Evaluation of the Effect of Food, Omeprazole, Itraconazole, and Carbamazepine on the Pharmacokinetics of LY3484356 in Healthy Females of Non-Child-Bearing Potential
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
Protocol J2J-MC-JZLD (b) 
 
 
EvaluaƟon of the Eﬀect of Food, Omeprazole, Itraconazole, and Carbamazepine on the 
PharmacokineƟcs of LY3484356 in Healthy Females of Non-Child-Bearing PotenƟal 
 
 
NCT04840888 
 
 
Approval Date: 06-Oct-2021 

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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 LY3484356, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act Exemption 4 and may not be reproduced or otherwise 
disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: Evaluation of the Effect of Food, Omeprazole, Itraconazole, and Carbamazepine
on the Pharmacokinetics of LY3484356 in Healthy Females of Non-Child-
Bearing Potential
Protocol Number: J2J-MC-JZLD
Amendment Number: (b)
Compound: LY3484356
Study Phase: 1
Short Title: Effect of Food, Omeprazole, Itraconazole, and Carbamazepine on the 
Pharmacokinetics of LY3484356 in Healthy Females of Non-Childbearing Potential
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Numbers
IND: 145311
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 06-Oct-2021 GMT

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Medical Monitor Name and Contact Information will be provided separately.

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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
25-June-2021
Amendment (a)
03-September 2021
Amendment (b)
Overall Rationale for the Amendment:
Section # and Name
Description of Change
Brief Rationale
Synopsis
Section 4.1. Overall 
Design (Section 4.1.2. 
Treatment and 
Assessment Period)
Updated description of Cohort 1 treatment and 
assessment period to clarify that a crossover 
design is utilized. 
Added further descriptions of study design for 
each cohort for clarity. 
Minor changes for clarity. 
Section 1.2. Schema 
(Section 1.2.1. Cohort 1 
– Food-Effect)
Updated schema for Cohort 1 to make it 
clearer that a crossover design is utilized.
Minor changes for clarity.
Section 1.3. Schedule of 
Activities (Section 1.3.4. 
Cohort 4 –
Carbamazepine DDI)
Updated the comment for clinical laboratory 
tests to identify Day 9 instead of Day 8.
To correct inconsistency 
in previous protocol. 
6.1. Study 
Intervention(s) 
Administered
Removed the brand name ‘Tegretol’ for 
carbamazepine dosing. 
Tegretol will not be 
available to the site. 
Generic carbamazepine 
will be utilized instead.
5.1. Inclusion Criteria
Removed the note describing that WOCBP
could change to a contraception method 
unaffected by carbamazepine, for consistency 
with updates to Appendix 4. 
To provide clarification to 
the site on the acceptable 
contraception methods in 
Cohort 5, as 
carbamazepine impacts 
the effectiveness of many 
standard contraception 
methods.
10.4. Appendix 4: 
Contraceptive Guidance 
and Collection of 
Pregnancy Information
Updated description of acceptable 
contraception for WOCBP enrolled in Cohort 
5. Clarified that only a copper IUD or 
vasectomy of sexual partner will be considered 
acceptable highly effective forms of 
contraception. Levonorgestrel-releasing IUD 
or depot progestogen-only injection are not 
considered acceptable forms of contraception.
5.1. Inclusion Criteria
Removed bilateral tubal occlusion as an 
example of surgical sterilization to define 
female participants of non-childbearing 
potential. As per Appendix 4, fallopian tube 
implants (ie, tubal occlusion) were already 
To ensure consistency 
throughout the protocol 
and adhere to site 
guidance regarding 
surgical sterilization 
methods.
10.4. Appendix 4: 
Contraceptive Guidance 

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Section # and Name
Description of Change
Brief Rationale
and Collection of 
Pregnancy Information
defined as a method of highly effective 
contraception. 
Throughout
Minor editorial and formatting changes
Minor, therefore have not 
been summarized. 
Abbreviations: DDI = drug-drug interaction; IUD = intrauterine device; WOCBP = women of childbearing 
potential. 

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Table of Contents
1.
Protocol Summary......................................................................................................8
1.1.
Synopsis.......................................................................................................................8
1.2.
Schema.......................................................................................................................12
1.2.1.
Cohort 1 – Food-Effect...............................................................................................12
1.2.2.
Cohort 2 – PPI-Effect .................................................................................................13
1.2.3.
Cohort 3 – Itraconazole DDI.......................................................................................14
1.2.4.
Cohort 4 – Carbamazepine DDI..................................................................................15
1.2.5.
Cohort 5 – Carbamazepine with Midazolam ...............................................................16
1.3.
Schedule of Activities (SoA) ......................................................................................17
1.3.1.
Cohort 1 – Food-Effect...............................................................................................17
1.3.2.
Cohort 2 – PPI-Effect .................................................................................................21
1.3.3.
Cohort 3 – Itraconazole DDI.......................................................................................25
1.3.4.
Cohort 4 – Carbamazepine DDI..................................................................................29
1.3.5.
Cohort 5 (optional) – Carbamazepine DDI with Midazolam........................................33
2.
Introduction..............................................................................................................37
2.1.
Study Rationale ..........................................................................................................37
2.2.
Background ................................................................................................................37
2.3.
Benefit/Risk Assessment ............................................................................................38
3.
Objectives and Endpoints.........................................................................................41
4.
Study Design .............................................................................................................42
4.1.
Overall Design............................................................................................................42
4.1.1.
Screening....................................................................................................................42
4.1.2.
Treatment and Assessment Period...............................................................................42
4.1.3.
Follow-up...................................................................................................................44
4.2.
Scientific Rationale for Study Design .........................................................................44
4.3.
Justification for Dose..................................................................................................44
4.3.1.
LY3484356 ................................................................................................................44
4.3.2.
Omeprazole ................................................................................................................46
4.3.3.
Itraconazole................................................................................................................46
4.3.4.
Carbamazepine ...........................................................................................................46
4.3.5.
Midazolam .................................................................................................................47
4.4.
End of Study Definition..............................................................................................47
5.
Study Population ......................................................................................................48
5.1.
Inclusion Criteria........................................................................................................48
5.2.
Exclusion Criteria.......................................................................................................49
5.3.
Lifestyle Considerations .............................................................................................51
5.3.1.
Meals and Dietary Restrictions ...................................................................................51
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................52
5.3.3.
Activity ......................................................................................................................52
5.3.4.
Other ..........................................................................................................................52
5.4.
Screen Failures...........................................................................................................53
6.
Study Intervention....................................................................................................54
6.1.
Study Intervention(s) Administered ............................................................................54

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6.1.1.
Administration Details................................................................................................54
6.2.
Preparation/Handling/Storage/Accountability.............................................................56
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................56
6.4.
Study Intervention Compliance...................................................................................56
6.5.
Concomitant Therapy .................................................................................................56
6.6.
Dose Modification......................................................................................................57
6.7.
Intervention After the End of the Study ......................................................................57
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................58
7.1.
Discontinuation of Study Intervention ........................................................................58
7.1.1.
Liver Enzymes and Other Laboratory Tests ................................................................58
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................59
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................59
7.3.
Lost to Follow-up .......................................................................................................60
8.
Study Assessments and Procedures .........................................................................61
8.1.
Efficacy Assessments .................................................................................................61
8.2.
Safety Assessments ....................................................................................................61
8.2.1.
Physical Examinations................................................................................................61
8.2.2.
Vital Signs..................................................................................................................61
8.2.3.
Electrocardiograms.....................................................................................................61
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................62
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring.........................................................62
8.2.6.
Safety Monitoring.......................................................................................................63
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................66
8.3.1.
Timing and Mechanism for Collecting Events ............................................................66
8.4.
Treatment of Overdose ...............................................................................................68
8.5.
Pharmacokinetics........................................................................................................68
8.5.1.
Bioanalysis .................................................................................................................68
8.6.
Pharmacodynamics.....................................................................................................69
8.7.
Genetics .....................................................................................................................69
8.8.
Biomarkers.................................................................................................................69
8.9.
Immunogenicity Assessments.....................................................................................69
8.10.
Health Economics.......................................................................................................69
9.
Statistical Considerations.........................................................................................70
9.1.
Statistical Hypotheses.................................................................................................70
9.2.
Analyses Sets .............................................................................................................70
9.2.1.
Study Participant Disposition......................................................................................70
9.2.2.
Study Participant Characteristics.................................................................................70
9.2.3.
Treatment Compliance................................................................................................70
9.3.
Statistical Analyses.....................................................................................................70
9.3.1.
Safety Analyses ..........................................................................................................71
9.3.2.
Pharmacokinetic Analyses ..........................................................................................71
9.3.3.
Pharmacodynamic Analyses .......................................................................................72
9.3.4.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................72

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9.4.
Interim Analysis .........................................................................................................72
9.5.
Sample Size Determination.........................................................................................72
10.
Supporting Documentation and Operational Considerations ................................73
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................73
10.1.1.
Regulatory and Ethical Considerations........................................................................73
10.1.2.
Financial Disclosure ...................................................................................................73
10.1.3.
Informed Consent Process ..........................................................................................74
10.1.4.
Data Protection...........................................................................................................74
10.1.5.
Dissemination of Clinical Study Data .........................................................................75
10.1.6.
Data Quality Assurance ..............................................................................................75
10.1.7.
Source Documents......................................................................................................76
10.1.8.
Study and Site Start and Closure.................................................................................77
10.1.9.
Publication Policy.......................................................................................................77
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................78
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................80
10.3.1.
Definition of AE.........................................................................................................80
10.3.2.
Definition of SAE.......................................................................................................81
10.3.3.
Definition of Product Complaints ...............................................................................82
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................82
10.3.5.
Reporting of SAEs......................................................................................................84
10.3.6.
Regulatory Reporting Requirements ...........................................................................84
10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................86
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................89
10.6.
Appendix 6: Abbreviations .........................................................................................91
11.
References.................................................................................................................93

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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: Evaluation of the Effect of Food, Omeprazole, Itraconazole, and Carbamazepine
on the Pharmacokinetics of LY3484356 in Healthy Females of Non-Child-Bearing Potential
Short Title: Effect of Food, Omeprazole, Itraconazole, and Carbamazepine on the 
Pharmacokinetics of LY3484356 in Healthy Females of Non-Childbearing Potential
Rationale:
Study J2J-MC-JZLD (JZLD) is a Phase 1 open-label, 5-cohort study of LY3484356 administered 
to healthy females of non-childbearing potential. The purpose of 4 cohorts of this study is to 
assess the safety, tolerability and PK of LY3484356 when dosed with and without food, and in 
the presence of omeprazole, carbamazepine, or itraconazole.
The results of this study will inform dosing restrictions in ongoing patient trials.  
In addition, an exploratory and optional 5th cohort is included for the assessment of the PK of
midazolam, a known sensitive CYP3A substrate, when dosed with carbamazepine. The results of 
this cohort will inform dosing regimens for future carbamazepine drug-drug interaction studies.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To assess the effect of food on the 
pharmacokinetics (PK) of LY3484356
after a low-fat meal in healthy females
of non-childbearing potential

To assess the effect of a gastric pH 
change on the PK of LY3484356 after 
multiple doses of a PPI (omeprazole) 
in healthy females of non-childbearing 
potential

Assess the effect of coadministration 
of LY3484356 given as a single dose 
(drug-drug interaction [DDI] victim) 
with itraconazole, on the PK of 
LY3484356 in healthy females of non-
childbearing potential

AUC(0-∞), Cmax, tmax of LY3484356

AUC(0-∞), Cmax, tmax of LY3484356

AUC(0-∞), Cmax, tmax of LY3484356

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
Assess the effect of coadministration 
of LY3484356 given as a single dose 
(DDI victim) with carbamazepine, on 
the PK of LY3484356 in healthy 
females of non-childbearing potential

AUC(0-∞), Cmax, tmax of LY3484356
Secondary

To evaluate the safety and tolerability 
of single 
 doses of 
LY3484356 in healthy females of 
non-childbearing potential

Incidence and severity of adverse 
events (AEs) and serious adverse 
events (SAEs)
Overall Design
Screening 
All participants will be screened within 28 days prior to enrollment.
Treatment and Assessment Period
Safety assessments, including AEs, concomitant medications, medical assessments, clinical 
laboratory tests, vital signs, and ECGs, and blood sampling for PK, will be performed for all 
cohorts.
Cohort 1 – Food-Effect
Cohort 1 will be an open-label, randomized, crossover design evaluating the effect of food on 
LY3484356. Eligible participants will take place in 2 treatment periods. Participants will be 
admitted to the clinical research unit (CRU) on Day -1. On Day 1 of Treatment Period 1, 
participants will be randomized (1:1) to 1 of 2 treatment sequences; fasted/fed or fed/fasted. . All 
participants will receive (according to the randomization schedule):

Day 1 Treatment Period 1:
LY3484356 in the fed or fasted state

Day 1 Treatment Period 2:
 LY3484356 in the fed or fasted state
There will be a washout period of 4 days between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 5 of Treatment Period 2.
Cohort 2 – PPI-Effect
Cohort 2 will be an open-label, fixed sequence design evaluating the effect of PPI on 
LY3484356. Eligible participants will take place in 1 treatment period. Participants will be 
admitted to the CRU on Day -1. All participants will receive:
There will be a washout period of 
 between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 14.
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Cohort 3 – Itraconazole Drug-Drug Interaction
Cohort 3 will be an open-label, fixed sequence design evaluating a potential drug-drug 
interaction of itraconazole on LY3484356. Eligible participants will take place in 1 treatment
period. Participants will be admitted to the CRU on Day -1. All participants will receive:
There will be a washout period of 
 between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 17.
Cohort 4 – Carbamazepine Drug-Drug Interaction
Cohort 4 will be an open-label, fixed sequence design evaluating a potential drug-drug 
interaction of carbamazepine on LY3484356. Eligible participants will take place in 1 treatment
period. Participants will be admitted to the CRU on Day -1. All participants will receive:
There will be a washout period of 
 between doses of LY3484356. All participants will
remain resident in the CRU until discharge on Day 27.
Cohort 5 (optional) – Carbamazepine Drug-Drug Interaction with Midazolam
Cohort 5 will be an open-label, fixed sequence design evaluating a potential drug-drug 
interaction of carbamazepine on midazolam. Eligible participants will take place in 1 treatment
period. Participants will be admitted to the CRU on Day -1. All participants will receive:
All participants will remain resident in the CRU until discharge on Day 15.
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Follow-up
Participants will attend a follow-up visit 7 to 10 days after discharge from the CRU.
Disclosure Statement: This is an open-label 5-cohort study. Cohort 1 is a 2-period, randomized,
crossover design evaluating the effect of food on LY3484356. Cohort 2 is a single period, fixed 
sequence design evaluating the effect of PPI on LY3484356. Cohort 3 is a single period, fixed 
sequence design evaluating a potential drug-drug interaction of itraconazole on LY3484356.
Cohort 4 is a single period, fixed sequence design evaluating a potential drug-drug interaction of 
carbamazepine on LY3484356. Cohort 5 is a single period, fixed sequence design evaluating a 
potential drug-drug interaction of carbamazepine on midazolam. Cohort 1-4 include healthy 
females of non-childbearing potential (defined as postmenopausal or infertile due to surgical 
sterilization or alternate medical cause/congenital anomaly). Cohort 5, which does not include 
exposure to LY3484356 is open to healthy males and non-pregnant and non-lactating females.
Number of Participants:
In Cohorts 1 and 2, approximately 10 participants will be enrolled in each cohort to ensure that at 
least approximately 8 evaluable participants in each cohort complete the study. 
In Cohort 3, approximately 20 participants will be enrolled to ensure that at least approximately 
18 evaluable participants in this cohort complete the study. 
In Cohort 4, approximately 26 participants will be enrolled to ensure that at least approximately 
18 evaluable participants in this cohort complete the study. 
In Cohort 5 (optional), approximately 15, participants will be enrolled to ensure that at least 
approximately 10 evaluable participants in this cohort complete the study. 
Intervention Groups and Duration:
Participants in Cohort 1 will participate in 2 treatment periods, and participants in Cohorts 2, 3, 
4, and 5 will participate in 1 treatment period. Participants will be screened within 28 days prior 
to enrollment and will receive 
 oral 
doses of LY3484356 or
with a follow-up visit 7 to 10 days after 
discharge from the study site.
The study duration for participants in each cohort is expected to be as follows:

Cohort 1 – Food-Effect: 44 to 47 days

Cohort 2 – PPI-Effect: 49 to 52 days

Cohort 3 – Itraconazole Drug-Drug Interaction: 52 to 55 days

Cohort 4 – Carbamazepine Drug-Drug Interaction: 62 to 65 days

Cohort 5 – Carbamazepine Drug-Drug Interaction with Midazolam (optional): 50 to 
53 days
Data Monitoring Committee: No
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2.
Introduction
LY3484356 is an orally bioavailable, non-covalent, selective estrogen receptor degrader 
(SERD). It is a potent degrader and selective antagonist of wild-type and mutant estrogen 
receptor α (ERα or ESR1). Full details of the preclinical safety, efficacy, and pharmacokinetics 
(PK) may be found in the Investigator’s Brochure (IB).
2.1.
Study Rationale
Study J2J-MC-JZLD (JZLD) is a Phase 1 open-label, 5-cohort study of LY3484356 administered 
to healthy females of non-childbearing potential. The purpose of this study is to assess the effect 
of food on LY3484356, to assess the effect of gastric acid by use of a proton pump inhibitor 
(PPI; omeprazole) on LY3484356 in the fasted state, and to investigate the effect of the 
inhibition and induction of CYP3A by use of itraconazole or carbamazepine on LY3484356 in 
the fasted state. The results of this study will inform dosing instructions in ongoing patient trials.  
In addition, an exploratory and optional 5th cohort is included in this study for the assessment of 
the PK of midazolam, a known sensitive CYP3A substrate, when dosed with carbamazepine. The 
results of this cohort will inform dosing regimens for future carbamazepine drug-drug interaction 
studies. 
2.2.
Background
Breast cancer is the most frequent cancer among women and is a major cause of cancer-related 
deaths worldwide. It is estimated that more than 2 million new cases of breast cancer occurred 
worldwide in women in 2018 (Bray et al. 2018). Clinical decision-making for the management of 
patients with advanced breast cancer takes into account multiple clinical factors such as hormone 
receptor-positive (HR)/HER2 status, age, comorbidities, and patient preference. More 
specifically, treatment options for women with breast cancer are largely determined by tumor HR 
and HER2 status (NCCN 2018; Waks and Winder 2019). 
Over two thirds of breast cancers express estrogen receptor (ER), which is a key driver of breast 
cancer initiation and progression. Hormone receptor-positive mBC is incurable and therefore 
considered a serious and life-threatening disease, with a median overall survival of only 2 to 
3 years (Cardoso et al. 2012). For patients with advanced HR+/HER2- status, treatment includes 
endocrine therapy (ET) (eg, tamoxifen, anastrozole, letrozole, fulvestrant) alone or in 
combination with cyclin-dependent kinase (CDK) 4 and 6 inhibitors as indicated (eg, 
abemaciclib, palbociclib, or ribociclib), as well as standard chemotherapy (eg, capecitabine, 
docetaxel, paclitaxel, nab-paclitaxel [NCCN 2018; Waks and Winer 2019]). For patients with 
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advanced HR+/HER2+ status, treatment includes HER2-directed therapies eg, trastuzumab,
pertuzumab, TDM-1 administered alone and in combination with other HER2-directed therapies, 
chemotherapy, or ET.
In most ER+ breast cancers, ER is an important therapeutic target even after development of 
resistance to endocrine therapies (Weatherman et al. 1999; Baselga et al. 2012; Turner et al. 
2015; Finn et al. 2016; André et al. 2019).
Selective estrogen receptor degraders (SERDs) are one of the treatment options for estrogen 
receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast 
cancer patients. Fulvestrant is currently the only regulatory agency-approved SERD for the 
treatment of ER+ metastatic breast cancer (mBC) [Nardone et al. 2019]). Its efficacy is highly 
dose-dependent, where increasing the administered dose led to improved survival (Di Leo et al. 
2014). However, the intramuscular (IM) route of fulvestrant administration limits the amount of 
fulvestrant that can be given to patients. Even though doses higher than 500 mg per month may 
lead to better ER degradation, the IM administration route limits the amount of fulvestrant that 
can be given to patients (Nardone et al. 2019). In addition, several studies have shown that with 
the current maximum feasible dose, fulvestrant treatment is not able to completely degrade ER in 
patients and can be associated with early progression (van Kruchten et al. 2015). Thus, there is 
unmet medical need to develop oral SERDs with higher bioavailability, greater ER targeting, and 
degradation efficiency (Nardone et al. 2019). 
2.3.
Benefit/Risk Assessment
LY3484356 is a potent antagonist and degrader of ERα and has demonstrated significant activity 
in preclinical models against ER wild-type and mutant tumors. There is no anticipated benefit for 
the healthy participants in this study.
Due to the early stage of the development of LY3484356, the clinical safety profile has not been 
fully established. There is no previous experience of LY3484356 in healthy participants. 
LY3484356 has been administered to patients in clinical study J2J-MC-JZLA (JZLA) (200- to 
1200-mg QD for 28 days).
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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the effect of food on the PK
of LY3484356 after a low-fat meal in 
healthy females of non-childbearing 
potential

To assess the effect of a gastric pH 
change on the PK of LY3484356 after 
multiple doses of a PPI (omeprazole) 
in healthy females of non-childbearing 
potential

Assess the effect of coadministration 
of LY3484356 given as a single dose 
(DDI victim), with itraconazole, on the 
PK of LY3484356 in healthy females
of non-childbearing potential

Assess the effect of coadministration 
of LY3484356 given as a single dose 
(DDI victim) with carbamazepine, on 
the PK of LY3484356 in healthy 
females of non-childbearing potential

AUC(0-∞), Cmax, tmaxof LY3484356

AUC(0-∞), Cmax, tmaxof LY3484356

AUC(0-∞), Cmax, tmax of LY3484356

AUC(0-∞), Cmax, tmax of LY3484356
Secondary

To evaluate the safety and tolerability 
of single 
 doses of 
LY3484356 in healthy females of 
non-childbearing potential

Incidence and severity of adverse 
events (AEs) and SAEs
Exploratory

Assess the PK of carbamazepine and
carbamazepine 10,11-epoxide

Investigate the impact of 
coadministration of carbamazepine on 
the PK of midazolam 

Assess exosomal mRNA in plasma

Cmax and AUC of carbamazepine and 
carbamazepine 10,11-epoxide

Cmax and AUC of midazolam and 1’-
hydroxymidazolam with and without 
carabamazepine.

Exosomal mRNA in plasma
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4.
Study Design
4.1.
Overall Design
Study JZLD is an open-label, 5-cohort, study comprising 4 fixed-sequence crossover cohorts,
and 1 randomized (1:1), 2-period crossover cohort. Cohorts 1 to 4 are in healthy females of 
non-childbearing potential to investigate the safety, tolerability, and PK of LY3484356 when 
administered as a 
oral dose, when dosed with and without food, and in the 
presence of omeprazole, or carbamazepine, and when administered as a 
 oral dose 
when dosed in the presence of itraconazole. Optional and exploratory Cohort 5 is in healthy 
participants (males and non-pregnant and non-lactating females) to investigate the PK of the 
sensitive CYP3A substrate midazolam (and 1’-hydroxymidazolam) when dosed at various times 
in the presence of carbamazepine.
The schema in Section 1.2 illustrates the study design.
Safety assessments, including AEs, concomitant medications, medical assessments, clinical 
laboratory tests, vital signs, and ECGs, and blood sampling for PK, will be performed according 
to the SoA (Section 1.3).
4.1.1.
Screening 
All participants will be screened within 28 days prior to enrollment.
4.1.2.
Treatment and Assessment Period
Cohort 1 – Food-Effect
Cohort 1 will be an open-label, randomized, crossover design evaluating the effect of food on 
LY3484356. Eligible participants will take place in 2 treatment periods. Participants will be 
admitted to the clinical research unit (CRU) on Day -1. On Day 1 of Treatment Period 1, 
participants will be randomized (1:1) to 1 of 2 treatment sequences; fasted/fed or fed/fasted. All 
participants will receive (according to the randomization schedule):
There will be a washout period of 
 between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 5 of Treatment Period 2.
Cohort 2 – PPI-Effect
Cohort 2 will be an open-label, fixed sequence design evaluating the effect of PPI on 
LY3484356. Eligible participants will take place in 1 treatment period. Participants will be 
admitted to the CRU on Day -1. All participants will receive:
There will be a washout period of 
 between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 14.
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Cohort 3 – Itraconazole Drug-Drug Interaction
Cohort 3 will be an open-label, fixed sequence design evaluating a potential drug-drug 
interaction of itraconazole on LY3484356. Eligible participants will take place in 1 treatment
period. Participants will be admitted to the CRU on Day -1. All participants will receive:
There will be a washout period of 
 between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 17.
Cohort 4 – Carbamazepine Drug-Drug Interaction
Cohort 4 will be an open-label, fixed sequence design evaluating a potential drug-drug 
interaction of carbamazepine on LY3484356. Eligible participants will take place in 1 treatment
period. Participants will be admitted to the CRU on Day -1. All participants will receive:
There will be a washout period of 
 between doses of LY3484356. All participants will 
remain resident in the CRU until discharge on Day 27.
Cohort 5 (optional) – Carbamazepine Drug-Drug Interaction with Midazolam
Cohort 5 will be an open-label, fixed sequence design evaluating a potential drug-drug 
interaction of carbamazepine on midazolam. Eligible participants will take place in 1 treatment
period. Participants will be admitted to the CRU on Day -1. All participants will receive:
All participants will remain resident in the CRU until discharge on Day 15.
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4.1.3.
Follow-up
Participants will attend a follow-up visit 7 to 10 days after discharge from the CRU.
4.2.
Scientific Rationale for Study Design
The 2-period, (1:1) randomized crossover design used in Cohort 1 has been chosen as this gives 
a within-participant assessment as well as effects of period and sequence on the PK of 
LY3484356 and so increases the power of the study for the given number of participants. The 
fixed-sequence, crossover design used in Cohorts 2 to 4 of this study is typical for interaction 
studies where a relatively small number of participants are required, because it allows 
intraparticipant comparisons and eliminates interparticipant comparisons.
This study will be open-label because the study endpoints are not considered subjective.
Conducting studies in healthy participants mitigates the potential confounding effects of the 
disease state and concomitant medications, and avoids non-beneficial drug exposures in cancer 
patients. Healthy females of non-childbearing potential have been selected as the study 
population since the pharmacologic mechanism of LY3484356 is to degrade the ER, and effects 
on the female reproductive organs are expected.
In Cohort 2, omeprazole was selected over antacids drugs because the PPI drug class is 
considered to suppress gastric acid secretion to a greater extent and for a longer duration than 
some other gastric pH-elevating agents, such as H2 blockers and antacids.
In Cohort 3, itraconazole has been chosen as the probe drug for Cohort 3 as it is a recommended 
CYP3A4 inhibitor by the FDA for quantifying clinical victim DDI (Chen et al. 2019). 
In Cohorts 4 and 5, carbamazepine has been chosen as the probe drug for Cohorts 4 and 5 as it is 
an inducer of several cytochrome P450 (CYP) and enzymes responsible for glucuronidation 
(UGTs). A fixed-sequence design has been selected in these cohorts due to the potential for 
carryover effects from carbamazepine dosing: the CYP induction caused by carbamazepine can 
linger for several weeks (Magnusson M et al 2008), which would require an increased study 
length if a 2-sequence crossover design were selected. In addition, fixed-sequence design is 
commonly used for DDI studies, and is consistent with FDA guidance.
4.3.
Justification for Dose
4.3.1.
LY3484356
The clinical safety experience from the JZLA study is described in Section 2.3. LY3484356 was 
well tolerated at dose levels of 200 mg to 1200 mg once-daily (QD) with no dose-limiting toxicities 
in Cycle 1. No MTD was established during dose escalation. Given the totality of efficacy, clinical 
PK, and safety data, the sponsor has selected the 400 mg (QD) dose level to be evaluated in planned 
patient trials.
The recommended Phase 2 dose of 
 will be used in the food effect and PPI parts of the 
study (Cohorts 1 and 2). 
 
 
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As described in the IB and Section 2.3,
 
 
 
 
 
(Table JZLD.1).
The planned safety monitoring (Section 8.2), clinical tolerability, and favorable nonclinical 
toxicity profile of LY3484356 support administration of 2 LY3484356 doses (≤
per 
dose) to healthy females of non-childbearing potential in the present study. 
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4.3.2.
Omeprazole
A dose of 
 omeprazole daily is within the recommended dose as prescribed in the labeling. 
In addition, multiple doses for 4 consecutive days prior to combination dosing with LY3484356
will ensure maximum inhibition of acid secretion by omeprazole, because the inhibitory effect of 
omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after 
4 days.
4.3.3.
Itraconazole
Itraconazole will be administered as a solution at 
, then 
 until 
the administration of LY3484356 on 
, followed by continued QD administration until 
 This regimen of loading dose, run-in and post-substrate administration is considered 
optimal to elicit CYP3A4 inhibition.
4.3.4.
Carbamazepine
A course of 100 mg BID for 3 days, followed by 200 BID for 3 days and 300 mg BID for 
12 days carbamazepine has been selected based on recommendations from the FDA and previous 
reported doses used to investigate drug-drug interactions with carbamazepine.  
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Participants will continue dosing with carbamazepine following LY3484356 administration on 
Day 18 in order to maintain enzyme induction until the PK sampling period is completed. The 
planned dose levels are within the limits of the recommended therapeutic dose range to treat 
patients with various medical conditions.
Significant adverse reactions reported with carbamazepine include serious dermatological 
reactions, strongly associated with HLA-B*1502 and HLA-A*3101 alleles more common 
in East Asian populations; aplastic anemia and agranulocytosis; hypersensitivity 
reactions, including drug reactions with eosinophilia and systemic symptoms (DRESS), 
anaphylactic reactions and angioedema; and suicidal behavior and ideation. The majority 
of these severe reactions are rarely reported.  
Particularly at the start of treatment, or if the initial dosage is too high, or when treating 
elderly patients, certain types of adverse reaction occur very commonly or commonly, 
e.g. central nervous system adverse reactions (dizziness, headache, ataxia, drowsiness, 
fatigue, diplopia), gastrointestinal disturbances (nausea, vomiting), as well as allergic 
skin reactions. The dose-related adverse reactions usually abate within a few days, either 
spontaneously or after a transient dosage reduction.
In DDI studies in which carbamazepine was administrated to healthy participants for less 
than 1 month in duration, carbamazepine was found to be tolerated with appropriate 
safety monitoring (Sitsen et al. 2001).
4.3.5.
Midazolam 
Midazolam is a sensitive CYP3A4 substrate recommended by the FDA for quantifying clinical 
perpetrator DDI. A 
 oral dose of midazolam is mildly sedating and high enough to ensure 
that midazolam concentrations remain above the detection limit of the assay 
 to 
characterize the CYP3A4 induction potential of carbamazepine. A 
 dose of midazolam is 
a dose considered safe to administer and has been used in previous clinical studies.
4.4.
End of Study Definition
A participant is considered to have completed the study if she has completed all scheduled 
procedures shown in the SoA (Section 1.3).
The end of the study is defined as the date of the last visit of the last participant in the study.
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C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2J-M C -J Z L D ( b)
4 8
5.
St u d y P o p ul ati o n
Eli gi bilit y of  p artici pa nts f or e nr oll me nt i n t he st u d y will be base d on t he res ults of scree ni n g 
me dical hist or y , p h ysical e xa mi nati on, vital si g ns, cli nical la b orat or y  tests, a n d E C G. All 
parti ci pa nts will be w o me n of n o n -c hil d beari n g p ote ntial.
T he nat ure of a n y c o n dit i ons prese nt at t he ti me of t he p h ysical e xa mi nat i on a n d a n y pre -e xist i n g 
c o n ditio ns will  be d o c u me nte d.
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, is n ot per mitte d.
5. 1.
I ncl usi o n Criteri a
P arti cipa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he fol l owi n g criteria a p pl y:
A ge
1.
P arti cip a nt m ust be 1 8 t o 6 5 years of a ge i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.
T y pe of P artici p a nt 
2.
P arti cipa nts w h o are o vertl y healt h y as deter mi ne d b y me dical assess me nt i ncl u di n g 
me dical hist or y , p h ysical e xa mi nati on, l a b orat or y tests, a n d vit al si g ns.
3.
P arti cipa nts w h o ha ve cli nical la b orat or y  test res ults wit hi n t he n or mal refere nce ra n ge 
f or t he p o p ulat i on or i n vest i gati ve site, or res ults with acce pta ble de viat i ons t hat are 
j u d ge d t o be n ot cli nicall y si g nifica nt b y t he i n vesti gat or.
4.
P arti cipa nts w h o ha ve ve n o us access s ufficie nt t o all o w f or bl o o d sa m pli n g as per t he 
pr ot oc ol .
Wei g ht
5.
B o d y  mass i n de x wit hi n t he ra n ge 1 8 . 0 t o 3 5. 0 k g/ m 2 (incl usi ve).
F or C o h orts 1 -4 Se x
6.
F e male parti ci pa nts of  n o n-c hil d beari n g p ote ntial. T his i ncl u des fe males w h o are n ot 
pre g na nt, n o n -lactati n g a n d eit her :

I nfertile d ue t o s ur gical sterilizati o n ( h ysterect o m y, bilateral o o p h orect o m y or 
bilateral  sal pi n gect o m y, or bilateral t u bal li gatio n), or alt er nate me dical 
ca use/c o n ge nital a n o mal y (for e xa m ple, M ülleria n a ge nesis )
or

P os t me n o pa usal as defi ne d i n A p pe n di x 4 ( Secti o n 1 0. 4 )
F or C o h ort 5 Se x
I n a d diti on t o C o h ort 1 - 4 se x criteria, C o h ort 5 m a y als o i nclu de ma le partici pa nts a n d 
n o n- pre g na nt a n d n o n -lact atin g fe male partici pa nts of  c hil d beari n g p ote ntial.
C o ntrace pti ve use b y partici pa nts s h o ul d be c o nsiste nt wit h l ocal re g ulati ons re gar di n g t he 
met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies.

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Protocol number J2J-MC-JZLD (b)
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Reproductive definitions and contraceptive requirements are provided in Appendix 4 
(Section 10.4).
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 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 LY3484356, related compounds or any components of the 
formulation, omeprazole, itraconazole, midazolam, or carbamazepine, as appropriate, or 
history of significant atopy
2. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, 
respiratory, endocrine, or psychiatric disorder, as determined by the investigator (or 
designee)
3. Current or chronic history of liver disease or known hepatic or biliary abnormalities
4. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the investigator (or designee)
5. Have a clinically significant abnormality of blood pressure and/or pulse rate as 
determined by the investigator
6. Have a history or presence of cardiovascular (eg, symptomatic bradycardia with resting 
heart rate of <60 beats per minute), respiratory, renal, gastrointestinal, endocrine, 
hematological, or neurological disorders 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. Appendectomy, hernia repair, 
and cholecystectomy are considered as acceptable
7. History of alcoholism or drug/chemical abuse within 2 years prior to check-in
8. Alcohol consumption of > 14 units for females and > 21 units in males. One unit of 
alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill 
(25 mL) of spirits
9. Positive ethanol breath/urine test result or positive urine drug screen at screening or 
check-in
10. Show evidence of hepatitis B, positive hepatitis B core antibody, and/or positive hepatitis 
B surface antigen. 
11. Show evidence of hepatitis C and/or positive hepatitis C antibody.
12. Have evidence of human immunodeficiency virus (HIV) infection and/or positive human 
HIV antibodies. 
13. Have donated blood of more than 500 mL within the previous 2 months of study 
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14. Have any medical conditions, medical history, or are taking any medications which are 
contraindicated in the omeprazole, itraconazole, midazolam, or carbamazepine labels, as 
appropriate
Prior/Concomitant Therapy
15. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior to 
dosing, unless deemed acceptable by the investigator (or designee)
16. Use or intend to use any prescription medications/products within 14 days prior to dosing
until completion of the follow-up visit, unless deemed acceptable by the investigator (or 
designee).
17. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to check-in, unless deemed acceptable by the investigator (or 
designee)
18. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to 
check-in until completion of the follow-up visit, unless deemed acceptable by the 
investigator (or designee)
19. Use or intend to use medications that inhibit or induce CYP3A4 within 14 days prior to 
dosing until completion of the follow-up visit. 
Prior/Concurrent Clinical Study Experience
20. Participation in a clinical study involving administration of an investigational drug (new 
chemical entity) in the past 30 days prior to dosing, or 5 half-lives; whichever is longer
21. Have previously completed or withdrawn from this study or any other study investigating 
LY3484356, and have previously received LY3484356
22. Have previously received a SERD in the past 30 days prior to dosing, or 5 half-lives; 
whichever is longer
Other Exclusions
23. Smoke more than 10 cigarettes or use the equivalent tobacco, smoking-cessation 
products, nicotine-containing products, or e-cigarettes (nicotine and non-nicotine) per 
day. Participants must be willing to abstain from smoking whilst resident at the CRU.
24. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages 
within 7 days prior to check-in.
25. Receipt of blood products within 2 months prior to check-in.
26. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to 
screening, or platelets from 6 weeks prior to screening.
27. Participants who, in the opinion of the investigator (or designee), should not participate in 
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In addition, for Cohort 3 only:
28. Have impaired hearing or a history of hearing problems (rationale: because itraconazole 
has been associated with transient or permanent hearing loss).
In addition, for Cohorts 4 and 5 only (due to carbamazepine administration):
29. Participants of Asian descent.
30. Have history of serious dermatological adverse reaction, such as toxic epidermal 
necrolysis, Stevens-Johnson syndrome, DRESS; or history of other significant 
allergic drug reaction, such as anaphylaxis or angioedema.
31. Have laboratory evidence of clinically significant anemia, leukopenia, or hepatic 
dysfunction; or hyponatremia.
32. History of significant neurological or psychological illness.
33. Are, in the judgment of the investigator, actively suicidal and therefore deemed to 
be at significant risk for suicide.
34. Have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the Columbia Suicide Severity Rating Scale (C-SSRS) or have answered “yes” 
to any of the suicide-related behaviors on the “suicidal behavior” portion of the C-SSRS,
and the ideation or behavior occurred within the past month.
In addition, for Cohort 5 females only (due to carbamazepine administration):
35. Use or intend to use any oral contraceptive drugs containing estrogen and/or progesterone
within 30 days prior to dosing
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions
During the confinement period, participants will consume only food and beverages that are 
provided to them by the CRU staff. Standard meals (e.g., breakfast, lunch, dinner, and snack) 
will be provided to the participants while resident at the CRU.
LY3484356 will be dosed in the fasted state with the exception of in the fed period of Cohort 1. 
On fasted dosing occasions, the participants will be fasted overnight (at least 10 hours) prior to 
dosing and refrain from consuming water from 1 hour predose until 2 hours postdose, excluding 
the amount of water consumed at dosing. Food is allowed from 4 hours postdose. At all other 
times during the study, participants may consume water ad libitum. 
When participants are dosed in the fed state, they will consume a low-fat breakfast 30 minutes 
prior to administration of study intervention and participants should eat this meal in 30 minutes 
or less. No additional food should be allowed for at least 4 hours after drug administration. An 
example of the low-fat breakfast to be provided is as follows:

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PRO
FAT
CHO
Calories
1c Special K Berry
2.0
0.0
27.0
116.0
4oz Fruit Cup (no citrus)
0.0
0.0
19.0
76.0
1 Slice Toast White Bread
3.0
0.5
12.0
64.5
1 oz Jelly (1 Tbsp)
0.0
0.0
13.0
52.0
1 hard-boiled egg
6.3
5.3
0.6
77
8oz 1% Milk
8.0
1.0
12.0
89.0
Totals
13.0
1.5
113.0
517.5
Total Calories
52
13.5
452
% of Calories
10%
3%
87%
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 7 days prior to check-in until follow-up. In addition, all other citrus fruits and 
tomato-based products will not be allowed from the time of check-in until discharge from the 
CRU.
5.3.2.
Caffeine, Alcohol, and Tobacco
1. During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours 
before the start of dosing until after collection of the final pharmacokinetic (PK) sample.
2. During each dosing session, participants will abstain from alcohol for 24 hours before the 
check-in until after collection of the final PK sample.
3. Participants are required to refrain from use of tobacco, smoking-cessation products, 
nicotine containing products, and e-cigarettes (nicotine and non-nicotine) from check-in
and through discharge from the CRU
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 studies 
(e.g., watching television, reading).
5.3.4.
Other
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5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are
not subsequently enrolled in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Individuals may be rescreened up to 1 time. The interval between re-screenings 
should be at least 1 week. Each time rescreening is performed, the individual must sign a new 
ICF and will be assigned a new identification number.
If subjects have minor deviations in screening assessments (e.g., laboratory safety tests, vital 
signs) these may be repeated at the investigator’s discretion to confirm eligibility.
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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Intervention(s) Administered
Table JZLD.2.
Study Interventions Administered
Study 
Intervention 
LY3484356
(Cohorts 1, 2, and 
4)
LY3484356
(Cohort 3)
Omeprazole
(Cohort 2)
Itraconazole 
(Cohort 3)
Carbamazepine 
(Cohorts 4 and 5)
Midazolam 
(Cohort 5)
Dosage 
Formulation
Tablet
Tablet
Capsule
Solution
Tablet 
Syrup
Unit dose 
strength(s)/
Dosage Level(s)
 
 
 
 
 
Route of 
Administration
Oral
Oral
Oral
Oral
Oral
Oral
Dosing 
Instructions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sourcing
 
 
 
 
 
 
Abbreviation: TP = treatment period
6.1.1.
Administration Details
All doses of LY3484356 will administered with approximately 240 mL of room temperature 
water while in a sitting position. 
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LY3484356 tablets should be swallowed whole. Participants should not break, crush, or chew the
study intervention.
Participants will not be allowed to lie supine for 2 hours after each dosing occasion, unless 
clinically indicated or for study procedures.
On dosing days, participants will adhere to meal restrictions as outlined in Section 5.3.1.
Cohort 1 – Food-Effect
A single oral dose of LY3484356
 will be administered in the morning of Day 1 in each 
treatment period. 
Cohort 2 – PPI-Effect
A single oral dose of LY3484356
 will be administered in the morning of 
Single oral doses of omeprazole 
 will be administered alone on 
 and in 
combination with LY3484356
 on Day 
All doses of omeprazole will be administered 
with approximately 240 mL of room temperature water while in a sitting position. No additional 
water is required when omeprazole is dosed in combination with LY3484356.
Omeprazole capsules should be swallowed whole. Participants should not break, crush, chew, or 
empty the contents of the study intervention.
Cohort 3 – Itraconazole Drug-Drug Interaction
A single oral dose of LY3484356
 will be administered in the morning of Days 
 
Single oral doses of itraconazole 
 will be administered alone on Days 
 
 
No additional water is required 
when dosing with itraconazole alone.
Cohorts 4 and 5 – Carbamazepine Drug-Drug Interaction
In Cohort 4, a single oral dose of LY3484356
will be administered in the morning of 
Days 
 Twice-daily oral doses of carbamazepine will be administered alone as 
 
 Carbamazepine will be administered with LY3484356 on the 
morning of Day 
In Cohort 5, a single oral dose of midazolam 
will be administered in the morning of 
Days
 Twice-daily oral doses of carbamazepine will be administered alone as 
 on Days 
 doses on Days 
 and 
 doses on Days
 
Carbamazepine will be administered with midazolam on the morning of Days 
Participants will not be allowed to lie supine for 2 hours after dosing carbamazepine, unless 
clinically indicated or for study procedure.
On days of LY3484356 or midazolam administration, LY3484356 or midazolam will be given 
after an overnight fast of at least 10 hours. Subjects will abstain from water 1 hour before and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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Protocol number J2J-MC-JZLD (b)
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after dosing (except for water given with the dose). Subjects will remain fasting for at least 
2 hours postdose at which time a meal may be served. 
Carbamazepine should be taken with breakfast and dinner with approximately 240 mL of room 
temperature water. The doses should be taken at approximately the same time of day for a given 
subject. On the days of LY3484356 or midazolam and carbamazepine coadministration, 
LY3484356 or midazolam should be administered fasted, carbamazepine will then be dosed with 
breakfast at least 2 hours after LY3484356 or midazolam dosing.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
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. Further guidance and information for the final disposition of unused study interventions 
are provided in the study materials.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study.
In Cohort 1, participants will be assigned a unique number (randomization number) on Day 1. 
The randomization number encodes the participant’s assignment to be dosed in the fed or fasted 
state on Day 1 of Treatment Period 1 according to the randomization schedule generated prior to 
the study by the Statistics Department at Covance.
Cohorts 2 to 5 will not be randomized.
6.4.
Study Intervention Compliance
Study intervention will be administered 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). 
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:
●
Reason for use

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Protocol number J2J-MC-JZLD (b)
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●
Dates of administration including start and end dates
●
Dosage information including dose and frequency for concomitant therapy of 
special interest
The Clinical Pharmacologist (CP)/CRP should be contacted if there are any questions regarding 
concomitant or prior therapy.
If acetaminophen (or paracetamol) 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/CRP, or designee.
6.6.
Dose Modification
Dose modification will not be permitted in this study.
6.7.
Intervention After the End of the Study
LY3484356 will not be made available to participants after completion of the study.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from study intervention prematurely for any reason should complete
AE and other follow-up/early discontinuation procedures as per the SoA (Section 1.3).
Participants discontinuing from the study prematurely for any reason must complete AE and
follow-up/early discontinuation procedures as per the SoA (Section 1.3).
Discontinuation of the study as a whole is described in Appendix 1 (Section 10.1).
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will not remain in the study. 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.
Discontinuation of investigational product (IP) should be considered by the investigator if any of 
the following occur in a participant:

an AE that is considered to be intolerable,

an abnormal safety laboratory test result, determined to be clinically significant by the 
investigator
In addition, for Cohorts 4 and 5 only:

systemic hypersensitivity reaction (including signs and symptoms suggestive of severe 
skin reactions (e.g. SJS, Lyell's syndrome/TEN), or clinically significant rash

answered "yes" to Question 4 or Question 5 on the "Suicidal Ideation" portion of the 
C-SSRS, or

answered "yes" to any of the suicide-related behaviors on the Suicidal Behavior portion 
of the C-SSRS.
7.1.1.
Liver Enzymes and Other Laboratory Tests
Discontinuation of the study intervention for abnormal liver tests should occur when a 
participant meets 1 of the following conditions after consultation with the Lilly-designated 
CP/CRP:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5× upper limit of 
normal (ULN)

ALT or AST >3× ULN and total bilirubin level (TBL) >2× ULN or international 
normalized ratio >1.5

ALT or AST >3× ULN and the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3× ULN

ALP >2.5× ULN and TBL >2× ULN

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
ALP >2.5× ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Participants who discontinue from study intervention due to the abnormal liver tests will undergo 
monitoring as described in Appendix 5 (Section 10.5).
Discontinuation of the IP due to abnormal laboratory results should be considered by the 
investigator when a participant meets 1 of the following conditions after consultation with the 
CP/CRP:

creatine kinase elevation of >8× ULN (or >1600 IU/L) 

lipase and/or amylase ≥3× ULN (Section 10.5; should be considered by the investigator).
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study:
●
at any time at her own request 
●
at the request of her designee (for example, parents or legal guardian)
●
at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons
●
if the participant becomes pregnant during the study
●
if enrollment in any other clinical study involving an IP or enrollment in any other 
type of medical research judged not to be scientifically or medically compatible 
with this study
●
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. 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 both from the study intervention and from 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.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment 
unless there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the Lilly CP agree it is medically appropriate 

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Protocol number J2J-MC-JZLD (b)
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to continue, the investigator must obtain documented approval from the sponsor CRP to allow 
the inadvertently enrolled participant to continue in the study with or without treatment with IP. 
Safety follow-up should be performed as outlined in Section 1.3 (SoA), Section 8.2 (Safety 
Assessments), and Section 8.3 (AEs and SAEs) of the protocol.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.

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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (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.
8.1.
Efficacy Assessments
Not applicable to 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
Physical examinations and routine medical assessments will be conducted as specified in the 
SoA (Section 1.3) and as clinically indicated.
8.2.2.
Vital Signs
For each participant, supine blood pressure, supine pulse rate, and oral body temperature 
should be assessed at the times indicated in the SoA (Section 1.3).
Blood pressure and pulse rate should be measured singly after at least 5 minutes supine. For each 
individual participant, the same cuff size should be used throughout the study for the 
measurements of blood pressure. The cuff should be attached to the participant’s dominant arm.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Where orthostatic measurements are required, participants should be 
supine for at least 5 minutes and then participants will stand, and standing blood pressure will be 
measured after 2 minutes, but no longer than 3 minutes. If the participant feels unable to stand, 
supine vital signs only will be collected. Additional vital signs may be measured if warranted.
8.2.3.
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 

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Electrocardiograms 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. Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary. All ECGs recorded should be stored 
at the investigational site.
Electrocardiograms will be interpreted by the investigator or qualified designee at the site as 
soon after the time of ECG collection as possible, and, ideally, while the participant is still 
present. This interpretation is to determine whether the participant meets entry criteria at the 
relevant visit(s) 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 
interval 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 her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an 
AE.
8.2.4.
Clinical Safety Laboratory Assessments
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. 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, CP, or CRP.
○
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, standard 
collection requirements.
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.
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring
Carbamazepine is considered to be a central nervous system active drug.

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Participants being treated with carbamazepine should be monitored appropriately and observed 
closely for suicidal ideation and behavior (SIB) or any other unusual changes in behavior, 
especially at the beginning and end of the course of intervention, or at the time of dose changes, 
either increases or decreases. Participants who experience signs of SIB should undergo a risk 
assessment. All factors contributing to SIB should be evaluated and consideration should be 
given to discontinuation of the study intervention.
8.2.5.1.
C-SSRS
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation 
and behavior during the assessment period via a questionnaire. The scale was developed by the 
National Institute of Mental Health trial group (Treatment of Adolescent Suicide Attempters) for 
the purpose of being counterpart to the Columbia Classification Algorithm of Suicide 
Assessment categorization of suicidal events. Safety Monitoring
8.2.6.
Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes including hematology and chemistry
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
8.2.6.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix2; Section 10.2), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if one or more of these 
conditions occur:
If a participant with baseline results 
of... 
develops the following elevations:
ALT or AST <1.5 × ULN
ALT or AST ≥3 × ULN
ALP <1.5 × ULN
ALP ≥2 × ULN
TBL <1.5 × ULN
TBL ≥2 × ULN (except for patients 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 patients 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 

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Protocol number J2J-MC-JZLD (b)
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the CP/CRP. At a minimum, this evaluation should include physical examination and a thorough 
medical history, including symptoms, recent illnesses (for example, heart failure, systemic 
infection, hypotension, or seizures), recent travel, history of concomitant medications (including 
over-the-counter), herbal and dietary supplements, history of alcohol drinking and other 
substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and 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:

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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 patients 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 patients 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 CP/CRP, 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 
phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety eCRF) in study participants who have 
abnormal liver tests during the study:
Additional hepatic safety data collection in hepatic safety eCRFs should be performed in study 
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 <1.5 × ULN)
In participants with baseline ALT ≥1.5 × ULN, the threshold is ALT 
≥3 × baseline on 2 or more consecutive tests
2. Elevated 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 
≥2 × 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

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5. Discontinuation of study drug 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 (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.
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 eCRF
N/A
Serious Adverse Event

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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
SAE and SAE 
updates – prior 
to start of study 
intervention and
deemed 
reasonably 
possibly related 
with study 
procedures
signing of 
the informed 
consent form 
(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
resolution of 
the SAE
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
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
Product Complaint 
form
N/A
PC not 
associated with 
an SAE
Start of study 
intervention
End of study 
intervention
Within 1 business day 
of awareness
Product Complaint 
form
N/A
Updated PC 
information
—
—
As soon as possible 
upon site awareness
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator
N/A

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Protocol number J2J-MC-JZLD (b)
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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
PC (if 
investigator 
becomes aware)
Participation
in study has 
ended
N/A
Promptly
Product Complaint 
form
8.4.
Treatment of Overdose
For this study, any dose of LY3484356 greater than 400 mg within a 24-hour time period will be 
considered an overdose.
In the event of an overdose, the investigator or treating physician should:
1. Contact the Lilly CP immediately
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities
In case of overdose, supportive therapy should be used.  There is no known antidote to 
LY3484356 overdose.
8.5.
Pharmacokinetics
At the visits and times specified in the SoA (Section 1.3), venous blood samples of up to 2 mL 
each will be collected to determine the plasma concentrations of LY3484356. In Cohort 3, blood
samples of approximately 2 mL will be collected for measurement of concentrations of 
itraconazole and its metabolite hydroxy itraconazole. In Cohort 4, blood samples of 2 mL will be 
collected for measurement of concentrations of carbamazepine and carbamazepine 
10,11-epoxide at the timepoints specified in the SoA (Section 1.3). In Cohort 5, blood samples of 
2 mL will be collected for measurement of concentrations of carbamazepine and carbamazepine 
10,11-epoxide and blood samples of 2 mL will be collected for measurement of concentrations 
of midazolam and 1’hydroxymidazolam at the timepoints specified in the SoA (Section 1.3). Up 
to 3 samples may be collected at additional time points during the study if warranted and agreed 
upon between both the investigator and sponsor.
Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded, 
as well as the date and time of each LY3484356 dose.
8.5.1.
Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3484356 will be assayed using a validated liquid chromatography mass 
spectrometry method. Samples collected for the analysis of plasma concentrations of LY3484356

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may be stored and analyzed for future exploratory analysis, such as quantification of metabolites 
of LY3484356.
Plasma concentrations of itraconazole, hydroxyitraconazole, carbamazepine, carbamazepine 
10,11-epoxide, midazolam, and 1’hydroxymidazolam will be determined using a validated 
analytical procedure.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last participant visit for the study. 
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the SoA
(Section 1.3), where local regulations allow.
8.8.
Biomarkers
In Cohorts 4 and 5, blood samples (10 mL) will be collected for exosomal mRNA analysis as 
specified in the SoA (Section 1.3). The mRNA of proteins involved in drug disposition will be 
quantified. 
8.9.
Immunogenicity Assessments
Not applicable for this study.
8.10.
Health Economics
This section is not applicable for this study.

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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The primary endpoints will be evaluated to assess the potential effect of food on LY3484356,
any potential effect of a gastric pH change on the PK of LY3484356, and any potential drug-
drug interaction between LY3484356 and itraconazole or carbamazepine. 
9.2.
Analyses Sets
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF.
Enrolled/Intent-to-Treat
All participants assigned to treatment, regardless of whether they 
take any doses of IP, or if they take the correct treatment.
Safety
All participants who take at least 1 dose of IP. 
Pharmacokinetic Analysis
All participants who received at least 1 dose of IP and have 
evaluable PK.
9.2.1.
Study Participant Disposition
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, and other demographic characteristics will be recorded and 
summarized. 
9.2.3.
Treatment Compliance
The date and time of dosing will be recorded and listed.
9.3.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor or its designee.
Pharmacokinetic analyses will be conducted on data from all participants who received at least 
1 dose of IP and have evaluable PK.
Safety analyses will be conducted for all enrolled participants who received at least 1 dose of IP, 
whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.

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9.3.1. Safety Analyses
9.3.1.1.
Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of AEs for each treatment will be presented by severity and by association with IP
as perceived by the investigator. Adverse events 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.
The number of investigational SAEs will be reported.
9.3.1.2.
Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters. Additional analysis will be performed if warranted upon review of the data.
9.3.2.
Pharmacokinetic Analyses
9.3.2.1.
PK Parameter Estimation
Pharmacokinetic parameter estimates will be calculated by standard noncompartmental methods. 
The primary PK parameters for analysis of LY3484356 will be: Cmax, AUC(0-∞), and tmax.
Other noncompartmental parameters, such as t1/2, apparent total body clearance of drug 
calculated after extravascular administration, and apparent volume of distribution during the 
terminal phase after extravascular administration, may be reported as appropriate. Plasma 
concentrations of itraconazole, carbamazepine, and midazolam, and their metabolites in Cohorts
3, 4, and 5 will be summarized using standard descriptive statistics as appropriate.
9.3.2.2.
PK Statistical Inference
Pharmacokinetic parameters will be evaluated to estimate food effect and drug-drug interactions
(with omeprazole, itraconazole, or carbamazepine) for LY3484356. Log-transformed Cmax and 
AUC(0-∞) parameters for LY3484356 will be evaluated separately. The treatment differences 
will be back-transformed to present the ratios of geometric means and the corresponding 90% 
CI.
To estimate the food effect in Cohort 1, a linear mixed-effects model with period and treatment 
as a fixed effect and participant as a random effect will be used.
To estimate the effect of a gastric pH change in Cohort 2, and the following drug-drug 
interactions:

LY3484356 with itraconazole (Cohort 3)

LY3484356 with carbamazepine (Cohort 4)

Midazolam with carbamazepine (Cohort 5),

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log-transformed Cmax and AUC(0-∞) parameters for LY3484356 (Cohorts 2, 3, and 4) and 
midazolam (Cohort 5) will be analyzed using a linear mixed-effects model with a fixed effect for 
treatment and a random effect for participant. 
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the difference between 
observed medians, 90% CIs, and p-values from the Wilcoxon test will be calculated.
Pharmacokinetic parameters will be summarized using descriptive statistics.
9.3.3.
Pharmacodynamic Analyses
Not applicable for this study.
9.3.4.
Pharmacokinetic/Pharmacodynamic Analyses
Not applicable for this study.
9.4.
Interim Analysis 
An interim analysis of safety will be conducted after the completion of Cohorts 1 and 2. The 
interim analysis will be conducted to inform dosing restrictions in patient trials.
9.5.
Sample Size Determination
In Cohorts 1 and 2, approximately 10 participants will be enrolled in each cohort to ensure that at 
least approximately 8 evaluable participants in each cohort complete the study. The sample size
(N=8) will provide at least 80% power that the 90% CI of the ratio is included in the acceptance 
interval between 0.7 and 1.43, assuming that the expected geometric mean ratio is 1 and
 
In Cohort 3, approximately 20 participants will be enrolled to ensure that at least approximately 
18 evaluable participants complete the study. In Cohort 4, approximately 26 participants will be 
enrolled to ensure that at least approximately 18 evaluable participants in this cohort complete 
the study. The sample size (N=18) will provide at least 80% power that the 90% CI of the ratio is 
included in the acceptance interval between 0.8 and 1.25, assuming that the expected geometric 
mean ratio is 1 and 
 
In Cohort 5 (optional), approximately 15, participants will be enrolled to ensure that at least 
approximately 10 evaluable participants in this cohort complete the study. 
CCI
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 (CIOMS) International Ethical Guidelines
○
Applicable ICH Good Clinical Practice (GCP) Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (for example, advertisements) must be submitted to an 
IRB/Independent Ethics Committees (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.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3.
Informed Consent Process
●
The investigator or her representative will explain the nature of the study, 
including the risks and benefits, to the participant or her legally authorized 
representative 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 regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act 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 re-consented to the most current version of the ICF(s) during 
their participation in the study.
●
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records,
datasets or tissue samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred.
The participant must be informed that her 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 her data to be used 
as described in the informed consent.
The participant must be informed that her 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.

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10.1.5.
Dissemination of Clinical Study Data
Communication of Suspended or Terminated Dosing
If a decision is taken to suspend or terminate dosing in the trial 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. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial 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.
10.1.6.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (for example, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Quality tolerance limits (QTLs) will be predefined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study and important 
excursions from the QTLs and remedial actions taken will be summarized in the 
clinical study report.
●
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.

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●
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 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, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
Data collected via the sponsor-provided data capture system will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse.
Data from complaint forms submitted to sponsor will be encoded and stored in the global 
product complaint management system.
10.1.7.
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 the CRF or entered in the eCRF that 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.

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●
Definition of what constitutes source data can be found in Section 10.1.6.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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:
●
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 of participants by the investigator
●
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assures
appropriate participant therapy and/or follow-up.
10.1.9.
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 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
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate (total CO2)
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Glucose
Platelets
Creatine kinase
Gamma-glutamyl transferase
Coagulation
Blood urea nitrogen (BUN)
Prothrombin time (PT)
Direct bilirubin
Uric acid 
Activated partial thromboplastin time (aPTT)
Total protein
International normalized ratio (INR)
Albumin
Total bilirubin
Differential WBC (absolute counts) of
Alkaline phosphatase (ALP)
Neutrophils
Aspartate aminotransferase (AST)
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Creatinine
Eosinophils
Lipase
Basophils
Amylase
Urinalysis
Specific gravity
pH
Protein
Glucose
Ethanol testinga
Ketones
Urine drug screena
Bilirubin
Hepatitis B surface antigenb
Urobilinogen
Hepatitis B core antibodyb
Blood
Hepatitis C antibodyb
Nitrite
HIV antibodiesb
FSH (if applicable)b
Pregnancy test (if applicable)c
Abbreviations: FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed at screening and check-in only.
b
Performed at screening only.
c
Performed in serum on Day -1 and in urine at all other times.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any 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 conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

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 overdose should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

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
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
SAE is defined as any untoward medical occurrence that, at any dose:
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 
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:

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
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3.
Definition of Product Complaints
Product Complaint

A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also PCs:
o
Deficiencies in labeling information, and
o
Use errors for device or drug-device combination products due to ergonomic 
design elements of the product.

Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements.

Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed.

An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE.
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product Complaints
AE, SAE, and Product Complaint Recording

When an AE/SAE/product complaint 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/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate (e)CRF page and 
product complaint information is reported on the Product Complaint Form.

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Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the (e)CRF page for AE/SAE 
and the Product Complaint Form for PCs.

There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:

Mild: A type of adverse event 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 adverse event 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 adverse event 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 a 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 1 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.

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.

The investigator will use clinical judgment to determine the relationship.

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
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB in her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee.

The investigator may change her 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 sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5.
Reporting of SAEs
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor or designee.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in 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.

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●
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, 
Institutional Review Boards (IRB)/IEC, and investigators.
●
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 Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
Females are considered a woman of childbearing potential if

they have had at least one cycle of menses, or

they have Tanner 4 breast development.
Any amount of spotting should be considered menarche.
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered.
1. Women in the following categories are not considered WOCBP:
a.
Premenopausal female with 1 of the following:

hysterectomy

bilateral salpingectomy

bilateral oophorectomy

bilateral tubal ligation
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (for example, Müllerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
b. Postmenopausal female, defined as women with:

12 months of amenorrhea for women >55, with no need for FSH

12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL 
and no other medical condition such as anorexia nervosa and not taking 
medications during the amenorrhea (e.g. oral contraceptives, hormones, 
gonadotropin releasing hormone, anti-estrogens, selective ER modulators, or 
chemotherapy that induced amenorrhea).
Contraception Guidance for Cohorts 1-4:

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Contraception is not required for these cohorts.
Contraception Guidance for Cohort 5:
Females
All females must have a negative urine pregnancy test result at screening followed by a negative 
serum result within 24 hours prior to treatment exposure.
Women not of Childbearing Potential
Women not of childbearing potential are not required to use contraception.
Women of Childbearing Potential 
Women of childbearing potential who are completely abstinent as their preferred and usual 
lifestyle, or in a same sex relationship, as part of their preferred and usual lifestyle
Must…
Must not…
agree to either remain abstinent, or

use periodic abstinence methods
o
calendar 
o
ovulation 
o
symptothermal, or
o
post-ovulation 

declare abstinence just for the duration 
of a trial, or

use the withdrawal method
stay in a same sex relationship without sexual 
relationships with males
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a same 
sex relationship, as part of their preferred and usual lifestyle must agree to use 1 of the following
forms of highly effective contraception for the duration of the study and for 28 days after 
discontinuation of carbamazepine:

copper intrauterine device (IUD)

vasectomy of sexual partner.
No other forms of highly effective contraception or effective contraception will be acceptable. 
Males
All males should refrain from sperm donation for the duration of the study and for 95 days after 
the last dose of carbamazepine.
Males in exclusively same sex relationships, as their preferred and usual lifestyle are not required 
to use contraception.
Males with partners of childbearing potential either must remain abstinent (if this is their 
preferred and usual lifestyle) or must use condoms during intercourse for the duration of the 
study and for 95 days following discharge from the study and agree to use an additional highly 
effective or effective form of contraception. 

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Examples of different forms of contraception: 
Methods
Examples
Highly effective contraception 

combination oral contraceptive pill and mini-pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women <198 pounds 
or 90 kg)

total abstinence

vasectomy (if only sexual partner)

fallopian tube implants (if confirmed by 
hysterosalpingogram)

combined contraceptive vaginal ring, or 

intrauterine devices
Effective contraception 

male or female condoms with spermicide 

diaphragms with spermicide or cervical sponges

barrier method with use of a spermicide
o
condom with spermicide
o
diaphragm with spermicide, or
o
female condom with spermicide
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.
Use of male and female condoms as a double barrier 
method is not considered effective.
Ineffective forms of contraception

spermicide alone 

immunocontraceptives

periodic abstinence

fertility awareness (calendar method, 
temperature method, combination of above 2, 
cervical mucus, symptothermal)

withdrawal,

post coital douche

lactational amenorrhea

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10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
See Section 8.2.6.1 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
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 Chemistrye
  Basophils
Acetaminophen
  Eosinophils
Acetaminophen protein adducts
Platelets
Alkaline phosphatase isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
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

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  HBV DNA d
Anti-actin antibody b
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.
e 
To be performed only in the event of increase AST/ALT.

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10.6.
Appendix 6: Abbreviations
Term
Definition
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BID
twice daily
CIOMS
Council for International Organizations of Medical Sciences
Companion diagnostic 
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
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.
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.
C-SSRS
Columbia Suicide-Severity Rating Scale
DMC
data monitoring committee
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 informed consent form directly 
or through their legally acceptable representatives.
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
Informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.

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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IWRS
interactive web-response system
NIMP
Non-investigational Medicinal Product
NOAEL
no observed adverse effect level
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PC
product complaint
PK/PD
pharmacokinetics/pharmacodynamics
PPS
per-protocol set: The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
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. 
SIB
suicidal ideation and behavior
SUSARs
suspected unexpected serious adverse reactions
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.

C O N FI D E N TI A L
Pr ot oc ol  n u m ber J 2J-M C -J Z L D ( b)
9 3
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Approval Date & Time: 06-Oct-2021 13:53:37 GMT
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