Clinical trial NCT05176314
Conditions: Healthy
Sponsor: Loxo Oncology, Inc.
Start date: 2022-01-11; Completion date: 2022-04-20
Enrollment: 32 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to determine the effect of pirtobrutinib on the levels of rosuvastatin in the blood stream in healthy participants. This study will also evaluate the safety and tolerability of rosuvastatin when administered in combination with pirtobrutinib in healthy participants. This study will last up to approximately 26 days excluding screening period.

Detailed description:

Arms: arm 1: Participants received study intervention through oral administration as follows:

* Day 1: 20 milligram (mg) rosuvastatin alone
* Day 6: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib
* Days 7 to 12: Once daily (QD) doses of 200 mg pirtobrutinib alone
* Day 13: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib
* Days 14 to 17: QD doses of 200 mg pirtobrutinib alone.
Interventions: intervention 1: Rosuvastatin intervention 2: Pirtobrutinib
Intervention descriptions: intervention 1: Administered Orally. intervention 2: Administered Orally.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Protocol: J2N-MC-JZNW (a) 
 
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single 
and Multiple Doses of Pirtobrutinib on the Pharmacokinetics of Rosuvastatin in 
Healthy Participants 
 
NCT05176314 
 
Approval Date: 22-Dec-2021 
 


CONFIDENTIAL
Protocol number J2N-MC-JZNW (a)
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 pirtobrutinib (LY3527727), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title:
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single and Multiple 
Doses of Pirtobrutinib on the Pharmacokinetics of Rosuvastatin in Healthy Participants
Protocol Number: J2N-MC-JZNW
Amendment Number: (a)
Compound: Pirtobrutinib (LY3527727)
Brief Title: 
A drug interaction study investigating the effect of pirtobrutinib on the pharmacokinetics of 
rosuvastatin. 
Study Phase: 1 
Sponsor Name: Eli Lilly and Company on behalf of Loxo Onocolgy, Inc., a wholly owned
subsidiary of Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana 46285, USA
Regulatory Agency Identifier Number(s)
IND: 139876
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 22-Dec-2021 GMT


CONFIDENTIAL
Protocol number J2N-MC-JZNW (a)
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Medical Monitor Name and Contact Information will be provided separately.


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Protocol number J2N-MC-JZNW (a)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
22-Oct-2021
Amendment (a)
This amendment is considered to be non-substantial.
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
1.3. Schedule of 
Activities (SoA)
Added footnote ‘g’ describing the 
allowed sampling windows for 
pirtobrutinib and rosuvastatin PK. 
To provide clarification to the 
site and for consistency with the 
database. 
4.1. Overall Design
Removed ‘single-site’ from the 
description of the study.
A second site has been added to 
conduct the study and therefore 
‘single-site’ no longer applies. 
5.2. Exclusion Criteria
Updated exclusion criterion #19 
to clarify that participants must be 
willing to stop alcohol 
consumption for 48 hours (rather 
than 24 hours) prior to admission.
Minor change to clarify an 
inconsistency in the original 
protocol.
6.1.1. Administration 
Details
Added language to instruct that 
pirtobrutinib be dosed at the same 
time as rosuvastatin or no more 
than 15 minutes beforehand.
To provide clarification to the 
site.


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Protocol number J2N-MC-JZNW (a)
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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.........................................................................................................................9
1.3.
Schedule of Activities (SoA) ......................................................................................10
2.
Introduction..............................................................................................................13
2.1.
Study Rationale ..........................................................................................................13
2.2.
Background ................................................................................................................13
2.3.
Benefit/Risk Assessment ............................................................................................14
3.
Objectives and Endpoints.........................................................................................16
4.
Study Design .............................................................................................................17
4.1.
Overall Design............................................................................................................17
4.2.
Scientific Rationale for Study Design .........................................................................17
4.3.
Justification for Dose..................................................................................................18
4.4.
End of Study Definition..............................................................................................18
5.
Study Population ......................................................................................................19
5.1.
Inclusion Criteria........................................................................................................19
5.2.
Exclusion Criteria.......................................................................................................20
5.2.1.
Rationale for Exclusion of Certain Study Participants.................................................21
5.3.
Lifestyle Considerations .............................................................................................22
5.3.1.
Meals and Dietary Restrictions ...................................................................................22
5.3.2.
Substance Use: Caffeine, Alcohol, and Tobacco .........................................................22
5.3.3.
Activity ......................................................................................................................22
5.4.
Screen Failures...........................................................................................................22
6.
Study Interventions and Concomitant Therapy......................................................23
6.1.
Study Interventions Administered...............................................................................23
6.1.1.
Administration Details................................................................................................23
6.2.
Preparation, Handling, Storage, and Accountability....................................................23
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................24
6.4.
Study Intervention Compliance...................................................................................24
6.5.
Dose Modification......................................................................................................24
6.6.
Continued Access to Study Intervention after the End of the 
Study..........................................................................................................................24
6.7.
Treatment of Overdose ...............................................................................................24
6.8.
Concomitant Therapy .................................................................................................25
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................26
7.1.
Discontinuation of Study Intervention ........................................................................26
7.1.1.
Hepatic Criteria for Discontinuation ...........................................................................26
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................26
7.3.
Lost to Follow-Up ......................................................................................................27
8.
Study Assessments and Procedures .........................................................................28
8.1.
Efficacy Assessments .................................................................................................28


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Protocol number J2N-MC-JZNW (a)
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8.2.
Safety Assessments ....................................................................................................28
8.2.1.
Physical Examinations................................................................................................28
8.2.2.
Height and Weight......................................................................................................29
8.2.3.
Vital Signs..................................................................................................................29
8.2.4.
Electrocardiograms.....................................................................................................29
8.2.5.
Clinical Laboratory Tests............................................................................................29
8.2.6.
Pregnancy Testing ......................................................................................................30
8.2.7.
Safety Monitoring.......................................................................................................30
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................32
8.3.1.
Timing and Mechanism for Collecting Events ............................................................33
8.3.2.
Pregnancy...................................................................................................................34
8.4.
Pharmacokinetics........................................................................................................35
8.4.1.
Bioanalysis .................................................................................................................35
8.5.
Pharmacodynamics.....................................................................................................35
8.6.
Genetics .....................................................................................................................35
8.7.
Biomarkers.................................................................................................................35
8.8.
Immunogenicity Assessments.....................................................................................35
8.9.
Health Economics.......................................................................................................35
9.
Statistical Considerations.........................................................................................36
9.1.
Statistical Hypotheses.................................................................................................36
9.2.
Analyses Sets .............................................................................................................36
9.2.1.
Study Participant Disposition......................................................................................36
9.2.2.
Study Participant Characteristics.................................................................................36
9.3.
Statistical Analyses.....................................................................................................36
9.3.1.
Pharmacokinetic Analyses ..........................................................................................37
9.3.2.
Safety Analyses ..........................................................................................................37
9.4.
Interim Analysis .........................................................................................................38
9.5.
Sample Size Determination.........................................................................................38
10.
Supporting Documentation and Operational Considerations ................................39
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................39
10.1.1.
Regulatory and Ethical Considerations........................................................................39
10.1.2.
Informed Consent Process ..........................................................................................39
10.1.3.
Data Protection...........................................................................................................40
10.1.4.
Dissemination of Clinical Study Data .........................................................................40
10.1.5.
Data Quality Assurance ..............................................................................................41
10.1.6.
Source Documents......................................................................................................42
10.1.7.
Study and Site Start and Closure.................................................................................42
10.1.8.
Publication Policy.......................................................................................................43
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................44
10.2.1.
Blood Sampling Summary..........................................................................................46
10.3.
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting .......................................................................................................47
10.3.1.
Definition of Adverse Event .......................................................................................47


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Protocol number J2N-MC-JZNW (a)
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10.3.2.
Definition of Serious Adverse Event...........................................................................48
10.3.3.
Definition of Product Complaints ...............................................................................49
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................49
10.3.5.
Reporting of Serious Adverse Events..........................................................................51
10.3.6.
Regulatory Reporting Requirements ...........................................................................51
10.4.
Appendix 4: Contraceptive and Barrier Guidance .......................................................53
10.4.1.
Definitions..................................................................................................................53
10.4.2.
Contraception Guidance..............................................................................................53
10.4.3.
Contraception Methods...............................................................................................54
10.5.
Appendix 5: Genetics .................................................................................................56
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................57
10.7.
Appendix 7: Abbreviations .........................................................................................59
11.
References.................................................................................................................61


CONFIDENTIAL
Protocol number J2N-MC-JZNW (a)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title:
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single and Multiple 
Doses of Pirtobrutinib on the Pharmacokinetics of Rosuvastatin in Healthy Participants
Brief Title:
A drug interaction study investigating the effect of pirtobrutinib on the pharmacokinetics of 
rosuvastatin.
Rationale:
The breast cancer resistance protein (BCRP) is a membrane-bound transporter located in the 
gastrointestinal tract, liver, kidney, brain endothelium, mammary tissue, testis, and placenta, 
responsible for exporting a wide range of substrates across biological membranes. Certain 
substrates of BCRP have been shown to have clinically significant drug interactions when 
administered with inhibitors of BCRP. 
Rosuvastatin is a commonly used index substrate for BCRP (FDA, 2021). Pirtobrutinib is an 
inhibitor of BCRP in vitro. Therefore, this study aims to investigate a potential drug-drug 
interaction by evaluating the pharmacokinetics (PK), safety, and tolerability of rosuvastatin in 
the presence of pirtobrutinib.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the effect of single and 
multiple doses of pirtobrutinib on 
BCRP activity in healthy participants

Cmax and AUC(0-∞) of rosuvastatin
Secondary

To evaluate the safety and tolerability 
of rosuvastatin in combination with 
pirtobrutinib in healthy participants. 

Incidence of TEAEs and SAEs
Abbreviations: AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; 
BCRP = breast cancer resistance protein; Cmax = maximum observed drug concentration; SAE = serious adverse 
event; TEAE = treatment-emergent adverse event.  


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Protocol number J2N-MC-JZNW (a)
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Overall Design
Brief Summary:
Study J2N-MC-JZNW (JZNW) is a Phase 1, open-label, drug interaction study evaluating the 
effect of single and multiple doses of pirtobrutinib on the PK, safety, and tolerability of 
rosuvastatin. 
Number of Participants:
Approximately 36 participants will be enrolled to ensure that at least 28 evaluable participants 
complete the study.
Intervention Groups and Duration:
All participants will be screened within 42 days prior to enrollment. Eligible participants will be 
admitted to the clinical research unit (CRU) on Day -1 and remain resident in the CRU until 
discharge on Day 18. A follow-up visit will be performed 7 (± 2) days after the last dose of study 
intervention. 
Participants will receive the following study intervention while resident in the CRU:

Day 1: 20 mg rosuvastatin alone

Day 6: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib

Days 7 to 12: once daily (QD) doses of 200 mg pirtobrutinib alone 

Day 13: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib

Days 14 to 17: QD doses of 200 mg pirtobrutinib alone.
Data Monitoring Committee: No


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Protocol number J2N-MC-JZNW (a)
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1.2.
Schema
Abbreviations: CRU = clinical research unit; QD = once daily. 


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Protocol number J2N-MC-JZNW (a)
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1.3.
Schedule of Activities (SoA)
Study Procedure
Screening
(D-42 to -2)
Treatment Period (Study Days)
FU/
EDb
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18a
24
(± 2
days)
Informed consent
X
Admission to 
CRU
X
Discharge from 
CRU
X
Outpatient visit
X
X
Medical history 
and demographics
X
Participant 
eligibility
X
X
Rosuvastatin
administration
X
X
X
Pirtobrutinib 
administration
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
Pregnancy testc
X
X
X
Urine drug screen 
(including 
cotinine)
X
X
Ethanol test
X
Supine vital signs 
(PR and BP)d
X
P, 2 h
24 
h
P, 2 h
24 
h
P, 2 h
24 
h
X
X
Oral body 
temperature
X


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Protocol number J2N-MC-JZNW (a)
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Study Procedure
Screening
(D-42 to -2)
Treatment Period (Study Days)
FU/
EDb
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18a
24
(± 2
days)
12-lead ECG
X
P
X
P
X
P
X
X
X
Clinical 
laboratory tests
X
P
X
P
X
P
X
X
X
Physical 
examinatione
X
X
X
Genetic blood 
sample for 
screening
X
Rosuvastatin PK 
samplesg
P, 0.5, 
1, 1.5, 
2, 2.5, 
3, 4, 5, 
6, 8, 
12 h
24 
h
48 
h
72 
h
96 
h
Pf, 0.5, 
1, 1.5, 
2, 2.5, 
3, 4, 5, 
6, 8, 
12 h
24 
h
48 
h
72 
h
96 
h
120 
h
P, 0.5, 
1, 1.5, 
2, 2.5, 
3, 4, 5, 
6, 8, 
12 h
24 
h
48 
h
72 
h
96 
h
120 
h
Adverse event 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI
CCI


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Protocol number J2N-MC-JZNW (a)
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Abbreviations: BP = blood pressure; CRU = clinical research unit; D = day; ECG = electrocardiogram; ED = early discontinuation; FU = follow-up; h = hours 
postdose; P = predose; PK = pharmacokinetic(s); PR = pulse rate.  
a
Participants will be discharged from the CRU on Day 18 once all study procedures are completed. 
b
Participants will attend an outpatient follow-up visit 7 (± 2) days after the final dose of study intervention. If participants are not able to attend the CRU for 
this visit, the CRU should contact the participant via phone call to conduct adverse event and concomitant medication review. If applicable, ED assessments 
should be performed on the day of discontinuation (or as close to it as possible).
c
Female participants only. Serum pregnancy test at screening and urine pregnancy test at all other times.
e
Complete physical examination at check-in, discharge from CRU, and follow-up. Additional symptom-driven physical examinations may be performed at the 
discretion of the investigator. 
CCI
CCI


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Protocol number J2N-MC-JZNW (a)
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2.
Introduction
2.1.
Study Rationale
The breast cancer resistance protein (BCRP) is a membrane-bound transporter located in the 
gastrointestinal tract, liver, kidney, brain endothelium, mammary tissue, testis, and placenta, 
responsible for exporting a wide range of substrates across biological membranes. Certain 
substrates of BCRP have been shown to have clinically significant drug interactions when 
administered with inhibitors of BCRP (International Transporter Consortium et al. 2010). 
Rosuvastatin is a commonly used index substrate for BCRP (FDA, 2021). Pirtobrutinib is an 
inhibitor of BCRP in vitro, with a half maximal inhibitory concentration of 18 µM. Therefore, 
this study aims to investigate a potential drug-drug interaction (DDI) by evaluating the 
pharmacokinetics (PK), safety, and tolerability of rosuvastatin in the presence of pirtobrutinib.
2.2.
Background
Pirtobrutinib is a selective inhibitor of the Bruton’s tyrosine kinase (BTK). BTK is a key 
component of the B-cell receptor signaling complex and plays a critical role in the proliferation 
and survival of diverse B cell malignancies. Pirtobrutinib is a small molecule designed to block 
the adenosine triphosphate binding site of the BTK kinase competitively.
Pirtobrutinib is currently being studied in an ongoing first-in-human study (LOXO-BTK-18001),
in patients with previously treated chronic lymphocytic leukemia/small lymphocytic leukemia, or
non-Hodgkin’s lymphoma. Pirtobrutinib is also being studied in three Phase 3 studies in patients 
with hematological malignancies. In addition, pirtobrutinib has been investigated in twelve 
Phase 1 studies in healthy participants and participants with renal impairment. One of these 
studies in participants with hepatic impairment and matched healthy controls is ongoing. 
As of a data cutoff date of September 27, 2020, safety data were available from a total of 
324 patients treated in Study LOXO-BTK-18001, with monotherapy doses ranging from 
25 to 300 mg once daily (QD).
From the available safety data across the 324 patients in the first-in-human study 
(LOXO-BTK-18001):

the treatment-emergent adverse events (TEAEs) reported in ≥10% of patients were
o
fatigue (20.1% total, 8.3% considered related to study drug) 
o
diarrhea (17.0% total, 8.6% considered related to study drug) 
o
contusion (13.0% total, 9.0% considered related to study drug). 

TEAEs considered related to study drug were reported in 156 of 324 patients (48.1%) 

TEAEs of severity Grade 3 or 4 were reported in 87 of 324 patients (26.9%), with 
41 (12.7%) of these Grade 3 or 4 TEAEs reported as related to study drug

On-study death (death within 28 days of the last dose of study drug) due to a Grade 5 
(fatal) adverse event (AE) was reported in 4 of 324 patients (1.2%)


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Protocol number J2N-MC-JZNW (a)
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
One Grade 5 AE, Enterococcus faecium-related septic shock, was considered related to 
study drug. All other Grade 5 AEs were considered to be not related to study drug; these 
included pneumonia fungal, shock, and pleural effusion.
Across the Phase 1 studies, pirtobrutinib has been administered to a total of 184 healthy 
participants (at the time of this protocol’s development) at single doses from 200 to 900 mg and 
multiple doses of 200 mg for a maximum of 14 days. 
From the available safety data in Phase 1 studies, treatment-related TEAEs have been reported in 
30 (16%) healthy participants. The most frequently reported treatment-related TEAEs were 
petechiae and headache. The majority of treatment-related TEAEs were Grade 1 (mild) in 
severity and all AEs had resolved by the end of study. 
As part of each clinical study conducted in patients or healthy participants, electrocardiogram 
(ECG) and vital signs are performed at intervals specified by the protocol. For study 
LOXO-BTK-18001 conducted in patients, no clinically significant findings of corrected QT 
interval (QTc) prolongation have been identified in the 330 patients as of September 27, 2020. In 
addition, there have been no clinically significant abnormal findings in vital signs and ECG data 
in the studies investigating pirtobrutinib conducted in healthy participants to date. 
Preliminary data after oral administration of single doses of pirtobrutinib ranging from 25 to 
300 mg QD suggest the median time to maximum drug concentration (tmax) is approximately 
2 hours, the terminal half-life (t1/2) is approximately 20 hours, and the PK is dose proportional.
2.3.
Benefit/Risk Assessment
The 200 mg QD dose of pirtobrutinib administered in this study is not anticipated to induce any 
potential risk to participants as the dose does not exceed the highest dose safely administered in
the clinical studies in patients or healthy participants. This dose and dosing regimen were
selected as they represent the recommended phase 2 dose (RP2D) based on the PK, safety, and 
antitumor activity observed in the Phase 1/2 study (Study LOXO-BTK-18001). In patients, 
pirtobrutinib has demonstrated a safe and tolerable profile across all doses tested (25 to 300 mg 
QD). No dose-limiting toxicities occurred in Study LOXO-BTK-18001, and no maximum 
tolerated dose was identified. No clinically significant safety or tolerability concerns have been 
identified in healthy participants to date for pirtobrutinib up to the highest single dose of 900 mg 
and multiple doses of 200 mg for up to 14 days. 
There is no anticipated therapeutic benefit for the participants in this study. However, 
participants may benefit from the screening procedures (through detection of unknown health 
issues) even if they receive no therapeutic benefit from the study.
More detailed information about the known and expected benefits and risks of pirtobrutinib may 
be found in the Investigator’s Brochure.
Rosuvastatin is a commonly used drug in DDI studies and the dosing regimen in the current 
study (20 mg) is consistent with the prescribing recommendations. The most frequent (≥2%) 
adverse reactions following rosuvastatin dosing are headache, myalgia, abdominal pain, asthenia, 
and nausea. Cases of myopathy and rhabdomyolysis have been reported with rosuvastatin. These 
risks can occur at any dose level, but are increased at the highest dose of 40 mg. The incidence of 
rhabdomyolysis is 0.3 to 13.5 cases per 1,000,000 (Mendes et al. 2014). During the current 


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Protocol number J2N-MC-JZNW (a)
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study, participants should promptly report any unexplained muscle pain, tenderness, or 
weakness. Elevations in liver enzymes (alanine aminotransferase [ALT] and aspartate 
aminotransferase [AST]) have been reported following rosuvastatin dosing. In most cases, the 
elevations were transient and resolved or improved on continued dosing or after brief 
interruption of dosing. In the current study, blood samples to determine liver enzymes (as part of 
clinical laboratory tests) will be collected prior to each dosing occasion of rosuvastatin.
More detailed information about the known and expected benefits and risk of rosuvastatin may 
be found in the prescribing information (Crestor® Prescribing Information, 2020). 


CONFIDENTIAL
Protocol number J2N-MC-JZNW (a)
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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the effect of single and 
multiple doses of pirtobrutinib on BCRP 
activity in healthy participants

Cmax and AUC(0-∞) of 
rosuvastatin
Secondary

To evaluate the safety and tolerability of 
rosuvastatin in combination with 
pirtobrutinib in healthy participants 

Incidence of TEAEs and SAEs
Abbreviations: AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; 
BCRP = breast cancer resistance protein; Cmax = maximum observed drug concentration; SAE = serious adverse 
event; TEAE = treatment-emergent adverse event. 


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Protocol number J2N-MC-JZNW (a)
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4.
Study Design
4.1.
Overall Design
Study J2N-MC-JZNW is a Phase 1, fixed sequence, open-label study in healthy participants that 
will investigate the effect of single and multiple doses of pirtobrutinib on the PK of rosuvastatin. 
The schema in Section 1.2 illustrates the study design.
Approximately 36 participants will be enrolled to ensure that at least 28 evaluable participants 
complete the study. 
Screening
All participants will be screened for study inclusion within 42 days prior to enrollment (Day 1).
Screening should not occur less than 14 days prior to enrollment (Day 1), in order to allow 
sufficient time to receive genotyping results. 
Treatment and Assessment Period
Participants will check in to the clinical research unit (CRU) on Day -1 and remain resident until 
discharge on Day 18. 
While resident at the CRU, all participants will receive study intervention as follows:

Day 1: 20 mg rosuvastatin alone

Day 6: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib

Days 7 to 12: QD doses of 200 mg pirtobrutinib alone 

Day 13: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib

Days 14 to 17: QD doses of 200 mg pirtobrutinib alone.
PK blood sampling and safety assessments, including vital signs measurements, physical 
examinations, clinical laboratory tests, ECGs, and AE recording, will be performed according to 
the Schedule of Activities (SoA; Section 1.3).
Participants will be discharged from the CRU on Day 18 following completion of study
procedures, provided they are deemed medically fit by the investigator or designee.
Follow-Up
Participants will attend an outpatient follow-up visit 7 (± 2) days after the final dose of study 
intervention. If participants are not able to attend the CRU for this visit, the CRU should contact 
the participant via phone call to conduct AE and concomitant medication review.
4.2.
Scientific Rationale for Study Design
In order to allow each subject to act as their own control for safety and PK comparisons, a fixed 
sequence design has been selected. 
This study will be open label as the study primary endpoint PK measures are objective rather 
than subjective.


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Protocol number J2N-MC-JZNW (a)
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Based on the t1/2 of rosuvastatin (19 hours; Crestor® Prescribing Information, 2020), a period of 
4 to 5 days between rosuvastatin doses is considered sufficient time for the study intervention to 
washout. Based on the PK profile of pirtobrutinib, QD dosing for 7 days is considered sufficient 
time for pirtobrutinib to reach steady state. 
The PK of rosuvastatin will be evaluated after a single pirtobrutinib dose on Day 6 to assess the 
effect on intestinal BCRP and after multiple pirtobrutinib doses on Day 13 to assess the effect on 
systemic BCRP. 
Conducting the study in healthy participants mitigates the potential confounding effects of the
disease state, other medical conditions, and concomitant medications in patients.
4.3.
Justification for Dose
Pirtobrutinib 200 mg QD is the chosen recommended Phase 2 dose for the ongoing global 
Phase 1/2 first-in-human study (LOXO-BTK-18001) in patients previously treated for chronic 
lymphocytic leukemia/small lymphocytic leukemia or non-Hodgkin’s lymphoma. Previous 
clinical data in healthy participants demonstrate that pirtobrutinib is safe and well tolerated at 
doses of 200 mg QD with no dose-limiting toxicities identified in humans. 
Rosuvastatin is a commonly used drug in DDI studies. The dosing regimen of rosuvastatin
(20 mg) in the current study is consistent with the prescribing recommendations. 
4.4.
End of Study Definition
The end of the study is defined as the date of the last scheduled procedure shown in the SoA
(Section 1.3) for the last participant in the study.
A participant is considered to have completed the study if the participant has completed the 
treatment period of the study and follow-up procedures as shown in the SoA (Section 1.3).


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Protocol number J2N-MC-JZNW (a)
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5.
Study Population
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, vital signs, clinical laboratory tests, and ECG, and physical examination at 
check-in (Day -1). The nature of any conditions present at the time of the physical examination 
and any pre-existing conditions will be documented.
Screening may occur up to 42 days prior to enrollment. Eligible participants who are not enrolled 
within 42 days of screening may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. In such instances, repeat the following tests and 
procedures: weight, vital signs, ECG, clinical laboratory tests, physical examination, and 
pregnancy test (females only). Any other procedures may be repeated at the discretion of the 
investigator.
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only, unless otherwise specified, and not continuously throughout the study.
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:
Participant Characteristics
1. Are males, or females not of childbearing potential
a.
Reproductive definitions and contraception requirements are provided in 
Appendix 4 (Section 10.4).
2. Are between 18 and 64 years of age inclusive, at the time of signing the informed 
consent.
3. Have a body mass index of 18.0 to 32.0 kg/m2 (inclusive) and a body weight of at least 
50 kg.
4. Are overtly healthy as determined by medical evaluation including medical history,
physical examination (at check-in/Day -1), vital signs, and ECG. 
5. Have clinical laboratory test results within normal reference range for the population or 
investigative site, or results with acceptable deviations that are judged to be not clinically 
significant by the investigator, except for the following parameters which must be within 
the specified ranges:
a.
ALT and AST ≤1.5 × upper limit of normal (ULN)
b. Total bilirubin (TBL) ≤1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if 
TBL is fractionated and direct bilirubin is <35%). 
6. Have venous access sufficient to allow for blood sampling as per protocol. 


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Protocol number J2N-MC-JZNW (a)
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Informed Consent
7. 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 informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have known allergies to pirtobrutinib or rosuvastatin, related compounds, or any 
components of the formulation.
2. Have an abnormal blood pressure and/or pulse rate, deemed to be clinically significant by 
the investigator.
3. Have a significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, neurological, or psychiatric disorder or 
surgery (including cholecystectomy) capable of significantly altering the absorption, 
metabolism, or elimination of drugs; of constituting a risk when taking the investigational 
product; or of interfering with the interpretation of data.
a.
Note: history of uncomplicated appendectomy will be allowed.
4. Have had lymphoma, leukemia, or any malignancy within the past 5 years except for 
basal cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years.
Prior/Concomitant Therapy
5. Have used or intend to use prescription or nonprescription medication (including dietary 
supplements, vitamins, and/or herbal medications), or modulators of CYP3A4 or BCRP
within 7 days prior to dosing, unless, in the opinion of the investigator and sponsor, the 
medication will not interfere with the study.
6. Vaccination with live vaccines within 28 days prior to screening, or plans to receive such 
vaccines during the study.
a.
Note: use of non-live (inactivated) vaccinations will be allowed.
Prior/Concurrent Clinical Study Experience
7. 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.
8. Have participated, within the last 30 days, in a clinical study involving an investigational 
product. If the previous investigational product has a long half-life, 5 half-lives or 
30 days (whichever is longer) should have passed.
9. Have previously completed or withdrawn from this study or any other study investigating 
pirtobrutinib (also known as LOXO-305).


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Protocol number J2N-MC-JZNW (a)
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Diagnostic Assessments
10. Show evidence of human immunodeficiency virus (HIV) infection and/or positive human 
HIV antibodies.
11. Show evidence of hepatitis C and/or positive hepatitis C antibody.
12. Show evidence of hepatitis B and/or positive hepatitis B surface antigen.
Other Exclusions
13. Have c.34AA, c.421AA, or c.34GA/421CA genotypes of ABCG2 as determined through 
genotyping.
14. Have c.521TC and c/521CC genotypes of SLCO1B1 as determined by genotyping. 
15. Are females who are lactating or have a positive pregnancy test.
16. Regularly use known drugs of abuse or show positive findings on drug screening.
17. Have donated blood of more than 500 mL within the previous 3 months of study 
screening.
18. Have an average weekly alcohol intake that exceeds 21 units per week (males) and 
14 units per week (females). If calculation of units is required, use the following
equation: Number of units = [total volume of drink (mL) × ABV (%)]/1000, where ABV 
is alcohol by volume.
19. Are unwilling to stop alcohol consumption 48 hours prior to admission and while resident 
at the CRU.  
20. Use of tobacco- or nicotine-containing products within 1 month prior to check-in, or 
positive cotinine test at screening or check-in.
21. Are investigative site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, biological or legal guardian, child, or 
sibling.
22. Are Lilly or Labcorp employees.
23. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study.  
5.2.1.
Rationale for Exclusion of Certain Study Participants
The human BCRP transporter (also known as ABCG2) is polymorphic. Participants with the 
c.34AA, c.421AA, and c.34GA/421CA genotypes will be excluded because these genetic 
polymorphisms are associated with impaired BCRP activity (Furukawa et al. 2009, Wan et al. 
2015, Keskitalo et al. 2009). Because the activity of BCRP is impaired with these participants, it 
would be anticipated that even complete inhibition of BCRP would not result in a substantial 
change in rosuvastatin exposure. Accordingly, excluding participants with these polymorphisms 
will ensure that the “worst-case” interaction between pirtobrutinib and rosuvastatin will be 
evaluated in this study.
The human OATP1B1 transporter (also known as SLCO1B1) is also polymorphic. In order to 
evaluate worst-case interactions between pirtobrutinib and rosuvastatin, participants with the 
c.521TC and c/521CC genotypes will be excluded from this study because this genetic 
polymorphism is associated with decreased transporting activity of OATP1B1 (Niemi et al. 
2011) and higher plasma rosuvastatin concentrations (Crestor® Prescribing Information, 2020).  


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Protocol number J2N-MC-JZNW (a)
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5.3.
Lifestyle Considerations
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.
5.3.1.
Meals and Dietary Restrictions
While resident in the CRU, participants will consume only food and beverages that are provided 
to them by the CRU staff. Standard meals (breakfast, lunch, dinner, and snack) will be provided 
to the participants while resident at the CRU.
Rosuvastatin and pirtobrutinib will be administered after an overnight fast of at least 8 hours on 
Days 1, 6, and 13. On these days, participants will remain fasted for approximately 4 hours 
postdose, at which time a meal will be served. Water is permitted ad libitum during the fasting 
period, except for 1 hour before and after dose administration (other than the water provided 
during dosing). On all other dosing days (i.e., pirtobrutinib alone on Days 7 to 12 and 14 to 17), 
there are no fasting requirements for dosing.
Participants will refrain from consumption of grapefruit or grapefruit juice from 7 days before 
the start of study intervention until after the final PK sample collection.
5.3.2.
Substance Use: Caffeine, Alcohol, and Tobacco
Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, 
tea, cola drinks, and chocolate) for 48 hours prior to check-in until discharge from the CRU. 
Participants will abstain from alcohol for 48 hours prior to check-in until discharge from the 
CRU.
Participants will not be permitted to use tobacco- or nicotine-containing products within 1 month 
prior to check-in until the follow-up visit. 
5.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during the 
study (e.g., watching television, reading).
5.4.
Screen Failures
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled in the study.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. There must be at least 2 weeks between the screen failure and the new screening.
Rescreened participants should be assigned a new participant number for the rescreening event. 
If applicable, participants may be re-tested up to 1 time at the discretion of the investigator (e.g., 
abnormal laboratory result) before being deemed a screen failure.
Eligible participants who are not enrolled within 42 days of screening may undergo an additional 
medical assessment and/or clinical measurements to confirm their eligibility; see Section 5 for a 
list of required assessments in these cases.


C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2 N-M C -J Z N W (a)
2 3
6.
St u d y I nter ve nti o n s a n d C o nc o mit a nt T her a p y
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s) or mar kete d pr o d uct(s), 
i nte n de d t o be a d mi nistere d t o / use d b y a st u d y partici pa nt acc or di n g t o t he st u d y pr ot oc ol .
6. 1.
St u d y I nter ve nti o ns A d mi nistere d
T his st u d y  in v o l ves t he c o m paris o n of r os u vastati n a d mi nistere d al o ne a n d r os u vastati n 
c o -a d mi nistere d wit h pirt o br uti ni b. Ta ble J Z N W. 1 s h o ws t he st u d y int er ve ntio ns t o be 
a d mi nistere d. 
T a ble J Z N W . 1
St u d y I nter ve nti o ns A d mi nistere d
St u d y I nter ve nti o n
R os u vastati n 
Pirt o br uti ni b
D os a ge F or m ul ati o n
Ta blet
Ta blet
U nit D ose Stre n gt h/ D os a ge Le vel
2 ×
1 0- m g ta blets 
( 2 0-m g d ose)
2 ×
1 0 0- m g ta blets
( 20 0- m g d ose)
R o ute of A d mi nistr ati o n
Oral
Oral
D osi n g I nstr ucti o ns
2 ta blets a d mi nistere d al o ne o n 
Da y 1 a n d wit h pirt o br uti ni b o n 
Da ys 6 a n d 1 3 
2 ta blets a d mi nistere d wit h 
r os u vastati n o n Da ys 6 a n d 1 3, a n d 
al o ne on D a ys 7 t o 1 2 a n d 1 4 t o 1 7
6. 1. 1.
A d mi nistr ati o n Det ails
Eac h d ose of r os u vastati n a n d pirt o br uti ni b will be a d mi nistere d orall y wi t h a p pr o xi matel y 
2 4 0 m L of r o o m te m perat ure water i n t he m or ni n g of eac h d osi n g da y (see Secti on 1. 3 ) i n a 
sitti n g p ositio n. W he n r os u vastati n a n d pirt o br uti ni b are a d mini stered c o nc urre ntl y, 2 4 0 m L of 
r o o m t e mperat ure water will be use d f or all ta blets a n d p irt o br uti ni b s h o ul d be a d mi nister e d at 
t he sa me ti me as r os u vastati n or n o m ore t ha n 1 5 mi n utes pri or t o r os u vastati n. If re q uire d t o 
c o mplete d osi n g, a d dit i onal water m a y be gi ve n i n 5 0 m L ali q u ots a n d will be rec or de d i n t he 
s o urce b ut will n ot be c o nsi dere d as a pr ot oc ol de viati on.
Par ticipa nts will n ot be all o we d t o lie s u pi ne f or 2 h o urs after d osi n g, u nless cli nicall y i n dicate d 
or f or st u d y  pr oce d ures.
D oses of  r os u vastatin a n d pi rt o br utini b o n Da ys 1, 6, a n d 1 3 will be a d mi nistere d after a n 
o ver ni g ht fast of at least 8 h o urs a n d par tici pa nts will re mai n fasti n g f or a p pr o xi matel y 4 h o urs 
p ost d ose. Water is per mitte d a d li bit u m d uri n g t he fast i n g p eri o d , e xce pt f or 1 ho ur bef ore a n d 
after d ose a d mi nistrati o n. O n all ot her d osi n g da ys (i.e., pirt o br uti ni b al o ne o n Da ys 7 t o 1 2 a n d 
1 4 t o 1 7), t here are n o fast i n g re q uire me nts f or d osi n g.
6. 2.
Pre p ar ati o n , H a n dli n g , St or a ge , a n d Acc o u nt a bilit y
1.
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  int er ve nt i on recei ve d a n d a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y int er ve nt i on.


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Protocol number J2N-MC-JZNW (a)
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2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel.
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records).
4. The investigator or designee will return all unused study intervention to Lilly or its 
designee at the end of the study. Note: In some cases, sites may destroy the material if, 
during the investigative site selection, the evaluator has verified and documented that the 
site has appropriate facilities and written procedures to dispose of clinical materials.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a non-randomized, open-label study. 
6.4.
Study Intervention Compliance
Participants will be dosed at the CRU and they will be administered study intervention under 
medical supervision by the investigator or designee. The dose of study intervention and study 
participant identification will be confirmed prior to the time of dosing. The date and time of each 
dose administered will be recorded in the source documents and in the case report form (CRF).  
Study site personnel will examine each participant’s mouth to ensure that the study intervention 
was ingested.
6.5.
Dose Modification
Dose modification is not permitted in this study.
6.6.
Continued Access to Study Intervention after the End of the Study
Pirtobrutinib or rosuvastatin will not be made available to participants after completion of the 
study.
6.7.
Treatment of Overdose
For this study, any dose of pirtobrutinib greater than 200 mg or rosuvastatin greater than 20 mg
within a calendar day will be considered an overdose.
The sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:

Contact the Lilly clinical pharmacologist (CP) immediately.

Closely monitor the participant for any AE/serious adverse event (SAE) and laboratory 
abnormalities 

Obtain a plasma sample for PK analysis if requested by the Lilly CP (determined on a 
case-by-case basis).


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
Document the quantity of the excess dose in the CRF.
6.8.
Concomitant Therapy
Any medication or vaccine (including prescription or nonprescription medication, dietary 
supplements, vitamins, and/or herbal medications) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency for concomitant therapy of special 
interest.
The Lilly CP should be contacted if there are any questions regarding concomitant or prior 
therapy.
Participants must abstain from taking prescription or nonprescription drugs (including dietary 
supplements, vitamins, and/or herbal medications), or modulators of CYP3A4 or BCRP within 
7 days prior to dosing until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study.
Participants will not have received a live vaccine within 28 days prior to screening and will 
abstain from receiving such vaccines until completion of the follow-up visit. 
Acetaminophen is permitted for use at the discretion of the investigator. If acetaminophen 
treatment is needed for pain management, the maximal allowed dose will be 3 g/day from all 
acetaminophen-containing medicinal products. Other concomitant medication may be considered 
on a case-by-case basis by the investigator in consultation with the Lilly CP.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from study intervention or from the study prematurely for any reason 
should complete AE and other early discontinuation procedures as per the SoA (Section 1.3).
Discontinuation of specific sites or of the study as a whole is described in Appendix 1
(Section 10.1.7).
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study for appropriate safety monitoring. See the SoA (Section 1.3) for data to be collected at the 
time of discontinuation of study intervention and follow-up and for any further evaluations that 
need to be completed.
7.1.1.
Hepatic Criteria for Discontinuation
The study intervention should be discontinued if one or more of these conditions occur: 
Elevation
Exception
ALT or AST >5× ULN 
ALT or AST >3× ULN and either TBL >2× ULN or INR >1.5 
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for drug interruption or discontinuation 
decisions rather than TBL >2× ULN.
ALT or AST >3× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)
ALP >3× ULN (when the source of increased ALP is the liver) 
ALP >2.5× ULN and TBL > 2× ULN 
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for drug interruption or discontinuation 
decisions rather than TBL >2× ULN.
ALP >2.5× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009  
and other consensus guidelines with minor modifications
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;
FDA = Food and Drug Administration; INR = international normalized ratio; TBL = total bilirubin; 
ULN = upper limit of normal.
Participants who discontinue from study intervention due to the abnormal liver tests will undergo
monitoring as described in Appendix 6 (Section 10.6).
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:


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Protocol number J2N-MC-JZNW (a)
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
at any time at the participant’s own request

at the request of the participant’s designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons

if enrollment in any other clinical study involving an investigational product or 
enrollment 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 another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent.
Discontinuation is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed.
The participant will be permanently discontinued from both the study intervention and the study 
at that time.
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, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he/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 (Section 1.3).
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.
The specifications in this protocol for the timings of safety and sample collection are given as 
targets to be achieved within reasonable limits. Modifications may be made to the time points 
based upon emerging clinical information. The scheduled time points may be subject to minor 
alterations; however, the actual time must be correctly recorded in the CRF.
Appendix 2 (Section 10.2) lists the laboratory tests that will be performed for this study.
Appendix 2 (Section 10.2.1) provides a summary of the maximum number and volume of 
invasive samples, for all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results. Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
8.1.
Efficacy Assessments
Efficacy is not evaluated in this study. 
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
A complete physical examination will be conducted as specified in the SoA (Section 1.3).
Complete physical examinations include, at a minimum, assessments of the following systems:

dermatological

head and eyes

ears, nose, mouth, and throat

pulmonary

cardiovascular 

abdominal

lymphatic

musculoskeletal/extremities

neurological.


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Symptom-directed examinations may be performed as deemed appropriate by investigator. 
Any clinically significant findings in a physical examination should be reported as AEs.
8.2.2.
Height and Weight
Height and weight will be measured and recorded at screening only (see SoA, Section 1.3).
8.2.3.
Vital Signs
For each participant, vital signs measurements should be conducted according to the SoA
(Section 1.3).
Blood pressure and pulse rate should be measured after at least 5 minutes in a supine position.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. If orthostatic measurements are required, participants should be 
supine for at least 5 minutes and stand for at least 2 minutes. If the participant feels unable to 
stand, supine vital signs only will be recorded. 
Oral body temperature will be recorded at screening only. 
Additional vital signs may be measured if warranted.
8.2.4.
Electrocardiograms
For each participant, a single12-lead digital ECG will be collected according to the SoA 
(Section 1.3). ECGs may be obtained at additional times, when deemed clinically necessary.
If scheduled at the same nominal time, ECGs must be recorded before collecting any blood 
samples. Participants must be supine for approximately 5 to 10 minutes before ECG collection 
and remain supine but awake during ECG collection. All ECGs recorded should be stored at the 
investigational site.
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) as soon 
after the time of ECG collection as possible, and ideally while the participant is still present, to 
determine whether the participant meets entry criteria at the relevant visits and for immediate 
participant management, should any clinically relevant findings be identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
intervals from baseline) after enrollment, the investigator will determine if 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 collection. 
Any new clinically relevant finding should be reported as an AE.
8.2.5.
Clinical Laboratory Tests
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
SoA (Section 1.3) for the timing and frequency.
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. 


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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. 
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 Appendix 2 (Section 10.2), 
must be conducted in accordance with the SoA (Section 1.3), 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 (e.g., SAE or AE or dose modification), then
report the information as an AE.
8.2.6.
Pregnancy Testing 
Where applicable, pregnancy tests will be performed as outlined in the SoA (Section 1.3).
8.2.7.
Safety Monitoring
The Lilly CP or clinical research physician (CRP) will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

AEs.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
8.2.7.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 6, Section 10.6), including ALT, AST, alkaline phosphatase (ALP),
and TBL, should be repeated, with the addition of direct bilirubin, gamma glutamyl transferase,
and creatine kinase, within 48 to 72 hours to confirm the abnormality and to determine if it is
increasing or decreasing, if 1 or more of these conditions occur:
If a participant with baseline results of...
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN
ALP <1.5 × ULN
ALP ≥2 × ULN


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TBL <1.5 × ULN
TBL ≥2 × ULN (except for participants with Gilbert’s 
syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥1.5 × baseline (except for participants with Gilbert’s 
syndrome)
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 CP. 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, and 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 laboratory results stabilize. Monitoring of ALT, AST, ALP,
and TBL should continue until levels normalize or return to approximate baseline levels.
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:
If a participant with baseline results of...
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN with hepatic signs/symptoms*, or
ALT or AST ≥5 × ULN
ALP <1.5 × ULN
ALP ≥3 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for participants with Gilbert’s syndrome)
ALT or AST ≥1.5 × ULN
ALT or AST ≥2 × baseline with hepatic signs/symptoms*, or
ALT or AST ≥3 × baseline
ALP ≥1.5 × ULN
ALP ≥2 × baseline
TBL ≥1.5 × ULN
TBL ≥2 × baseline (except for participants with Gilbert’s syndrome) 
* 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 prothrombin time-international normalized ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or computed tomography scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated CP, 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 serum 


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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 in study participants who have abnormal liver test 
results during the study
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following conditions:  

Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5× ULN)
o
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT ≥3 × 
baseline on 2 or more consecutive tests

Elevated serum TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of 
known Gilbert’s syndrome)
o
In participants with baseline TBL ≥1.5 × ULN, the threshold should be TBL ≥2 × 
baseline

Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5 × ULN)
o
In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × baseline 
on 2 or more consecutive blood tests

Hepatic event considered to be an SAE

Discontinuation of study intervention due to a hepatic event.
Note: The interval between the 2 consecutive blood tests should be at least 2 days.
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
The definitions of the following events can be found in Appendix 3 (Section 10.3):

AEs

SAEs

Product complaints (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 or study (see Section 7).
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.


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The investigator is responsible for the appropriate medical care of participants during the study.
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For PCs, 
the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Appendix 3 (Section 10.3).
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
Adverse Event
AE
Signing of 
the informed 
consent form 
(ICF)
Participation 
in study has 
ended
As soon as possible 
upon site awareness
AE CRF
N/A
Serious Adverse Event
SAE and SAE 
updates – prior 
to start of study 
intervention and
deemed 
reasonably 
possibly related 
with study 
procedures
Signing of 
the ICF
Start of 
intervention
Within 24 hours of 
awareness
SAE paper form
SAE paper 
form
SAE# and SAE 
updates – after 
start of study 
intervention
Start of 
intervention
Participation 
in study has 
ended
Within 24 hours of 
awareness
SAE paper form
SAE paper 
form
SAE* – 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


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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Pregnancy
Pregnancy in 
female partners 
of male 
participants
After the 
start of study 
intervention
1 week after 
the last dose
Within 24 hours (see 
Section 8.3.2)
Pregnancy paper 
form
Pregnancy 
paper form
Product Complaints
PC associated 
with an SAE or 
might have led 
to an SAE
Start of study 
intervention
End of study 
intervention
Within 24 hours of 
awareness
PC form
N/A
PC not 
associated with 
an SAE
Start of study 
intervention
End of study 
intervention
Within 1 business day 
of awareness
PC form
N/A
Updated PC 
information
—
—
As soon as possible 
upon site awareness
Originally 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
* SAEs should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation.
8.3.2.
Pregnancy
Collection of pregnancy information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.

After learning of a pregnancy in the female partner of a study participant, the investigator 
will obtain a consent to release information from the pregnant female partner directly, 
and within 24 hours after obtaining this consent will record pregnancy information on the 
appropriate form and submit it to the sponsor.

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 


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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.
8.4.
Pharmacokinetics
Venous blood samples of approximately 2 mL will be collected for measurement of plasma
concentrations of rosuvastatin and pirtobrutinib as specified in the SoA (Section 1.3).
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. 
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.
8.4.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of rosuvastatin and pirtobrutinib will be assayed using a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) method.  
Bioanalytical samples collected to measure investigational product 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 and/or protein binding work.
8.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.6.
Genetics
A blood sample will be collected at screening to determine genetic polymorphisms for 
participants to meet eligibility criteria prior to enrollment (Section 5.2 and Section 5.2.1).
A separate blood sample will be collected for storage for potential pharmacogenetic analysis as 
specified in the SoA (Section 1.3). See Appendix 5 (Section 10.5) for information regarding 
genetic research. 
8.7.
Biomarkers
Biomarkers are not evaluated in this study.
8.8.
Immunogenicity Assessments
Immunogenicity is not evaluated in this study. 
8.9.
Health Economics
This section is not applicable for this study.


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9.
Statistical Considerations
The statistical analysis plan (SAP) will be finalized prior to first participant first visit, and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses.
9.1.
Statistical Hypotheses
The primary objective variables will be evaluated to assess the potential DDI. No significant 
DDI for rosuvastatin will be concluded if the respective 90% confidence interval for area under 
the concentration versus time curve from time zero to infinity (AUC[0-∞]) and maximum 
observed drug concentration (Cmax) is completely contained within the no-effect boundaries 
(0.80, 1.25).
9.2.
Analyses Sets
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF. 
Enrolled
All participants assigned to study intervention, regardless of 
whether they take any doses.
Safety
All participants who receive at least 1 dose of rosuvastatin.
Participants will be analyzed according to the intervention they 
actually received.
Pharmacokinetic
All participants who receive at least 1 dose of rosuvastatin and
have evaluable PK data.
9.2.1.
Study Participant Disposition
All participants who discontinue from the study will be identified and the extent of their
participation in the study will be reported. If known, a reason for their discontinuation will be
given. 
A detailed description of participant disposition will be provided at the end of the study.
9.2.2.
Study Participant Characteristics 
The participant’s age, sex, weight, height, and other demographic characteristics will be 
recorded.
9.3.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 


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37
in the SAP and the clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
Study results may be pooled with the results of other studies for safety and population PK 
analysis purposes to avoid issues with post-hoc analyses and incomplete disclosures of analyses.
9.3.1.
Pharmacokinetic Analyses
All PK analyses will be made using the Pharmacokinetic Population.
9.3.1.1.
Pharmacokinetic Parameter Estimation
PK parameter estimates for rosuvastatin will be calculated by standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be Cmax and AUC(0-∞) of rosuvastatin. Other 
noncompartmental parameters, such as tmax, t1/2, apparent clearance, and apparent volume of 
distribution may be reported.
Blood samples collected for the PK of pirtobrutinib alone will be used to determine plasma 
concentration only, to ensure sufficient exposure. 
9.3.1.2.
Pharmacokinetic Statistical Inference
PK parameters will be evaluated to estimate drug interaction for rosuvastatin with single (Day 6) 
and multiple (Day 13) doses of pirtobrutinib. A subject may be excluded from the PK summary 
statistics and statistical analysis if the subject has an AE of vomiting that occurs at or before 
2 times median tmax.
Log-transformed Cmax and AUC(0-∞) parameters for rosuvastatin will be evaluated in a linear
mixed-effects model with a fixed effect for treatment, and a random effect for participant. The 
treatment differences will be back transformed to present the ratios of geometric means and the 
corresponding 90% confidence interval.
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the median difference 
based on the observed medians, 90% confidence intervals, and p-values from the Wilcoxon test 
will be calculated.
9.3.2.
Safety Analyses 
All safety analyses will be made using the Safety Population.
9.3.2.1.
Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of AEs for each treatment will be presented by severity and by association with 
investigational product as perceived by the investigator. AEs reported to occur prior to 
enrollment will be distinguished from those reported as new or increased in severity during the 
study. Each AE will be classified by the most suitable term from the medical regulatory 
dictionary. AEs by day of onset will be presented. 


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The number of SAEs will be reported.
9.3.2.2.
Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs. The 
parameters will be listed, and summarized using standard descriptive statistics. Additional 
analysis will be performed if warranted upon review of the data.
9.4.
Interim Analysis 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
9.5.
Sample Size Determination
CCI


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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 Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations.
The protocol, protocol amendments, ICF, Investigator’s Brochure (IB), and other relevant 
documents (for example, advertisements) must be submitted to an institutional review board 
(IRB)/independent ethics committee (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 (CFR), 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.
Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 


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regulations, ICH guidelines, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center.
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.3.
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.
10.1.4.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the study due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by phone and/or email) 
as soon as possible. It will be a requirement that investigators respond upon receipt to confirm 
that they understand the communication and have taken the appropriate action prior to further 
dosing any participants with study intervention. Any investigator not responding will be 
followed up by Lilly personnel prior to any further planned dosing. If a dose is planned 
imminently, Lilly personnel will immediately, and continually, use all efforts to reach 
investigators until contact is made and instructions verified.
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. 


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Data 
The sponsor does not proactively share data from Phase 1 clinical studies. Requests for access to 
Phase 1 clinical study data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected.
10.1.5.
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. Source data may include laboratory tests, medical records, and 
clinical notes.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
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 (e.g., contract 
research organizations).
Study monitors will perform ongoing source data verification to confirm that data entered 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 (CTA)
unless local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.
In addition, the sponsor or its representatives will periodically check a sample of the participant
data recorded against source documents at the study site. The study may be audited by the 
sponsor or its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.


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An electronic data capture 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 electronic data capture 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.
10.1.6.
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 
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 10.1.5.
10.1.7.
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
Study or Site Termination
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:

Discontinuation of further study intervention development.
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator

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 


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regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.8.
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 if the results are deemed to be of significant medical 
importance.


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10.2.
Appendix 2: Clinical Laboratory Tests
The tests detailed in the table below will be performed by the local laboratory.
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.


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Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Alanine aminotransferase
Hemoglobin
Albumin
Erythrocyte count (RBC)
Alkaline phosphatase
Mean cell volume 
Aspartate aminotransferase
Mean cell hemoglobin 
Bicarbonate
Mean cell hemoglobin concentration 
Blood urea nitrogen
Leukocytes (WBC) 
Calcium
Platelets
Chloride
Differential WBC (Absolute counts and %) of:
Cholesterol
Basophils 
Creatinine
Eosinophils 
Creatinine phosphokinase
Lymphocytes
Gamma-glutamyl transferase
Monocytes
Glucose (random)
Neutrophils
Potassium
Sodium
Total bilirubina
Urinalysis
Total protein
Bilirubin 
Uric acid
Blood 
Glucose 
Serologyb
Ketones
Hepatitis B surface antigen
Nitrite
Hepatitis C antibody
pH
Human immunodeficiency virus
Protein
Specific gravity
Ethanol testingd
Urobilinogen
Urine drug screen (including cotinine)e
Microscopic examination of sedimentc
Follicle-stimulating hormoneb,f
Pregnancy testg
Abbreviations: RBC = red blood cells; WBC = white blood cells.
Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the 
above parameters are calculated from measured values. Omission of calculated values will not be considered as a 
protocol violation.
a
Direct and indirect bilirubin will be analyzed if total bilirubin is elevated.
b
Performed at screening only.
c
Test only if dipstick result is abnormal.
d
Performed at check-in (Day -1) only.
e
Performed at screening and check-in (Day -1) only.
f
Females only to confirm postmenopausal status.
g
Performed in serum at screening and in urine at all other times. A positive urine pregnancy test will be confirmed 
with a serum pregnancy test. 


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10.2.1.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all
blood sampling during the study. 
Protocol J2N-MC-JZNW Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
21.5
1
21.5
Clinical laboratory testsa
12.5
8
100
Rosuvastatin pharmacokineticsb
2
53
106
Pirtobrutinib pharmacokineticsb
2
15
30
Pharmacogenetics for storage
10
1
10
Total
267.5
Total for clinical purposes 
270
a
Additional samples may be drawn if needed for safety purposes.
b
Includes additional 3 samples, if required.


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10.3.
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting
10.3.1.
Definition of Adverse Event
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 unfavourable 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.
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 DDI.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
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.


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
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 Serious Adverse Event
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, 
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 (e.g., 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 


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Protocol number J2N-MC-JZNW (a)
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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.
10.3.3.
Definition of Product Complaints
PCs

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.

PCs related to study interventions used in clinical studies 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.
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.


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
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the 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 the 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 the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will 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.
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 and/or Product Information, for marketed 
products in their assessment.


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
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 the 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 the sponsor
or designee.

The investigator may change their opinion of causality in light of follow-up 
information and send a 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 the sponsor 
or designee to elucidate the nature and/or causality of the AE/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 the sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5.
Reporting of Serious Adverse Events
SAE Reporting via SAE Report

Facsimile transmission of the SAE Report 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 Report within the designated reporting time frames.

Contacts for SAE reporting can be found in the SAE Report.
10.3.6.
Regulatory Reporting Requirements
SAE Regulatory Reporting

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards 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.


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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.


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10.4.
Appendix 4: Contraceptive and Barrier Guidance
10.4.1.
Definitions
Females of Childbearing Potential
Females are considered a woman of childbearing potential 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. 
Females NOT of Childbearing Potential
Females are considered women not of childbearing potential if

they have a congenital anomaly such as Mullerian agenesis 

they are infertile due to surgical sterilization
o
hysterectomy
o
bilateral oophorectomy
o
tubal ligation

they are post-menopausal.
Post-Menopausal
The post-menopausal state should be defined as:
1. A female at any age at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note; or 
2. A female 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 female 55 or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or
4. A female at least 55 years of age with a diagnosis of menopause prior to starting hormone 
replacement therapy
* Female participants should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen 
receptor modulators (SERMs), or chemotherapy that could induce transient amenorrhea.
10.4.2.
Contraception Guidance
10.4.2.1.
Female Participants
Females of childbearing potential are excluded from this study. 


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Female participants not of childbearing potential, as defined in Section 10.4.1, may participate in 
this study and are not required to adhere to contraceptive requirements. 
All female participants must test negative for pregnancy prior to initiation of treatment as 
indicated by a negative serum pregnancy test at the screening visit followed by a negative urine
pregnancy test within 24 hours prior to exposure (Day -1). A positive urine test will be 
confirmed with a serum pregnancy test.
10.4.2.2.
Male Participants
Male participants, regardless of their fertility status, with partners who are non-pregnant females 
of childbearing potential, must agree to either
1. remain abstinent (if this is their preferred and usual lifestyle), or
2. use condoms with spermicide plus 1 additional highly effective contraception method 
(see Section 10.4.3), during intercourse.
They must agree to adhere to these restrictions for the duration of the study and for 6 months
after the last dose of study intervention.
Male participants with pregnant partners must agree to use condoms with spermicide during 
intercourse.
All male participants should refrain from sperm donation for the duration of the study and for 
6 months after the last dose of study intervention.
10.4.3.
Contraception Methods
This table illustrates examples of highly effective, effective, and ineffective 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
o
diaphragm with spermicide, or
o
female condom with spermicide


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Note:  The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective.
Male and female condoms should not be used in 
combination.
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


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10.5.
Appendix 5: Genetics
CCI


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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
See Section 8.2.7.1 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 (TBL)
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
Copper
Coagulation
Ethyl alcohol (EtOH)
Prothrombin time, international normalized ratio (INR) 
(PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (quantitative)
Hepatitis A virus (HAV) testing:
Immunoglobulin IgG (quantitative)
    HAV total antibody
Immunoglobulin 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)
    Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA) a
    HBV DNA d
Anti-actin antibody b


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Hepatitis C virus (HCV) testing:
Epstein-Barr virus (EBV) testing:
    HCV antibody
    EBV antibody
    HCV RNA d
    EBV DNA d
Hepatitis D virus (HDV) testing:
Cytomegalovirus (CMV) testing:
    HDV antibody
    CMV antibody
Hepatitis E virus (HEV) testing:
    CMV DNA d
    HEV IgG antibody
Herpes simplex virus (HSV) testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody 
    HEV RNA d
    HSV (Type 1 and 2) DNA d
Microbiology c
Liver kidney microsomal type 1 (LKM-1) antibody
Culture:
    Blood
    Urine
a
Not required if anti-actin antibody is tested.
b Not required if anti-smooth muscle antibody (ASMA) is tested.
c
Assayed ONLY by investigator-designated local laboratory; no central testing available.
d Reflex/confirmation dependent on regulatory requirements, testing availability, or both.


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10.7.
Appendix 7: Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC(0-∞)
area under the concentration versus time curve from time zero to infinity
BCRP
breast cancer resistance protein
BTK
Bruton’s tyrosine kinase
CFR
Code of Federal Regulations
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies related to 
the identity, quality, purity, durability, reliability, safety or effectiveness, or performance of a 
drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CP
clinical pharmacologist
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 study participant.
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research scientist, global 
safety physician or other medical officer.
CRU
clinical research unit
CV
coefficient of variation
DDI
drug-drug interaction
ECG
electrocardiogram
enroll
The act of assigning a participant to a treatment. Participants who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the ICF directly or through their legally 
acceptable representatives.


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GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
informed 
consent
A process by which a participant voluntarily confirms their willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to the 
participant’s decision to participate. Informed consent is documented by means of a written, 
signed and dated ICF.
investigation
al product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a 
clinical study, including products already on the market when used or assembled (formulated or 
packaged) in a way different from the authorized form, or marketed products used for an 
unauthorized indication, or marketed products used to gain further information about the 
authorized form.
IRB
institutional review board
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical study, either as 
recipient of an investigational medicinal product or as a control
PC
product complaint
PK
pharmacokinetic(s)
QD
once daily
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
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. 
SoA
Schedule of Activities
t1/2
terminal half-life
TBL
total bilirubin
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this treatment.
tmax
time to maximum drug concentration
ULN
upper limit of normal


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11.
References
Crestor® (rosuvastatin calcium) Tablets [Prescribing Information]. Wilmington, DE: 
AstraZeneca Pharmaceuticals LP; 2003. Revised May 2020. Accessed at 
https://www.azpicentral.com/crestor/crestor.pdf#page=1 on 15 September 2021. 
Food and Drug Administration (FDA). Drug Development and Drug Interactions. Table of 
Substrates, Inhibitors and Inducers. Accessed at https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers on 
19 August 2021.
Furukawa T, Wakabayashi K, Tamura A, et al. Major SNP (Q141K) variant of human ABC 
transporter ABCG2 undergoes lysosomal and proteasomal degradations. Pharm Res. 
2009;26(2):469-479.
International Transporter Consortium; Giacomini KM, Huang SM, Tweedie DJ, et al. Membrane 
transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236.
Keskitalo JE, Zolk O, Fromm MF, et al. ABCG2 polymorphism markedly affects the 
pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86(2):197-203.
Mendes P, Robles GP, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of 
case reports. Physiother Can. 2014;66(2):124-132.
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically 
polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 
2011;63(1):157-181.
Wan Z, Wang G, Li T, et al. Marked alteration of rosuvastatin pharmacokinetics in healthy 
Chinese with ABCG2 34G>A and 421C>A homozygote or compound heterozygote. 
J Pharmacol Exp Ther. 2015;354(3):310-315.


Leo Document ID = 12ff9aea-8f09-411a-9bf2-2305c169a69d
Approver: 
Approval Date & Time: 22-Dec-2021 14:39:57 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Dec-2021 15:40:28 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan: J2N-MC-JZNW (Final Version 1.0) 
 
 
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single 
and Multiple Doses of Pirtobrutinib on the Pharmacokinetics of Rosuvastatin in 
Healthy Participants 
 
NCT05176314 
 
Approval Date: 22-Dec-2021 


Final Version 1.0, 21 Dec 2021
             Page 1 of 18
STATISTICAL ANALYSIS PLAN
A Phase 1, Open-Label, Drug Interaction Study to Investigate the Effect of Single and 
Multiple Doses of Pirtobrutinib on the Pharmacokinetics of Rosuvastatin in Healthy 
Participants
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Version: 1.0
Statistical Analysis Plan Date: 21-December-2021
Study Drug: LY3527727 (Pirtobrutinib)
Sponsor Reference: J2N-MC-JZNW
Labcorp Drug Development Study: 8478556
Clinical Phase I
Approval Date: 22-Dec-2021 GMT


Final Version 1.0, 21 Dec 2021
             Page 2 of 18
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Drug Development Study: 8478556
Sponsor Reference LY3527727
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 5
5.
STUDY DESIGN........................................................................................................... 5
6.
TREATMENTS............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 8
9.1
General.................................................................................................................... 8
9.2
Demographics and Participant Disposition............................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 12
9.4
Safety and Tolerability Assessments...................................................................... 13
9.4.1
Adverse events ............................................................................................. 13
9.4.2
Concomitant medication............................................................................... 14
9.4.3
Clinical laboratory parameters...................................................................... 14
9.4.4
Vital signs .................................................................................................... 14
9.4.5
Electrocardiogram (ECG)............................................................................. 14
9.4.6
Hepatic Monitoring ...................................................................................... 14
9.4.7
Other assessments......................................................................................... 16
9.4.8
Safety and Tolerability Statistical Methodology............................................ 16
10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 16
12. REFERENCES ............................................................................................................ 16
13. DATA PRESENTATION ............................................................................................ 16
13.1 Derived Parameters ............................................................................................... 16
13.2 Missing Data ......................................................................................................... 17
13.3 Insufficient Data for Presentation .......................................................................... 17
14. APPENDICES ............................................................................................................. 18
Appendix 1: Document History...................................................................................... 18


Final Version 1.0, 21 Dec 2021
             Page 3 of 18
Statistical Analysis Plan 
CONFIDENTIAL
Labcorp Drug Development Study: 8478556
Sponsor Reference LY3527727
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
Percentage of AUC(0-∞) extrapolated
Adverse event
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Area under the concentration versus time curve
%AUC(tlast-∞) 
AE
ALP
ALT
AST
AUC
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BQL
Below the lower limit of quantitation
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
NA
Not applicable
PG
Plasma Glucose
PK
Pharmacokinetic
QD
Once daily
SAE
Serious adverse event
SAP
Statistical Analysis Plan


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SD
Standard deviation 
SOP
Standard Operating Procedure
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
WHO
World Health Organization


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
22 October 2021).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. For open-label 
studies, this SAP must be signed off prior to first participant visit for this study. When the SAP 
and TFL shells are agreed upon and finalized, they will serve as the template for this study’s 
CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the effect of single and 
multiple doses of pirtobrutinib on breast 
cancer resistance protein activity in 
healthy participants.

Maximum observed drug concentration
(Cmax), area under the concentration 
versus time curve from time zero to 
infinity [AUC (0-∞)] of rosuvastatin.
Secondary

To evaluate the safety and tolerability of 
rosuvastatin in combination with            
pirtobrutinib in healthy participants.

Incidence of treatment-emergent adverse 
events and serious adverse events
(SAEs).
5. STUDY DESIGN
Study J2N-MC-JZNW is a Phase 1, fixed sequence, open-label study in healthy participants that 
will investigate the effect of single and multiple doses of pirtobrutinib on the PK of rosuvastatin. 


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Schema 1- study design. 
Approximately 36 participants will be enrolled to ensure that at least 28 evaluable participants 
complete the study. 
Screening
All participants will be screened for study inclusion within 42 days prior to enrollment (Day 1). 
Screening should not occur less than 14 days prior to enrollment (Day 1), in order to allow 
sufficient time to receive genotyping results. 
Treatment and Assessment Period
Participants will check in to the clinical research unit (CRU) on Day -1 and remain resident until 
discharge on Day 18. While resident at the CRU, all participants will receive study intervention 
as follows:

Day 1: 20 mg rosuvastatin alone

Day 6: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib

Days 7 to 12: Once daily (QD) doses of 200 mg pirtobrutinib alone

Day 13: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib

Days 14 to 17: QD doses of 200 mg pirtobrutinib alone. 
The PK blood sampling and safety assessments, including vital signs measurements, physical 
examinations, clinical laboratory tests, electrocardiograms (ECGs), and adverse event (AE)
recording, will be performed. 
Participants will be discharged from the CRU on Day 18 following completion of study 
procedures, provided they are deemed medically fit by the investigator or designee. 
Follow-Up
Participants will attend an outpatient follow-up visit 7 (± 2) days after the final dose of study 
intervention. If participants are not able to attend the CRU for this visit, the CRU should contact 
the participant via phone call to conduct AE and concomitant medication review.


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6. TREATMENTS
The following is the study treatment sequence that will be used as a sub header in the TFLs.
Study Treatment Sequence Name
Treatment order in TFL
20 mg rosuvastatin alone (Day 1) / 20 mg rosuvastatin + 200 mg pirtobrutinib (Day 6) / 200 
mg pirtobrutinib QD (Days 7 to 12) / 20 mg rosuvastatin + 200 mg pirtobrutinib (Day 13) / 
200 mg pirtobrutinib QD (Days 14 to 17).
1
Abbreviation: QD=Once daily.
The following is a list of the study treatment abbreviations that will be used in the AE and PK
TFLs.
Day
Study Treatment Name
Treatment order in TFL
1
20 mg rosuvastatin 
1
6
20 mg rosuvastatin + 200 mg pirtobrutinib
2
7-12
200 mg pirtobrutinib QD
3
13
20 mg rosuvastatin + 200 mg pirtobrutinib
4
14-17
200 mg pirtobrutinib QD
5
Abbreviation: QD=Once daily
7. SAMPLE SIZE JUSTIFICATION
8. DEFINITION OF ANALYSIS POPULATIONS
The “Entered” population will consist of all participants who sign the informed consent form.
The “Enrolled” population will consist of all participants assigned to study intervention, 
regardless of whether they take any doses (all enrolled population have meet the inclusion 
criteria and assigned to study interventions (assigned with planned treatment in DB).
The “Safety” population will consist of all participants who receive at least 1 dose of 
rosuvastatin. Participants will be analyzed according to the intervention they actually received.
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The “Pharmacokinetic” population will consist of all participants who receive at least 1 dose of 
rosuvastatin and have evaluable PK data. 
All protocol deviations and adverse events that occur during the study will be considered for 
their severity/impact and will be taken into consideration when participants are assigned to 
analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is collected and entered to clinical electronic data 
base. Data listings will be provided for all participants up to the point of withdrawal, with any 
participants excluded from the relevant population highlighted. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
minimum, maximum and n; for log-normal data (e.g. the PK parameters: area under the 
concentration versus time curve [AUCs] and Cmax) the geometric mean and geometric CV% will 
also be presented. For categorical data, frequency count and percentages will be presented. 
Summary statistics and statistical analyses will generally only be performed for participants
included in the relevant analysis population. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual participants’ change from baseline 
values in a given population. Each individual change from baseline will be calculated by 
subtracting the individual participant’s baseline value from the value at the timepoint. The 
individual participant’s change from baseline values will be used to calculate the mean change 
from baseline using a SAS procedure such as Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Participant Disposition
Participant disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized and listed. All other demographic 
variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined for rosuvastatin using non-compartmental 
procedures in validated software program (Phoenix WinNonlin Version 8.1 or later).
No PK parameters will be derived for the plasma concentrations of pirtobrutinib.
Plasma concentrations of rosuvastatin will be used to determine the following PK parameters, 
where possible, on Days 1, 6 and 13: 


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Parameter
Units
Definition
AUC(0-tlast) 
ng.h/mL 
Area under the concentration versus time curve from time zero to time t, 
where t is the last time point with a measurable concentration
AUC(0-∞) 
ng.h/mL 
Area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-∞) 
% 
Percentage of AUC(0-∞) extrapolated
Cmax
ng/mL 
Maximum observed drug concentration
tmax
h 
Time of maximum observed drug concentration
t1/2
h 
Half-life associated with the terminal rate constant (λZ) in 
non-compartmental analysis
CL/F 
L/h 
Apparent total body clearance of drug calculated after extra-vascular 
administration
VZ/F 
L 
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
Apparent volume of distribution at steady state after extra vascular
administration
Additional PK parameters may be calculated, as appropriate.  
The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the CSR.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

The Cmax and tmax will be reported from observed values. If Cmax occurs at more than one-
time point, tmax will be assigned to the first occurrence of Cmax. 

The AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification, with at least 
one of these concentrations following Cmax.

The AUC(0-) values where the percentage of the total area extrapolated is more than 
20% will be flagged. Any AUC(0-) value excluded from summary statistics will be 
noted in the footnote of the summary table.


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
Half-life (t1/2) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each participant will be defined by visual inspection and generally will be the 
first point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t1/2 is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t1/2 value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on the last observed quantifiable drug concentration will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero
when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a participant or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a profile, 
the profile will be deemed to have terminated and therefore any further quantifiable 
concentrations will be set to missing for the calculation of the PK parameters unless it is 
considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times on the same figure.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.


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
The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time which are greater than ± 10% of the planned sampling 
time will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the CSR.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements at actual sampling times 
which are within ± 10% of the planned sampling time. An average concentration 
estimated with less than 2/3 but more than 3 data points with quantifiable measurements 
that are within the sampling time as stated above may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
CSR.
Treatment of Outliers during PK Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.


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b. Find the most extreme value from the arithmetic mean of the log transformed values 
and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic mean 
±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not an 
outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another a typical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the CSR. Approval of the CSR will 
connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
The PK parameters will be evaluated to estimate drug interaction for rosuvastatin with single 
(Day 6) and multiple (Day 13) doses of pirtobrutinib compared to rosuvastatin administered 
alone on Day 1. A participant may be excluded from the PK summary statistics and statistical 
analysis if the participant has an AE of vomiting that occurs at or before 2 times median tmax.
Log-transformed Cmax and AUC(0-∞) parameters for rosuvastatin will be evaluated in a linear
mixed-effects model with a fixed effect for treatment, and a random effect for participant.
Treatment can be rosuvastatin with single or multiple doses of pirtobrutinib, or rosuvastatin 
administered alone. 
The least squares (LS) means for each treatment, the difference between the treatment LS means 
of

20 mg rosuvastatin + 200 mg pirtobrutinib on Day 6 (test) – 20 mg rosuvastatin on Day 
1(reference)

20 mg rosuvastatin + 200 mg pirtobrutinib on Day 13 (test) – 20 mg rosuvastatin on Day 
1 (reference)]
associated 90% CIs will be estimated from the model and back-transformed from the log scale to 
provide estimates of the geometric means, geometric mean ratio, and corresponding 90% CIs.
Example of the SAS code for the analysis:


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The tmax will be analyzed non-parametrically using a Wilcoxon signed rank test. Estimates of the 
median difference comparing 

20 mg rosuvastatin + 200 mg pirtobrutinib on Day 6 (test) – 20 mg rosuvastatin on Day 1 
(reference)

20 mg rosuvastatin + 200 mg pirtobrutinib on Day 13 (test) – 20 mg rosuvastatin on Day 
1 (reference),
corresponding 90% confidence intervals, and p-values from the Wilcoxon signed rank test will 
be calculated.
Example SAS code to be used for the Wilcoxon signed-rank test:
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the participant has provided 
written informed consent and is ongoing at consent. A non-TEAE is defined as an AE which 
starts after informed consent but prior to dosing. A TEAE is defined as an AE which occurs 
postdose or which is present prior to dosing and becomes more severe postdose. 
All AEs will be listed. TEAEs will be summarized by treatment, severity and relationship to the 
study drug. The frequency (the number of AEs, the number of participants experiencing an AE
and the percentage of participants experiencing an AE) of TEAEs will be summarized by 
treatment, Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 system organ 
class and preferred term. The summary and frequency AE tables will be presented for all 
causalities and those considered related to the study drug by the investigator. Any serious AEs
will be listed. 
Discontinuations due to AEs will be listed.
CCI
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9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version September
2021). Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter, along with 
changes from baseline, where baseline is the Day 1 predose assessment, and listed. Urinalysis 
data will be listed. Additionally, clinical chemistry, hematology and urinalysis data outside the 
reference ranges will be listed and flagged on individual participant data listings.
9.4.4
Vital signs
Vital signs data will be summarized by timepoint together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by timepoint. 
Values for individual participants will be listed.
9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.6
Hepatic Monitoring
Close hepatic monitoring
If a participant who had normal or near normal baseline alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBL) (i.e., <1.5×
upper limit of normal [ULN]), experiences elevated ALT≥3× ULN, AST≥3× ULN, ALP≥2×
ULN, or TBL≥2× ULN, laboratory tests should be repeated within 48 to 72 hours, including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyltransferase, and creatinine kinase to
confirm the abnormality and to determine if it is increasing or decreasing.
In participants enrolled with elevated baseline ALT, AST, ALP or TBL (≥1.5× ULN), the 
thresholds for close monitoring are ALT≥2× baseline, AST≥2× baseline, ALP≥2× baseline, or 
TBL≥1.5× baseline (except for participants with Gilbert’s syndrome).
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, other substance abuse and 
additional laboratory tests and/or abdominal imaging studies, as medically indicated.


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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.
Comprehensive hepatic evaluation
If a study participant, who had baseline ALT, AST, ALP, TBL<1.5× ULN, experiences elevated
ALT≥5× ULN, AST≥5× ULN, ALP ≥3× ULN, TBL ≥2× ULN (except for participants with 
Gilbert’s syndrome), or elevated ALT, AST ≥3× ULN with hepatic signs/symptoms (severe 
fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia>5%), a comprehensive evaluation should be performed to search for possible causes 
of liver injury.
In participants who had elevated baseline ALT, AST, ALP, or TBL (≥1.5× ULN), the thresholds 
for performing this evaluation are ALT≥3× baseline, AST≥3× baseline, ALP≥2× baseline, 
TBL≥2× baseline (except for participants with Gilbert’s syndrome), or ALT, AST ≥2× baseline 
with hepatic signs/symptoms.
At a minimum, this evaluation should include physical examination and a thorough medical
history, as outlined above, as well as tests for prothrombin time-international normalized ratio,
viral hepatitis A, B, C, E, tests for autoimmune hepatitis, and an abdominal imaging study (for
example, ultrasound or computed tomography scan).
Additional hepatic data collection in participants who have abnormal liver tests during the 
study
Additional hepatic safety data collection should be performed in participants who meet 1 or more 
of the following 5 conditions:
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline
ALT<1.5x ULN)
In participants with baseline ALT≥1.5× ULN, the threshold is ALT≥3x baseline 
on 2 or more consecutive tests
2. Elevation of serum TBL to ≥2× ULN (if baseline TBL <1.5× ULN) (except for cases of 
known Gilbert’s syndrome)
In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2x
baseline
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline
ALP <1.5× ULN)
In participants with baseline ALP≥1.5× ULN, the threshold is ALP ≥2× baseline 
on 2 or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of the investigational product due to a hepatic event


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Where applicable, the following will be presented. The participants’ liver disease history and 
associated person liver disease history data will be listed. Any concomitant medications that have 
potential for hepatotoxicity, including acetaminophen will be listed. Results from any hepatic 
monitoring procedures, such as a magnetic resonance elastography scan, and biopsy assessments
will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings.
9.4.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.8
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.


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13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.”


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14.
APPENDICES
Appendix 1: Document History
Status and Version
Date of Change
Summary/Reason for Changes
Final Version 1.0
NA
NA; the first version.
NA = not applicable


Leo Document ID = f4548492-04f8-4913-aaed-4860e39990c2
Approver: 
Approval Date & Time: 21-Dec-2021 15:48:04 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 21-Dec-2021 16:34:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Dec-2021 09:42:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Dec-2021 14:40:18 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD