
agree to either remain abstinent, or 
 
stay in a same sex relationship without 
sexual relationships with males 
 
use periodic abstinence methods 
o calendar  
o ovulation  
o symptothermal, or 
o post-ovulation  
 
declare abstinence just for the duration of 
a trial, or 
 
use the withdrawal method 
 
 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a same sex 
relationship, as part of their preferred and usual lifestyle 
Topic 
Condition 
Pregnancy testing 
Negative serum result at screening, followed by a 
negative urine result within 24 hours prior to 
treatment exposure. 
Contraception 
Agree to use 2 forms of effective contraception, 
where at least one form must be highly effective 
(less than 1% failure rate) for the duration of the 
trial and for 30 days thereafter. 
 
 
Examples of different forms of contraception: 
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 
mini-pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or 
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide 
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
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o  diaphragm with spermicide, or 
o female condom with spermicide 
 
Note: The barrier method must include use of a 
spermicide (that is, condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone 
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal 
 
post coital douche 
 
lactational amenorrhea 
 
10.4.2.2. Males  
The table below describes contraception guidance for all men. 
Topic 
Guidance 
For all men  
should refrain from sperm donation for the 
duration of the study and for 120 days (4 months) 
from the last dose of study intervention received 
Contraception for men with partners of 
childbearing potential  
 
either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 
must use condoms during intercourse for 
the duration of the study, and 
 
for 120 days (4 months) from the last 
dose of study intervention received 
Contraception for men in exclusively same sex 
relationships, as their preferred and usual lifestyle 
Are not required to use contraception 
Examples of highly effective, effective and unacceptable methods of contraception are listed in Section 
10.4.2.1, Appendix 4. 
 
 
 
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10.5. 
Appendix 5: Genetics  
Use/Analysis of DNA 
Genetic variation may impact a participant’s response to study intervention, susceptibility to, and 
severity and progression of disease. Variable response to study intervention may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease being 
treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected 
for DNA analysis from consenting participants. 
DNA samples will be used for research related to tirzepatide, OSA, obesity and related diseases. 
They may also be used to develop tests/assays including diagnostic tests related to tirzepatide, 
OSA, and obesity. Genetic research may consist of the analysis of 1 or more candidate genes or 
the analysis of genetic markers throughout the genome or analysis of the entire genome (as 
appropriate). 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to tirzepatide or study interventions of this class to understand study disease or 
related conditions. 
The results of genetic analyses may be reported in the CSR or in a separate study summary. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained while research on tirzepatide, OSA, and obesity continues but no 
longer than the sample retention limits described in Section 10.1.12, Appendix 1. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
10.6.1. 
Hepatic Evaluation Testing  
See Sections 10.6.2 and 10.6.3, Appendix 6 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs – red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs – white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
  Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
  Lymphocytes 
Creatine kinase (CK) 
  Monocytes 
Other Chemistry 
  Basophils 
Acetaminophen 
  Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) (quantitative) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin A (IgA) (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin G (IgG) (quantitative) 
  HAV total antibody 
Immunoglobulin M (IgM) (quantitative) 
  HAV IgM antibody 
Phosphatidylethanol (Peth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
  Hepatitis B surface antigen (HbsAg) 
Drug screen 
  Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
  Hepatitis B core total antibody (anti-HBc) 
Other Serology 
  Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
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  Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
  HBV DNA b 
Anti-actin antibody c 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
  HCV antibody 
  EBV antibody 
  HCV RNA b 
  EBV DNA b 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
  HDV antibody 
  CMV antibody 
Hepatitis E virus (HEV) testing: 
  CMV DNA b 
  HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
  HEV IgM antibody 
  HSV (Type 1 and 2) antibody 
  HEV RNA b 
  HSV (Type 1 and 2) DNA b 
Microbiology d 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
  Blood 
 
  Urine 
 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 
 
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10.6.2. 
Close Hepatic Monitoring  
Laboratory tests (Section 10.2, Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if one or more of these 
conditions occur: 
If a participant with baseline results 
of…  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants with 
Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and total 
bilirubin level should continue until levels normalize or return to approximate baseline levels. 
10.6.3. 
Comprehensive Hepatic Evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
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If a participant with baseline results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or 
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT= alanine aminotransaminase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus , 
cytomegalovirus , Epstein-Barr virus , acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
 In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline on 2 
or more consecutive tests 
2. Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
 In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
 In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline on 2 
or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study intervention due to a hepatic event 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
 
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10.7. 
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting  
Refer to Appendix 3 for definitions and procedures for recording, evaluating, follow-up, and 
reporting of all events. 
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10.8. 
Appendix 8: Protocol GPIF Standardized Protocols for the 
Measurement of Height, Weight, Neck Circumference, Waist 
Circumference, Vital Signs, and Electrocardiogram  
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2017). 
10.8.1. 
Measuring Height  
Step 1. Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured). 
Step 2. Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall. 
Step 3. Ask the participant to look straight ahead without tilting their head up. 
Step 4. Ask the participant to breathe in and stand tall. Measure and record the participant’s 
height in centimeters to 1 decimal place. 
 
10.8.2. 
Measuring Weight  
 Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms to 1 decimal place. 
 All weights for a given participant should be measured using the same scale, 
whenever possible, at approximately the same time in the morning after evacuation of 
bladder contents. 
 Body weight will be measured in fasting state at all visits except Visit 1. If the 
participant is not fasting, the participant should be called in for a new visit within the 
visit window to have the fasting body weight measured. 
Step 1.  Ask the participant to empty their pockets, remove their footwear, outerwear (coat, 
jacket, etc.), and any headgear (light headgear worn for religious reasons can remain, but this 
should be worn by the participant at every clinic visit when weight is measured). 
Step 2.  Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface). 
Step 3.  Ask the participant to step onto the scale with 1 foot on each side of the scale. 
Step 4.  Ask the participant to stand still with arms by sides and then record weight in kilograms 
to the nearest one-tenth kilogram. 
10.8.3. 
Measuring Hip and Waist Circumference  
 Hip circumference measurements should be obtained with the participant in the standing 
position. The hip circumference should be measured at the maximal circumference of the 
buttocks. 
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 Waist circumference should be measured in the horizontal plane and at the midpoint 
between the lower margin of the last palpable rib and the top of the iliac crest. 
 Measurements should be taken at the end of a normal expiration using a nonstretchable 
measuring tape. The tape should lie flat against the skin without compressing the soft 
tissue. 
 
The waist circumference should be measured twice, rounded to the nearest 0.5 cm. The 
measuring tape should be removed between the 2 measurements. Both measurements will 
be recorded in the CRF. If the difference between the 2 measurements exceeds 1 cm, this 
set of measurements should be discarded and the 2 measurements repeated. 
Step 1. Ask the participant to wear light clothing (if available, patient gowns could also be used). 
Step 2. Ask the participant to stand with their feet close together, arms at their side, body weight 
evenly distributed. 
Step 3. Ask the participant to relax and measure the participant’s waist circumference. 
10.8.4. 
Measuring Neck Circumference  
 
 Participants should look straight ahead during the measurement, with shoulders down 
(not hunched). 
 Measure the neck circumference at a point just below the larynx (Adam’s Apple) and 
perpendicular to the long axis of the neck. 
 Do not place the tape measure over the Adam’s Apple. 
 The tape will be as close to horizontal as anatomically feasible (the tape line in the 
front of the neck should be at the same height as the tape line in the back of the neck). 
 Care should be taken so as not to involve the shoulder/neck muscles (trapezius) in the 
measurement. 
 Round neck measurement up to the nearest half centimeter. 
10.8.5. 
Vital Sign Measurements (Blood Pressure and Heart Rate)  
 Vital sign measurements (BP and heart rate, measured by pulse) should be taken before 
obtaining an ECG tracing and before collection of blood samples for laboratory testing 
 The participant should sit quietly for at least 5 minutes before vital signs measurements are 
taken 
 For each parameter, 3 measurements will be taken using the same arm, preferably the 
nondominant arm 
 The recordings should be taken at least 1 minute apart. Each measurement of sitting pulse 
and BP needs to be recorded in the CRF 
 Blood pressure must be taken with an automated BP instrument 
 If BP and pulse measurements are taken separately, pulse should be taken prior to BP. 
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Note: In the event pulse measurement cannot be taken via an automated BP instrument, the 
preferred location for measurement of pulse is the radial artery. 
10.8.6. 
Electrocardiogram  
 All digital ECGs will be obtained using local ECG machines. 
 12-lead ECGs should be obtained after the participant has rested in a supine position for at 
least 5 minutes. 
 Electrocardiograms should be collected prior to collection of blood samples for laboratory 
testing, including PK samples. 
 
 
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10.9. 
Appendix 9: Provisions for Changes in Study Conduct Due to the 
COVID-19 Pandemic  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Study disruptions due to the COVID-19 pandemic 
Individual, site, or regional restrictions due to the COVID-19 pandemic may cause disruptions to 
the conduct of the study. These disruptions may limit the ability of the investigators or 
participants, or both, to attend on-site visits or to conduct planned study procedures. 
Implementing changes due to the COVID-19 pandemic 
After receiving the sponsor’s written approval, sites may implement changes if permitted by 
local regulations. 
After approval by local ERBs/IRBs, regulatory bodies and any other relevant local authorities, 
implementation of these changes will not typically require additional notification to these groups, 
unless they have specific requirements in which notification is required (for example, upon 
implementation and suspension of changes). All approvals and notifications must be retained in 
the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct due to the COVID-19 pandemic 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
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Remote visits 
Types of remote visits 
Telephone/Telemedicine 
Telephone or technology-assisted virtual visits, or both, are acceptable to complete appropriate 
assessments. Assessments to be completed in this manner include, but are not limited to, 
collection of AEs and PCs, concomitant medications review, review study participant diary 
(including study intervention compliance), review diet and exercise goals, C-SSRS (Since Last 
Visit Assessed) and PHQ-9. PROs will be completed by the participant on the provisioned 
device per the SoA. 
Mobile healthcare visit 
Healthcare visits may be performed by a mobile healthcare provider at locations other than the 
study site when participants cannot travel to the site due to the COVID pandemic, if written 
approval is provided by the sponsor. Procedures performed at such visits include, but are not 
limited to, weight measurement, blood sample collection, vital signs (temperature, PR, BP), 
concomitant medication review, conducting physical assessments, collection of AEs and PCs, 
and collecting health information. PROs will be completed by the participant on the provisioned 
device per the SoA. 
Every effort should be made for the participant to return to on-site visits as soon as reasonably 
possible, while ensuring the safety of the participant and investigational site staff. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for PK, immunogenicity, hsCRP, insulin and lipid samples. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Study intervention and supplies 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include: 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
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 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at Visit 1 are valid for a maximum of 90 days. The following rules will be applied for active 
participants not randomly assigned to study intervention whose participation in the study must be 
paused due to the COVID-19 pandemic: 
 If screening is paused for less than 90 days from Visit 1 to Visit 2: the participant will 
proceed to the next study visit per the usual SoA, provided that Visit 2 must be 
conducted within 90 days from Visit 1. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 90 days from Visit 1 to Visit 2: the participant 
must be discontinued because of screening interruption due to the COVID-19 
pandemic. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. This rescreen is in addition to the 
one allowed by the main protocol. The screening procedures per the usual SoA should 
be followed, starting at Visit 1 to ensure participant eligibility by Visit 2. 
 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
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This table describes the allowed adjustments to visit windows. 
Visit Number 
Tolerance 
Visit 1  
(Screening) 
No change 
Visit 2 
(Randomization) 
Within 90 days after Visit 1. 
Visits 3 through 6 
Within 7 days before or after the intended date. 
Visits 7 through 
10 
Within 14 days before or after the intended date.  
Visit 11 
Within 14 days before the intended date, or up to 28 days 
after the intended date.  
Visit 801 
Up to 28 days after the intended date  
 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected due to the COVID-19 pandemic. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
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10.10. Appendix 10: Abbreviations and Definitions  
Term 
Definition 
AASM 
American Academy of Sleep Medicine 
Abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
antidrug antibody 
AE 
adverse event 
AHI 
Apnea-Hypopnea Index 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Apnea 
decrease in airflow ≥90% from baseline for ≥10 seconds 
AST 
aspartate aminotransferase 
AX6 
Axivity 6 
blinding/masking 
A single-blind study is one in which the investigator and/or the investigator’s staff are 
aware of the treatment but the participant is not, or vice versa, or when the sponsor is 
aware of the treatment but the investigator and/the investigator’s staff and the 
participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the 
participants are aware of the treatment received. 
BMI 
body mass index 
BP 
blood pressure 
CBD 
cannabidiol 
COA 
clinical outcome assessment 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
cardiovascular  
Device deficiencies 
Equivalent to product complaint 
DMC 
data monitoring committee. A data monitoring committee, or data monitoring board 
(DMB) is a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to 
the sponsor regarding the stopping of a study for efficacy, or for harms, or for futility. 
The composition of the committee is dependent upon the scientific skills and 
knowledge required for monitoring the particular study. 
DPP-4 
dipeptidyl-peptidase-4 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
ED 
early discontinuation 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
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enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
ERB 
ethical review board 
EQ-5D-5L 
EuroQol - 5 Dimension - 5 Level 
ESS 
Epworth Sleepiness Scale 
FAS 
full analysis set 
FG 
fasting glucose 
FOSQ 
Functional Outcomes of Sleep Questionnaire 
GCP 
good clinical practice 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GLP-1 
glucagon-like peptide-1 
GLP-1R 
glucagon-like peptide-1 receptor 
GLP-1RA 
glucagon like peptide 1 receptor 
HbA1c 
hemoglobin A1c 
HDL 
high-density lipoprotein 
HSAT 
home sleep apnea test 
hsCRP 
high-sensitivity C-reactive protein 
Hypopnea 
an abnormal respiratory event lasting ≥10 seconds with ≥30% reduction in 
thoracoabdominal movement or airflow as compared to baseline, and with ≥ 4% oxygen 
desaturation. 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees  
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial.  
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form. 
INR 
International normalized ratio 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB 
institutional review board 
ISA 
intervention-specific appendix 
ISR 
injection site reaction 
ITT 
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
IWRS 
interactive web-response system 
MACE 
major adverse cardiovascular events 
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medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors: 
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
MEN 
multiple endocrine neoplasia 
MI 
myocardial infarction 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription. 
MMRM 
Mixed model repeated measures 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
OGTT 
oral glucose tolerance test 
OSA 
obstructive sleep apnea 
OTC 
Over the counter 
PAP 
positive airway pressure 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control. 
PC 
product complaint 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Status 
PHQ-9 
Patient Health Questionnaire-9 
PK/PD 
pharmacokinetics/pharmacodynamics 
PR 
pulse rate 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PSG 
polysomnography  
QTc 
corrected QT interval 
QW 
weekly 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SASHB 
sleep apnea specific hypoxic burden 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SD 
standard deviation 
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.  
SF-36v2 
Short-Form 36 version 2 
SIB 
suicidal ideation and behavior 
SoA 
Schedule of Activities 
SS 
safety analysis set 
T1DM 
Type 1 diabetes mellites 
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T2DM 
Type 2 diabetes mellites  
TBL 
total bilirubin level 
TEE 
total energy expenditure 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
THC 
Tetrahydrocannabinol  
TSH 
thyroid-stimulating hormone 
UACR 
urinary albumin/creatinine ratio 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 
 
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10.11. Appendix 11: Country-Specific Requirements  
10.11.1. 
Germany  
This section describes protocol changes applicable for adult participants in study sites in 
Germany. 
This table describes the changes and provides a rationale for the changes. 
Protocol Section Number and 
Name 
Description of the 
Change 
Brief Rationale 
7.2. 
Participant Discontinuation/ 
Withdrawal from the Study 
8.3. 
Adverse Events, Serious 
Adverse Events, and Product 
Complaints 
10.1.3 Informed Consent Process 
10.10. Abbreviations and 
Definitions 
Deleted references to 
“legally authorized 
representative,” “legal 
guardian,” “parents”  
The German Drug Law (Arzneimittelgesetz – 
AMG) requires per Paragraph 40 (1-3) and 
Paragraph 41 (3) that adult participants act 
on their own behalf and provide their own 
written informed consent. If written consent 
is not possible, verbal consent with a witness 
is acceptable. No legal representative consent 
is accepted. 
The revised text in the following subsections show the changes applicable for adult participants 
to study sites in Germany. Additions are identified by underline. Deletions are identified by 
strikethrough format. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
 at any time at the participant’s own request 
 at the request of the participant’s designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
o If the participant becomes pregnant during the study (see Section 8.3.2 for 
additional details) 
 if enrolled in any other clinical study involving an investigational product, or enrolled in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication. In this case, discontinuation from the study occurs prior to introduction 
of the new agent. 
 
 
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8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Section 10.3, Appendix 3: 
 AEs 
 SAEs 
 PCs 
These events will be reported by the participant (or, when appropriate, by a caregiver, or 
surrogate, or the participant's legally authorized representative). 
 
 
 
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10.1.3 
Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or the participant’s legally authorized 
representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets the 
requirements of 21 Code of Federal Regulations 50, local regulations, ICH guidelines, privacy 
and data protection requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
 
 
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10.10. 
Appendix 10: Abbreviations and Definitions 
 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
 
 
 
 
 
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10.12. Appendix 12: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [b]: 30-Sep-2022 
This amendment is considered to be substantial. 
 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the  
● safety or the rights of the study participants, and 
● reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
This amendment includes the addition of a key secondary objective, “Change in AHI”. The 
endpoint for key secondary objective “Change in SBP” and other secondary objective “Change 
in DBP” has been updated to Week 48 from Week 52. Changes have been made to the Schedule 
of Activities to reflect the synchronization of timing of C-SSRS to PHQ-9. 
 
Protocol changes have been made as outlined in the following table. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis  
and  
3. Objectives, Endpoints, and 
Estimands 
 
Key Secondary Objectives: 
Added “Change in AHI” as a 
key secondary objective with 
endpoint “Change in AHI” 
To align with 
recommendations from 
health authority.  
Key Secondary Objectives: 
Moved “change in SBP” to 
“From baseline to Week 48” 
section 
BP will be assessed at Week 
48 because PAP suspension 
at Week 52 may confound 
BP assessment. 
Added footnote a 
“BP will be assessed at Week 48 
because PAP suspension at 
Week 52 may confound BP 
assessment”. 
For additional information. 
1.3. Schedule of Activities 
 
Removed text, “Note: Visit 10 is 
eligible to be conducted 
remotely (that is, by telephone, 
IT-assisted virtual visit, or in 
combination with on-site visit) 
at the direction of the sponsor, 
according to local laws and 
regulations.” 
Vital signs will be measured 
at Week 48, so this visit will 
be on site. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
“Fasting Visit” row: Removed 
text, “If V10 is remote, then the 
visit will not be fasting.” 
This instruction is no longer 
applicable. 
“Weight” row: Removed text, 
“If V10 is remote, then weight 
will not be obtained at the visit.” 
This instruction is no longer 
applicable. 
“Vital signs” row: Removed 
text, “If V10 is remote, vital 
signs will not be obtained at the 
visit.” 
This instruction is no longer 
applicable. 
“Symptom-directed physical 
assessment” row: Removed text, 
“If V10 is remote, then 
symptom-directed physical 
assessment will not be done at 
the visit.” 
This instruction is no longer 
applicable. 
Removed “Schedule Sleep 
Center Study for PSG” and 
“Sleep Center Study for PSG” 
from ED visit.  
Sleep study is not required 
for participants who 
discontinue early.  
“Review Lifestyle Program 
instructions” row: Updated 
comment to “Diet and exercise 
goals established during the 
lifestyle consultation and the 
importance of adherence to the 
lifestyle component of the trial 
will be reinforced at each trial 
contact by study staff.” 
To clarify the requirement. 
“ESS, EQ-5D-5L, FOSQ, and 
PGIS” rows: Updated comment 
“When the PROs are scheduled 
for visits at which the PSG will 
be done, they should be 
completed on the same day as 
PSG and in the following order 
(FOSQ, ESS, PROMIS Short 
Form v1.0 Sleep Disturbance 8b, 
PROMIS Short Form v1.0 
Sleep-related Impairment 8a, 
PGIS, PGIC, SF-36v2 acute 
form, and EQ-5D-5L) before the 
To clarify the requirement. 
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Section # and Name 
Description of Change 
Brief Rationale 
PSG is conducted, and should be 
done at the same time of day for 
each of those visits. Completing 
the PRO assessments on the next 
day after PSG is not considered 
a protocol violation. 
 
“PHQ-9”, “C-SSRS 
screening/baseline”, and “C-
SSRS (since last visit version)” 
rows: added “if both collected 
on the same day” to comments. 
To clarify timing and allow 
further flexibility for AE 
collection independent of 
PHQ-9 and C-SSRS 
assessments. 
“C-SSRS (since last visit 
version)” row: 
Removed assessment from 
Visits 3, 4, 5, 6, 8, 9, 10, and 
801. 
Collection schedule has been 
updated to align with PHQ-9 
assessments. 
“Participant returns all unused 
study intervention” row: 
Removed text, “If V10 is 
remote, participant will return 
any unused study intervention 
dispensed at V9 during the V11 
visit.” 
This instruction is no longer 
applicable. 
“Assess study intervention 
compliance” row: Removed text, 
“If V10 is remote, the next study 
intervention compliance will be 
done at V11.” 
This instruction is no longer 
applicable. 
3. Objectives, Endpoints, and 
Estimands 
Other Secondary Objectives: 
Moved “change in DBP” to 
“From baseline to Week 48” 
section 
BP will be assessed at Week 
48 because PAP suspension 
at Week 52 may confound 
BP assessment. 
5.2. Exclusion Criteria 
Exclusion Criterion 42: Updated 
formatting. 
For clarification. 
Exclusion Criterion 53: 
Removed “(4 months for studies 
conducted in Japan, 3 months 
for studies conducted in the 
United Kingdom). 
This information is no 
longer applicable. 
6.5. Dose Modification 
Modified text, “Dose 
modification is permitted for 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
management of intolerable GI 
symptoms during the first 24 
weeks of the treatment period 
(Section 6.5.1). 
Modified text, “Participants who 
do not tolerate at least 10 mg 
even after the described 
measures, including 1 de-
escalation and re-escalation 
attempt, will be discontinued 
from the study intervention but 
remain in the study for 
continued follow-up.” 
Clarification. 
6.5.1. Management of 
Participants with 
Gastrointestinal Symptoms 
 
Modified text, “For participants 
unable to tolerate any dose 
escalation between 7.5 mg and 
15 mg inclusive, despite the 
above measures, the investigator 
should contact Lilly to consider 
a dose de-escalation step with 
subsequent re-escalation by 2.5 
mg every 4 weeks up to MTD 
will be allowed in a blinded 
fashion, to reach either the 10-
mg or 15-mg dose as described 
below.” 
Direct the investigator to 
contact sponsor to ensure 
that dose modifications are 
completed according to 
protocol. 
Added text “Dose modifications 
after the first 24 weeks of the 
treatment period are not 
permitted. For temporary study 
treatment discontinuation see 
Section 7.1.2.” 
Clarification. 
6.5.1. Management of 
Participants with 
Gastrointestinal Symptoms 
Modified text,  
“Participants who tolerate 
• 
10 mg, but do not 
tolerate 12.5 mg or 15 mg even 
following the above measures, 
including 1 de-escalation and re-
escalation attempt, will continue 
on 10 mg as their MTD dose. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
• 
12.5 mg, but do not 
tolerate 15 mg even after the 
above measures, including 1 de-
escalation and re-escalation 
attempt, will continue on 10 mg 
as their MTD dose.” 
7.1. Discontinuation of Study 
Intervention 
Removed text in clinical 
considerations section, 
“inadvertent enrollment if 
continued treatment with study 
intervention would not be 
medically appropriate”  
 
Participants who do not meet 
enrollment criteria will 
discontinue from the study. 
Added text, “The participant 
should be referred to a MHP for 
further evaluation and care.” 
To provide further detail for 
participant care. 
7.2. Participant 
Discontinuation/Withdrawal 
from the Study 
Added text, “A participant will 
be withdrawn from the study in 
case of inadvertent enrollment” 
Text updated to align with 
relevant edits in Section 7.1. 
8.2.3. Electrocardiograms 
(ECG) 
Modified instructions for timing 
of ECG collection. 
“ECGs should be collected at 
least 30 minutes prior to 
collection of blood samples for 
laboratory testing, including PK 
samples. Participants should be 
supine for at least approximately 
5 to 10 minutes before ECG 
collections and remain supine 
but awake during the ECG 
collection. ECGs may be 
repeated at the investigator’s 
discretion at any visit.” 
Clarification. 
8.3.1.1. Adverse Event 
Monitoring with a 
Systematic Questionnaire 
Added text, “if AE and C-
SSRS/PHQ-9 collections done 
on the same day”. 
To clarify timing and allow 
further flexibility for AE 
collection independent of 
PHQ-9 and C-SSRS 
assessments. 
9.2. Analyses Sets 
FAS and EAS descriptions 
updated to include “excluding 
those discontinuing study due to 
inadvertent enrollment” 
Text revised to reflect 
updated definitions for FAS 
and EAS. 
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Section # and Name 
Description of Change 
Brief Rationale 
Added “(last dose +7 days)” to 
the description of data excluded 
due to the discontinuation of 
study intervention in the EAS 
population. 
Clarification. 
9.3. Statistical Analysis 
Modified text for “hybrid” 
estimand, changed “hybrid” to 
“treatment regimen” throughout 
Section 9.3. 
To keep terminology 
consistent with the literature. 
9.3.1. General 
Considerations 
Modified text, “Efficacy 
analyses will be conducted on 
all participants randomly 
assigned to study intervention 
according to the treatment to 
which the participants are 
assigned and were exposed to at 
least one dose. 
To add details for 
clarification. 
Modified text, “For the 
“efficacy” estimand, the analysis 
will include data collected prior 
to permanent discontinuation of 
study intervention and will be 
conducted using the EAS. 
This was duplicate 
information. 
“Missing Value Imputation” 
information moved and 
modified. 
To reflect that the endpoint 
for SBP is at Week 48 
instead of Week 52 and to 
clarify that no explicit 
imputation will be 
performed for efficacy 
analysis relative to 
“efficacy” estimand. 
 
Moved description of handling 
of missing data for “efficacy” 
estimand earlier in the 
paragraph. 
Clarification. 
9.3.2. Primary Analysis 
 
Deleted text, “There will be 2 
primary analysis methods, each 
tested at the full significance 
level of 0.05” 
This information has been 
moved to the last sentences 
of the primary analysis 
section and key secondary 
analysis section for 
clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Modified text, “Missing values 
will be imputed following 
imputation methods based on the 
strategy to handle intercurrent 
events described in Section 
9.3.1” 
Clarification. 
Added text, “Analysis aligned to 
each estimand will be evaluated 
at the full significance level of 
0.05. 
To substitute the deleted text 
“There will be 2 primary 
analysis methods, each 
tested at the full significance 
level of 0.05”. 
9.3.3. Analysis of Key 
Secondary Endpoints 
 
Updated text, “Analysis of 
change in AHI, percent change 
from baseline in body weight, 
change in SBP, and CRP at the 
52-week visit and change in 
SBP at the 48-week visit will be 
conducted in a manner similar to 
the primary efficacy analyses 
with baseline AHI stratum added 
in the model, and baseline of the 
corresponding variable as a 
covariate. 
To align with changes in 
Section 3. 
Added text, “Analysis of change 
in AHI will not include the 
baseline AHI stratum.” 
Clarification. 
Added text, “Analysis aligned to 
each estimand will be evaluated 
at the full significance level of 
0.05 contingent on reaching 
statistical significance of the 
primary objective.” 
To substitute the deleted text 
“There will be 2 primary 
analysis methods, each 
tested at the full significance 
level of 0.05”. 
10.3.7.1. Hypoglycemia 
Updated text, “Hypoglycemic 
episodes will be recorded in the 
eDiary on a specific CRF and 
should not be recorded as AEs 
unless the event meets serious 
criteria. 
Correction. 
10.3.7.3. Injection-Site 
Reactions 
Modified text, “At the time of 
AE occurrence in the tirzepatide 
group, samples will be collected 
Correction. 
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Section # and Name 
Description of Change 
Brief Rationale 
for measurement of tirzepatide 
ADAs and tirzepatide 
concentration.” 
10.8.5. Vital Sign 
Measurements (Blood 
Pressure and Heart Rate) 
Modified text, “ 
 The participant should sit 
quietly for at least 5 minutes 
before vital signs 
measurements are taken” 
Clarification. 
10.8.6. Electrocardiogram 
Modified text, “ 
 12-lead ECGs should be 
obtained after the participant 
has rested in a supine 
position for at least 5 10 
minutes. 
 Electrocardiograms should 
be collected at least 30 
minutes prior to collection of 
blood samples for laboratory 
testing, including PK 
samples. 
 Electrocardiograms should 
be obtained approximately 1 
minute apart, with all 3 
tracings to be obtained 
within approximately 5 
minutes. Measurements that 
deviate substantially from 
previous readings should be 
repeated immediately.” 
Clarification. One tracing of 
ECG is considered adequate. 
Throughout 
Editorial corrections.  
Minor, therefore not 
described. 
 
 
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Master Protocol I8F-MC-GPIF(c) 
 
120 
 
Amendment a: 10-Feb-2022 
 
Overall Rationale for the Amendment: 
This amendment corrects terminology used in the protocol for intervention-specific appendix 
(ISA), and adds selected clarifications.   
 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
1.1. Synopsis 
1.3. Schedule of Activities 
10.10. Abbreviations and 
Definitions 
Changed “indication-specific 
appendix” to “intervention-
specific appendix.  
Correction. 
1.3. Schedule of Activities 
“Symptom-directed physical 
assessment” row: Clarified 
marks for symptom-directed 
physical assessment during the 
study, and added a clarifying 
statement in notes. 
Clarification.   
Original language could be 
interpreted to mean symptom-
directed physical assessment 
is required at all visits. 
Symptom-directed physical 
assessment from visits 2-11 
and ED will be conducted at 
the discretion of the PI, as 
indicated based on participant 
status and standard of care. 
 
“Participant diary dispensed” 
row: Specified which diaries are 
electronic versus paper. 
Clarification.  
 
“Review Lifestyle Program 
instructions” row: comments 
updated/moved from the 
“Review diet and exercise goals” 
row, which has been deleted. 
Clarification. 
 
“Review diet and exercise goals” 
row: Removed.   
Clarification. This review is 
part of Review Lifestyle 
Program instructions. 
5.2. Exclusion Criteria 
Deleted criterion 48. 
Duplicate criterion 
(Criterion 49). 
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Section # and Name 
Description of Change 
Brief Rationale 
8.1.3.1. Actigraphy 
Modified text, “Participants 
should wear the aActigraphy 
device for 7 consecutive days, 5 
times during the study, per the 
SoA.” 
Clarification. 
8.2.1. Physical 
Examination 
Modified text, “A symptom-
directed physical assessment will 
be performed at visits as 
indicated in the SoA, as 
clinically indicated.” 
Clarification, for consistency 
with changes in the 
“Symptom-directed physical 
assessment” row in the SoA. 
10.8.2. Measuring Weight 
Modified text, “Body weight will 
be measured in fasting state at all 
visits except Visit 1.” 
Clarification. 
Throughout 
Editorial corrections.   
Minor, therefore not 
described. 
 
 
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11. 
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