A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single- and Multiple-Ascending Doses of LY3522348 in Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
 
Protocol: J2U-MC-YBAA(c) 
 
 
A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of 
Single-and Multiple-Ascending Doses of LY3522348 in Healthy Participants 
 
 
NCT04559568 
 
 
Approval Date: 11-Aug-2021 

CONFIDENTIAL 
Protocol J2U-MC-YBAA(c) 
 
1 
 
Title Page 
Confidential information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3522348, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release. In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single- 
and Multiple-Ascending Doses of LY3522348 in Healthy Participants 
Protocol Number: J2U-MC-YBAA 
Amendment Number: (c) 
Compound: LY3522348 
Study Phase: 1 
Short Title: Single- and Multiple-Ascending Doses of LY3522348 in Healthy Participants 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number(s) 
IND 149487 
Document ID: VV-CLIN-002395 
 
 
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CONFIDENTIAL 
Protocol J2U-MC-YBAA(c) 
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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Protocol J2U-MC-YBAA(c) 
 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Protocol amendment (b) 
04-Mar-2021 
Protocol amendment (a) 
09-Sep-2020 
Original Protocol 
14-Jul-2020 
Amendment [c]  
Overall Rationale for the Amendment: 
Protocol was amended to remove sorbitol analysis from pharmacodynamic analysis section, as it 
is an indirect biomarker. The fructose level is a direct biomarker, and its analysis was confirmed 
to provide robust and sufficient pharmacodynamic information. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.6 
Pharmacodynamics 
Removed sorbitol analysis 
Fructose analysis was confirmed to provide 
robust information, as fructose level is a direct 
biomarker while sorbitol is indirect.  
Section 9.4.3.1 
Pharmacodynamic 
Parameter 
Estimation 
Removed sorbitol analysis 
Fructose analysis was confirmed to provide 
robust information, as fructose level is a direct 
biomarker while sorbitol is indirect.  
Throughout the 
protocol 
Minor editorial and formatting changes 
Minor, therefore, not described 
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Protocol J2U-MC-YBAA(c) 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
1.3.1. 
Schedule of Activities for Part A ....................................................................................10 
1.3.2. 
Schedule of Activities for Part B ....................................................................................12 
2. 
Introduction ...................................................................................................................15 
2.1. 
Study Rationale ...............................................................................................................15 
2.2. 
Background .....................................................................................................................15 
2.3. 
Benefit/Risk Assessment ................................................................................................16 
3. 
Objectives and Endpoints ............................................................................................18 
4. 
Study Design ..................................................................................................................19 
4.1. 
Overall Design ................................................................................................................19 
4.1.1. 
Part A ..............................................................................................................................19 
4.1.2. 
Part B ..............................................................................................................................20 
4.2. 
Scientific Rationale for Study Design ............................................................................20 
4.2.1. 
Participant Input into Study Design ................................................................................21 
4.3. 
Justification for Dose ......................................................................................................21 
4.4. 
End of Study Definition ..................................................................................................23 
5. 
Study Population ...........................................................................................................25 
5.1. 
Inclusion Criteria ............................................................................................................25 
5.2. 
Exclusion Criteria ...........................................................................................................25 
5.3. 
Lifestyle Considerations .................................................................................................27 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................27 
5.3.2. 
Caffeine, Alcohol, and Tobacco .....................................................................................28 
5.3.3. 
Activity ...........................................................................................................................28 
5.4. 
Screen Failures ................................................................................................................28 
6. 
Study Intervention ........................................................................................................29 
6.1. 
Study Intervention(s) Administered................................................................................29 
6.1.1. 
Packaging and Labeling ..................................................................................................29 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................30 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................30 
6.4. 
Study Intervention Compliance ......................................................................................31 
6.5. 
Concomitant Therapy .....................................................................................................31 
6.6. 
Dose Modification ..........................................................................................................31 
6.6.1. 
Dose Decision/Escalation ...............................................................................................32 
6.6.2. 
Data Review during the Study ........................................................................................33 
6.7. 
Intervention after the End of the Study ...........................................................................33 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34 
7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.1.1. 
Hepatic Criteria for Discontinuation ...............................................................................34 
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7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................34 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................35 
7.2.2. 
Discontinuation of the Study ..........................................................................................35 
7.3. 
Lost to Follow-up............................................................................................................36 
8. 
Study Assessments and Procedures.............................................................................37 
8.1. 
Efficacy Assessments .....................................................................................................37 
8.2. 
Safety Assessments .........................................................................................................37 
8.2.1. 
Physical Examinations ....................................................................................................37 
8.2.2. 
Vital Signs .......................................................................................................................38 
8.2.3. 
Electrocardiograms .........................................................................................................38 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................39 
8.2.5. 
Body Temperature ..........................................................................................................39 
8.2.6. 
Safety Monitoring ...........................................................................................................39 
8.3. 
Adverse Events and Serious Adverse Events .................................................................42 
8.3.1. 
Time Period and Frequency for Collecting AE and 
SAE Information .............................................................................................................42 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................43 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................43 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................43 
8.3.5. 
Pregnancy ........................................................................................................................43 
8.3.6. 
Complaint Handling ........................................................................................................44 
8.4. 
Treatment of Overdose ...................................................................................................45 
8.5. 
Pharmacokinetics ............................................................................................................45 
8.5.1. 
Bioanalysis ......................................................................................................................45 
8.5.2. 
LY3522348 Measurement ..............................................................................................45 
8.5.3. 
Drug-Drug Interaction with Midazolam .........................................................................45 
8.5.4. 
Renal Clearance ..............................................................................................................46 
8.6. 
Pharmacodynamics .........................................................................................................46 
8.7. 
Genetics ..........................................................................................................................46 
8.8. 
Biomarkers ......................................................................................................................46 
8.8.1. 
Fasting Insulin and Adiponectin .....................................................................................46 
8.8.2. 
Coproporphyrins .............................................................................................................46 
8.8.3. 
Nonpharmacogenetic Biomarkers ...................................................................................47 
8.9. 
Immunogenicity Assessments.........................................................................................47 
8.10. 
Health Economics ...........................................................................................................48 
9. 
Statistical Considerations .............................................................................................49 
9.1. 
Statistical Hypotheses .....................................................................................................49 
9.2. 
Sample Size Determination ............................................................................................49 
9.3. 
Populations for Analyses ................................................................................................49 
9.3.1. 
Study Participant Disposition .........................................................................................49 
9.3.2. 
Study Participant Characteristics ....................................................................................49 
9.4. 
Statistical Analyses .........................................................................................................49 
9.4.1. 
Safety Analyses ...............................................................................................................50 
9.4.2. 
Pharmacokinetic Analyses ..............................................................................................50 
9.4.3. 
Pharmacodynamic Analyses ...........................................................................................51 
9.4.4. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................51 
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9.5. 
Interim Analyses .............................................................................................................51 
9.6. 
Data Monitoring Committee (DMC) ..............................................................................51 
10. 
Supporting Documentation and Operational Considerations ..................................52 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................52 
10.1.1. Regulatory and Ethical Considerations ...........................................................................52 
10.1.2. Financial Disclosure........................................................................................................52 
10.1.3. Informed Consent Process ..............................................................................................52 
10.1.4. Data Protection................................................................................................................53 
10.1.5. Dissemination of Clinical Study Data.............................................................................53 
10.1.6. Data Quality Assurance ..................................................................................................54 
10.1.7. Source Documents ..........................................................................................................55 
10.1.8. Study and Site Start and Closure ....................................................................................55 
10.1.9. Publication Policy ...........................................................................................................56 
10.1.10. Long-Term Sample Retention.........................................................................................56 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................57 
10.2.1. Blood Sampling Summary ..............................................................................................58 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ..........................................................62 
10.3.1. Definition of AE .............................................................................................................62 
10.3.2. Definition of SAE ...........................................................................................................63 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................64 
10.3.4. Reporting of SAEs ..........................................................................................................66 
10.3.5. Sponsor Surveillance Process for Dose Escalation or Cohort 
Expansion ........................................................................................................................66 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................67 
10.4.1. Definitions.......................................................................................................................67 
10.4.2. Contraception Guidance..................................................................................................67 
10.4.3. Collection of Pregnancy Information..............................................................................69 
10.5. 
Appendix 5: Genetics......................................................................................................71 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................72 
10.7. 
Appendix 7: Excluded Concomitant Medications ..........................................................74 
10.8. 
Appendix 8: Abbreviations .............................................................................................75 
10.9. 
Appendix 9: Protocol Amendment History ....................................................................78 
11. 
References ......................................................................................................................82 
 
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Protocol J2U-MC-YBAA(c) 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study of Single- 
and Multiple-Ascending Doses of LY3522348 in Healthy Participants 
Short Title: Single- and Multiple-Ascending Doses of LY3522348 in Healthy Participants 
Rationale 
LY3522348, a novel KHK inhibitor, is being developed as a daily oral treatment for NASH. 
Study J2U-MC-YBAA (YBAA) is a first-in-human study, which aims to assess the safety, 
tolerability, PK, and PD of single and multiple oral doses of LY3522348 in healthy participants. 
The PK, PD, safety, and tolerability data from this study in healthy participants will assist in 
identifying an appropriate dose range for subsequent clinical studies in participants with NASH. 
In addition, this study will assess the impact of LY3522348 on midazolam metabolism. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
  
• 
To investigate the safety and tolerability of 
LY3522348 following single and multiple 
oral doses 
• 
Incidence of TEAEs and SAEs 
• 
Clinically significant changes in vital signs data, 
safety laboratory parameters, and 
electrocardiograms 
Secondary 
  
• 
To determine the PK of LY3522348 
following single and multiple oral doses 
• 
AUC(0-24), AUC(0-inf), Cmax, and tmax 
Abbreviations: AUC = area under the concentration versus time curve; AUC(0-24) = AUC from time zero to 24 
hours; AUC(0-inf) = AUC from time zero to infinity; Cmax = maximum observed drug concentration; ECG = 
electrocardiogram; PK = pharmacokinetics; SAE = serious adverse event; tmax = time of Cmax; TEAE = treatment-
emergent adverse event. 
Overall Design 
Study YBAA is a Phase 1, single site, randomized, investigator- and participant-blind, placebo-
controlled, 2-part study in healthy participants. 
Disclosure Statement 
This is a sequential single- and multiple-ascending dose study that is investigator- and 
participant-blind. 
 
 
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Protocol J2U-MC-YBAA(c) 
 
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Number of Participants 
A maximum of 100 participants will be randomly assigned to study intervention such that 
approximately 
• 
48 evaluable participants complete Part A, and 
• 
32 evaluable participants complete Part B of the study. 
Intervention Groups and Duration 
Intervention groups 
Eligible participants will be randomly assigned to study intervention, 
• 
6 LY3522348 and 2 placebo per cohort in Part A, and 
• 
6 LY3522348 and 2 placebo per cohort in Part B. 
Duration 
Part A duration 
Each participant’s involvement in the study is expected to last up to 7 weeks, including 
• 
a 4-week screening period 
• 
a 1-week treatment period 
• 
and a 
• 
follow-up visit 2 weeks after the dose. 
Part B duration 
Each participant’s involvement in the study is expected to last up to 8 weeks, including 
• 
a 4-week screening period 
• 
a 2-week treatment period, and a 
• 
2-week follow-up period after the last dose. 
Data Monitoring Committee 
No 
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Protocol J2U-MC-YBAA(c) 
 
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1.2. 
Schema 
 
Abbreviations: LY = LY3522348; PBO = placebo. 
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Protocol J2U-MC-YBAA(c) 
 
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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Schedule of Activities for Part A 
 
Screening 
Days 
FU 
ED 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 
4 
5-6 
7 
Day 
14±1 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Occurs prior to study intervention 
administration. 
Discharge 
 
 
 
 
 
 
 
X 
 
 
If clinically indicated, participants 
may remain inpatient longer.  
Non-Residential Visit 
 
 
 
 
 
 
 
 
X 
X 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
X 
 
 
 
X 
 
X 
X 
X 
At the discretion of the 
investigator, targeted PE may be 
conducted at other visits. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
X 
X 
Serum test at screening. Urine test 
at all other time points. 
Blood Pressure and Pulse 
Rate 
X 
X 
P, 0.75, 1.5, 3, 4, 6, 
8, 10, 12 h  
24, 36 h 
48 h 
72 h 
 
X 
X 
X 
If agreed upon between the 
sponsor and the investigator, 
more time points may be added. 
Body Temperature 
X 
X 
 
 
 
 
 
 
X 
X 
 
Clinical Laboratory Tests 
X 
X 
P 
X 
X 
 
 
X 
X 
 
See Section 10.2 for complete list. 
Serum Creatinine 
 
 
P, 4, 12, 24 h 
 
 
 
 
 
 
 
Sampling times are relative to the 
time of study intervention 
administration (0 min). 
Triplicate 12-Lead ECG 
 
 
-1.5, -1, -0.5, 0.75, 
1.5, 3, 4, 6, 12 h 
24 h 
 
 
 
 
 
 
Sampling times are relative to the 
time of study intervention 
administration (0 min). 
Single 12-Lead ECG 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
Adverse Event Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LY3522348 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
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Protocol J2U-MC-YBAA(c) 
 
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Screening 
Days 
FU 
ED 
Comments 
Procedure 
≤28 days 
before 
Day -1 
-1 
1 
2 
3 
4 
5-6 
7 
Day 
14±1 
 
 
Pharmacokinetic 
Sampling 
 
 
P, 0.75, 1.5, 3, 4, 6, 
8, 10, 12, 16 h 
24 h 
48 h 
72 h 
96 h 
144 h 
 
 
Sampling times are relative to the 
time of study intervention 
administration (0 min). 
Low Fructose Meal  
 
 
20 minutes, 6, 12 h 
 
 
 
 
 
 
 
 
Fructose Beverage (for 
FTT) 
 
 
during meal: 20 
minutes, 6, 12 h 
 
 
 
 
 
 
 
 
FTT Assay 
 
 
0 (pre-meal), 1.5, 3, 
4, 5, 6 (pre-meal), 8, 
10, 12 (pre-meal), 
14, 16 h 
20, 24 h 
(pre-meal) 
 
 
 
 
 
 
Sampling times are relative to the 
time of study intervention 
administration (0 min). 
Genetic Sample 
 
 
X 
 
 
 
 
 
 
 
Only 1 sample is needed per 
participant. 
Fasting Biomarker 
Samples -
Nonpharmacogenetic 
 
 
P 
X 
 
 
 
 
 
 
 
24-hour Urine Collection 
for LY3522348 and 
Creatinine 
 
 
0-24 h 
 
 
 
 
 
 
 
Sampling times are relative to the 
time of study intervention 
administration (0 min). 
Abbreviations: ECG = electrocardiogram; ED = early discontinuation; FTT = fructose tolerance test; FU = follow-up; h = hours; min = minutes; P = predose; PE = physical 
examination. 
Notes: If multiple procedures take place at the same time point, the following order of the procedures should be used: ECG, vital signs, and venipuncture. Samples collected for 
clinical laboratory tests including urine analysis may be analyzed at a local laboratory. All time points specified in the table are approximate and may be adjusted at the discretion 
of the investigator. 
 
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Protocol J2U-MC-YBAA(c) 
 
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1.3.2. 
Schedule of Activities for Part B 
Procedure 
Screening 
Days 
Follow-up 
Comments 
≤28 days 
before Day 
-2 or -1 
-2 
-1 
1 
2 
3 to 
6 
7 
8 
9 
to 
13 
14 
15 to 17 
18/19 
20/21 
28±
2 
ED 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission 
 
C3 
C4 
C1, 
C2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
C3, 
C4 
C1, C2 
 
 
 
 
 
 
 
 
 
 
 
Occurs prior to 
study intervention 
administration. 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
Day 20: 
C1, C2; 
Day 21: 
C3, C4 
 
 
If clinically 
indicated, 
participants may 
remain inpatient 
longer.  
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
At the investigator’s 
discretion, targeted 
PE may be 
conducted at other 
visits. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
C3
C4 
C1, 
C2 
 
 
 
 
 
 
 
Day 15 
 
 
X 
X 
 
Pregnancy Test 
X 
C3 
C4 
 C1, 
C2 
 
 
 
 
 
 
 
 
 
 
X  
X  
Serum test at 
screening. Urine test 
at all other time 
points. 
Blood Pressure and 
Pulse Rate 
X 
 
X 
P, 0.75, 
1.5, 3, 4, 
6, 12 h  
24, 
36 h 
48,  
72 h 
P, 
0.75, 
1.5, 
3, 4, 
6, 12 
h 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 12 h 
 
 
 
X 
X 
If agreed upon 
between the sponsor 
and the investigator, 
more time points 
may be added. 
Body Temperature 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Clinical Laboratory 
Tests 
X 
C3 
C4 
C1, 
C2 
P 
 
Day 
4 
X 
 
 
X 
 
 
Day 20: 
C1, C2 
Day 21: 
C3, C4 
X 
X 
See Section 10.2 for 
complete lists. 
Single 12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
(before 
X 
X 
 
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Procedure 
Screening 
Days 
Follow-up 
Comments 
≤28 days 
before Day 
-2 or -1 
-2 
-1 
1 
2 
3 to 
6 
7 
8 
9 
to 
13 
14 
15 to 17 
18/19 
20/21 
28±
2 
ED 
144 h 
PK 
samplin
g) 
Triplicate 12-Lead 
ECG 
 
 
 
-1.5, -1,  
-0.5, 0.75, 
1.5, 3, 4, 
6, 12 h  
 
 
P, 
0.75, 
1.5, 
3, 4, 
6, 12 
h 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 12 h 
24 h (P) 
96 h 
(befo
re 
PK 
samp
ling)  
 
 
 
Sampling times are 
relative to the time 
of study 
intervention 
administration. 
Day 18 for Cohorts 
1 and 2 
Day 19 for 
Cohorts 3 and 4 
Adverse Event 
Recording 
X 
C3 
C4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study intervention 
administration 
 
 
 
X 
Day 15: 
C3, C4  
 
 
 
 
 
Pharmacokinetic 
Sampling for Cohorts 
1 and 2 
 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24 h 
(P) 
 
P 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24, 48, 72 
h  
Day 
18: 
96 h 
Day 20: 
144 h 
 
 
Sampling times are 
relative to the time 
of study 
intervention 
administration. 
After a review of 
preliminary PK 
data, sampling times 
may be adjusted. 
Pharmacokinetic 
Sampling for Cohorts 
3 and 4 
 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24 h 
(P) 
 
P 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
P, 0.75, 
1.5, 3, 4, 6, 
8, 12, 16, 
24, 48 h  
72, 
96 h 
Day 21: 
144 h 
 
 
 
Midazolam 
administration 
 
 
X 
 
 
 
 
 
 
 
Day 15 
 
 
 
 
For Cohorts 3 and 4 
only. 
Midazolam PK 
sampling 
 
 
P, 0.5, 
1, 1.5, 
3, 5, 8, 
12 h 
24 h (P) 
 
 
 
 
 
 
Day 15: P, 
0.5, 1, 1.5, 
3, 5, 8, 12, 
24 h 
 
 
 
 
For Cohorts 3 and 4 
only. Sampling 
times are based on 
midazolam 
administration. 
Fasting Insulin and 
Adiponectin 
 
 
 
P 
 
 
 
 
 
P 
 
 
 
 
 
 
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Protocol J2U-MC-YBAA(c) 
 
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Procedure 
Screening 
Days 
Follow-up 
Comments 
≤28 days 
before Day 
-2 or -1 
-2 
-1 
1 
2 
3 to 
6 
7 
8 
9 
to 
13 
14 
15 to 17 
18/19 
20/21 
28±
2 
ED 
Low Fructose Meal 
 
 
 
20 
minutes, 
6, 12 h 
 
 
 
 
 
20 
minutes, 
6,  
12 h 
 
 
 
 
 
 
Fructose Beverage 
(for FTT) 
 
 
 
during 
meal: 20 
minutes, 
6, 12 h 
 
  
 
 
 
during 
meal: 20 
minutes, 
6, 12 h 
 
 
 
 
 
 
FTT Assay 
 
 
 
0 (pre-
meal), 1.5, 
3, 4, 6 
(pre-
meal), 7, 
8, 10, 12 
(pre-
meal), 13, 
14, 16 h 
 24 h 
(pred
ose 
and 
pre-
meal) 
 
 
 
 
0 (pre-
meal), 
1.5, 3, 4, 
6 (pre-
meal), 7, 
8, 10, 12 
(pre-
meal), 
13, 14, 
16 h 
 24 h  
(pre-meal 
for C1 and 
C2 and 
predose 
and 
premeal for 
C3 and C4) 
 
 
 
 
Sampling times are 
relative to the time 
of study 
intervention 
administration (0 
min) on Day 1 or 
Day 14. 
Genetic Sample 
 
 
 
P 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Biomarker 
Samples -
Nonpharmacogenetic 
 
 
 
P 
X 
 
 
 
 
 
Day 15 
 
 
 
 
 
Coproporphyrin 
samples (stored) 
 
 
P, 
0.75, 
1.5, 3, 
4, 6, 8, 
12, 16 
h 
(C3, 
C4) 
P 
 
 
 
 
 
P, 0.75, 
1.5, 3, 4, 
6, 8, 12, 
16 h 
24 h (P) 
 
 
 
 
All cohorts should 
have a P sample 
collected on Day 1 
Abbreviations: C1 = Cohort 1; C2 = Cohort 2; C3 = Cohort 3; C4 = Cohort 4; ECG = electrocardiogram; ED = early discontinuation; FTT = fructose tolerance test; FU = follow-
up; h = hours; min = minutes; P = predose; PE = physical examination; PK = pharmacokinetics. 
Notes: If multiple procedures take place at the same time point, the following order of the procedures should be used: ECG, vital signs, and venipuncture. Samples collected for 
clinical laboratory tests including urine analysis may be analyzed at a local laboratory. All time points specified in the table are approximate and may be adjusted at the discretion 
of the investigator.
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Protocol J2U-MC-YBAA(c) 
 
15 
2. 
Introduction 
LY3522348, a novel KHK inhibitor, is being developed as a daily oral treatment for NASH. 
2.1. 
Study Rationale 
Study J2U-MC-YBAA (YBAA) is a first-in-human study, which aims to assess the safety, 
tolerability, PK, and PD of single and multiple oral doses of LY3522348 in healthy participants. 
The PK, PD, safety, and tolerability data from this study in healthy participants will assist in 
identifying an appropriate dose range for subsequent clinical studies in patients with NASH. In 
addition, this study will assess the impact of LY3522348 on midazolam metabolism. 
2.2. 
Background 
Ketohexokinase 
KHK, also known as fructokinase, is the enzyme responsible for the first step in fructose 
metabolism, which occurs through phosphorylation of fructose to fructose 1-phosphate. Fructose, 
per se, is biologically inactive and requires metabolism by KHK to elicit negative metabolic 
consequences. Excessive fructose causes pro-lipogenic and inflammatory profiles in the liver 
where KHK is abundantly expressed and is the primary site of fructose metabolism (Hannou et 
al. 2018). 
Various epidemiological and human intervention studies revealed the association of fructose 
consumption with 
• 
insulin resistance (Basciano et al. 2005) 
• 
NAFLD and NASH (Vos and McClain 2009; Weber et al. 2018)  
• 
CV disease (Fung et al. 2009; de Koning et al. 2012), and 
• 
accompanying mortality (Collin et al. 2019). 
Conversely, human intervention trials suggest significant metabolic benefits from isocaloric 
fructose restriction including 
• 
reduced liver steatosis 
• 
suppressed hepatic de novo lipogenesis 
• 
decreased inflammation, and 
• 
improved insulin sensitivity. 
KHK inhibition is anticipated to mimic the isocaloric fructose restriction profiles. 
Ketohexokinase as a therapeutic target 
Human genetic validation of KHK as a therapeutic target exists based on loss-of-function 
mutations that result in essential fructosuria, an autosomal recessive disorder (Laron 1961; 
Froesch 1969; Bonthron et al. 1994). Individuals with this benign condition have inactive 
isoforms of KHK, which 
• 
limits the liver’s ability to metabolize and clear fructose 
• 
increases fructose excursion into the serum, and 
• 
results in excretion of fructose into urine. 
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Due to the low prevalence of condition (approximately 1/100,000) and/or its benign nature, 
individuals with essential fructosuria have not been characterized well enough to define potential 
metabolic phenotype improvements. However, characterization of these individuals supports the 
notion that a KHK inhibitor is anticipated to eliminate excess carbohydrates without a 
mechanism-based safety issue. 
KHK inhibition (via mouse knockout, siRNA, small molecule) in nonclinical animal models 
support efficacy in NAFLD/NASH (Ishimoto et al. 2012; Ishimoto et al. 2013; Lanaspa et al. 
2013; Lanaspa et al. 2018; Softic et al. 2017). KHK inhibition is expected to attenuate fructose 
metabolism resulting in 
• 
reduction of liver fat, inflammation, and fibrosis 
• 
improvement in glycemic control 
• 
improvement in insulin sensitivity, and 
• 
reduction in body weight, free fatty acids, and triglycerides. 
A clinical trial in patients with NAFLD treated for 6 weeks with a KHK inhibitor demonstrated  
• 
a statistically greater reduction from baseline in the whole liver fat 
• 
a dose-dependent decrease in fasting insulin and insulin resistance 
• 
a dose-dependent percentage changes in high-sensitivity C-reactive protein (reduction) 
and adiponectin (increase), and 
• 
an acceptable safety and tolerability profile (Calle et al. 2019). 
Nonclinical data 
The nonclinical safety profile of LY3522348 was evaluated in a set of GLP in vitro and in vivo 
studies, including genetic toxicology assays, safety pharmacology studies, and repeat-dose 
toxicity studies in rats and dogs. In the 4-week GLP toxicology and toxicokinetic studies, a 
NOAEL was determined in both species. A no-observed-effect level was also determined in a 
single-dose CV safety pharmacology study in dogs. The key nonclinical safety characteristics of 
LY3522348 consist of 
• morbidity and/or emesis/reflux resulting in early termination 
• liver effects 
• CV effects 
• gastrointestinal effects, and 
• lymphoid/hematopoietic effects. 
It should be noted that the majority of the repeat-dose toxicity findings in both species occurred 
at the highest dose tested, which exceeded the maximum tolerated dose. At the mid-dose in each 
of the studies, effects were mild and not considered adverse. LY3522348 was not considered 
genotoxic based on the weight of evidence from a battery of genotoxicity tests and no notable 
findings in respiratory or neurologic safety pharmacology assessmentsLY3522348 IB. 
2.3. 
Benefit/Risk Assessment 
LY3522348 has not been administered to humans previously. 
There is no anticipated therapeutic benefit for the healthy participants in this study. 
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Study YBAA will be conducted in accordance with principles outlined in the Guideline on 
strategies to identify and mitigate risks for first-in-human and early clinical trials with 
investigational medicinal products (EMA 2017). While this guidance recommends use of 
sentinel dosing in first-in-human studies, it also allows for flexibility in a proposed dosing 
approach based on the available scientific data and preclinical assessment of a given molecule. 
Based on the risk assessment of the available data, LY3522348 does not present a high-
uncertainty profile, which would necessitate inclusion of sentinel dosing approach (DeGeorge et 
al. 2018). Nonetheless, sentinel dosing will be introduced in SAD and MAD cohorts anticipated 
to exceed 1/10th of the dog NOAEL exposure observed in the 1-month toxicity study that 
showed steep dose response. 
The available nonclinical safety information for LY3522348 supports its evaluation in healthy 
participants. The overall nonclinical safety profile suggests that there is a low risk to human 
participants administered LY3522348 at the proposed dose range. The doses at the NOAELs in 
rat (30 mg/kg) and dog (20 mg/kg) produced exposures that are at least 3-fold greater and 4-fold 
greater than the predicted human exposures at the maximum planned doses in the SAD (400 mg) 
and MAD (300 mg) studies, respectively. The LY3522348-related adverse findings in the rat and 
dog repeat-dose toxicity studies were limited to dose levels that were not tolerated. 
Any identified risks from nonclinical studies (gastrointestinal irritation, CV and vital signs 
changes, and liver function changes) are considered monitorable and manageable at the planned 
dose range of 5 to 400 mg of LY3522348 in healthy participants. To further minimize any 
potential risk, study participants will remain at the investigative site for at least 7 days in Part A 
and 20 or 21 days in Part B to monitor safety and tolerability during the treatment phase. During 
the inpatient stay, participants will be closely monitored with scheduled clinical safety laboratory 
tests, vital signs, and triplicate ECG measurements. The investigator will have the discretion to 
extend the participant inpatient stay if necessary, for further safety monitoring. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3522348 may be found in the IB. 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
  
• 
To investigate the safety and 
tolerability of LY3522348 following 
single and multiple oral doses 
• 
Incidence of TEAEs and SAEs 
• 
Clinically significant changes in vital signs, safety 
laboratory parameters, and ECGs 
Secondary 
  
• 
To determine the PK of LY3522348 
following single and multiple doses 
• 
AUC(0-24), AUC(0-inf), Cmax, and tmax 
Exploratory 
  
• 
To determine the PD of LY3522348 
following single and multiple doses 
• 
AUC(0-24) of fructose concentration over time 
following FTT 
• 
To investigate the effect of multiple 
doses of LY3522348 on the PK of 
midazolam 
• 
For midazolam and its metabolite, 1ʹ-
hydroxymidazolam 
o 
AUC 
o 
Cmax, and 
o 
the ratio of 1ʹ-hydroxymidazolam:midazolam 
Abbreviations: AUC = area under the concentration versus time curve; AUC(0-24) = AUC from time zero to 24 
hours; AUC(0-inf) = AUC from time zero to infinite hours; Cmax = maximum observed drug concentration; FTT 
= fructose tolerance test; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; tmax = 
time of Cmax; TEAE = treatment-emergent adverse event. 
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4. 
Study Design 
4.1. 
Overall Design 
Study YBAA is a Phase 1, single site, randomized, investigator- and participant-blind, placebo-
controlled, 2-part study in healthy participants. Part A is a SAD study and Part B is a MAD study 
with a DDI component. 
All participants will enter a screening period prior to randomization to Part A or B of Study 
YBAA. Screening may occur up to 28 days prior to admission to the investigative site. 
Participants who are not enrolled within 28 days of screening may repeat screening assessments 
to confirm their eligibility. 
Safety, PK, PD, and other assessments and activities will be performed as specified in 
Section 1.3. Section 6.6 describes the criteria for dose escalation.  
At the end of the treatment period, all participants will attend a follow-up visit. Additional 
follow-up visits may occur depending upon emerging safety and PK data. 
Study governance considerations are described in Section 10.1. 
Refer to Section 1.2. 
4.1.1. 
Part A 
Single-ascending oral dose of LY3522348 or placebo will be administered in up to 6 cohorts. It 
is planned that each cohort will consist of 8 participants, 6 will receive LY3522348 and 2 will 
receive placebo. Cohort 6 is an optional cohort that may be assessed based on the available 
safety and PK data from the previous cohorts. 
A sentinel dosing strategy will be utilized for Cohorts 4, 5, and 6 anticipated to have predicted 
mean exposure(s) between 8.1 μg hr/mL and 25.5 μg hr/mL. Two participants (1 LY3522348 
and 1 placebo) in each cohort will receive the study drug (Sentinel dose) on the same day. After 
at least 48 hours of safety monitoring post-Sentinel dosing, the remaining participants in the 
cohort will be dosed based on the available safety data from the 2 Sentinel participants 
previously dosed. 
A 7-day inpatient stay to allow intensive monitoring will be included for Cohorts 1 to 6. 
A follow-up visit will occur approximately 14 days after the dose of study intervention as 
specified in Section 1.3.1. 
The planned starting dose in Part A is 5 mg of LY3522348. Dose escalation will be based on 
safety and tolerability results from all previous cohorts and PK/PD information when available. 
Doses in the SAD study will escalate until the mean predicted AUC reaches approximately 
25.5 µg∙h/mL, which is 10-fold lower than the Day 1 exposure observed in the male rats at 250 
mg/kg (this dose resulted in morbidity in rats) approximately 7.5-fold lower than the exposure 
observed at the rat NOAEL, see Section 4.3 for more details. Dose escalation in the SAD study 
will not proceed if the predicted mean exposure, AUC(0-inf), in the next cohort is higher than 
25.5 μg hr/mL. A dose of 400 mg is predicted to result in this exposure. Dose escalation to next 
cohort will be no more than 3.3-fold (approximately half-log). The current planned doses are 5, 
15, 50, 150, and 400mg, but may be adjusted to reach the desired exposure. 
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4.1.2. 
Part B 
Part B will be initiated after assessing safety and tolerability through Cohort 4 and PK and PD 
data through Cohort 3 in Part A. 
Multiple-ascending oral doses of LY3522348 or placebo will be administered once daily for 14 
days in Cohorts 1 and 2 and for 15 days in Cohorts 3 and 4. Each cohort will consist of 8 
participants, 6 will receive LY3522348 and 2 will receive placebo.  
In Cohorts 3 and 4, all participants will receive midazolam on Day -1 and study intervention co-
administered with midazolam on Day 15. 
A Sentinel dosing strategy will be utilized for Cohorts 3 and 4, which are anticipated to result in 
the exposure(s) between 8.1 μg hr/mL and 19.1 μg hr/mL. Two participants (1 LY3522348 and 1 
placebo) in each cohort will receive the study drug (Sentinel dose) on the same day. After at least 
48 hours of safety monitoring post Sentinel dosing, the remaining participants in the cohort will 
be dosed based on the available safety data. 
Participants will be discharged on Day 20 for Cohorts 1 and 2 and on Day 21 for Cohorts 3 and 
4. 
A 21-day inpatient stay to allow intensive monitoring will be included for Cohorts 3 and 4. 
A follow-up visit will occur approximately 28 days after the first dose of study intervention as 
specified in Section 1.3.2. 
The current proposed starting dose in Part B is 25 mg of LY3522348, which is predicted to result 
in plasma concentrations less than the half maximal inhibitory concentration (IC50). This dose 
may be modified based on safety and tolerability results and available PK/PD information in the 
SAD study. Doses will be escalated until the mean predicted AUC reaches approximately 
19.1 µg∙hr/mL, which is 1/10th of the NOAEL exposure in rats in the 1-month toxicity study, see 
Section 4.3 for more details. Dose escalation to next cohort will be based on safety and 
tolerability results from all previous cohorts and PK/PD information when available and the dose 
increase will be no more than 3.3-fold (approximately half-log). The current presumed doses are 
approximately 25, 75, 150, and 300mg but may be adjusted to reach the desired exposure. 
4.2. 
Scientific Rationale for Study Design 
Healthy participants 
Conducting the study in healthy participants mitigates the potential confounding effects of the 
disease state and concomitant medications in patients, and therefore provides the most unbiased 
assessment of the safety and tolerability in this first-in-human study. 
Safety, tolerability, PK, and PD data in healthy participants will assist in identifying an 
appropriate dose range for subsequent clinical studies. 
Blinding 
A participant- and investigator-blinded, randomized, placebo-controlled design has been chosen 
to minimize bias during the conduct of the study. 
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Seamless SAD and MAD studies 
Participants will be inpatient during dose administration. If safety concerns arise, the investigator 
may delay discharge from the investigative site. 
In Part A, participants will be admitted to the investigative site on Day -1 and discharged on 
Day 7 to monitor safety and tolerability of the study intervention.  
Part B will be initiated after a review of the safety and tolerability data through Cohort 4 and PK 
and PD data through Cohort 3 in Part A. The starting dose for Part B will have a predicted mean 
steady-state AUC(0-24) and Cmax that are no higher than the mean AUC(0-inf) and Cmax at the 
dose completed in Cohort 4 of Part A. 
In Part B, participants in Cohorts 1 and 2 will be admitted to the investigative site on Day -1 and 
discharged on Day 20 to monitor safety and tolerability of the study intervention. However, 
participants in Cohorts 3 and 4 will be admitted to the investigative site on Day -2 and discharge 
on Day 21. Participants in each of the 4 cohorts will receive a once-daily dose of study 
intervention starting on Day 1 and ending on Day 14. Participants in Cohorts 3 and 4 will receive 
an additional dose of study intervention on Day 15. 
Sentinel dosing approach 
Sentinel dosing will be included for the Cohorts 4, 5, and 6 in the SAD anticipated to result in 
the exposure(s) between 8.1 μg•hr/mL and 25.5 μg hr/mL and also for Cohorts 3 and 4 in the 
MAD, anticipated to result in the exposure(s) between 8.1 μg hr/mL and 19.1 μg hr/mL. 
Midazolam 
The impact of LY3522348 on in vivo CYP3A4 activity will be assessed in Cohorts 3 and 4 in 
Part B. The concentrations of LY3522348 in the intestinal lumen at doses to be evaluated in this 
study are likely to exceed concentrations that are able to be tested against enzyme activity in 
vitro. As such, plasma concentrations of CYP3A index substrate midazolam and its metabolite, 
1ʹ-hydroxymidazolam, will be collected in the absence and presence of LY3522348. 
Periodic reviews 
In case of any AE requiring such a decision, periodic trial-level safety data reviews will ensure 
that 
• 
any participant can be discontinued early 
• 
the dose escalation can be terminated, or 
• 
the study can be terminated. 
4.2.1. 
Participant Input into Study Design 
Throughout this protocol, the term “participant” is used to indicate an individual who participates 
in a clinical trial, as a recipient of a study intervention. This usage reflects preferences indicated 
by patient advocates to more accurately reflect the role of people who take part in clinical trials. 
4.3. 
Justification for Dose 
Human apparent clearance of drug (CL/F) is predicted to be 10 to 22 L/h and half-life (t1/2) of 15 
to 28 hours, supporting once-daily dosing. The human efficacious dose was predicted as the dose 
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that results in unbound steady-state plasma concentrations of LY3522348 greater than the target 
(KHK) IC50 measured in vitro for 24 hours. This results in a predicted efficacious dose of 30 to 
75 mg once daily. The human dose that results in unbound steady-state plasma concentrations of 
LY3522348 greater than the target (KHK) IC90 measured in vitro for 24 hours is predicted to be 
approximately 300 to 400 mg. Refer to the LY3522348 IB for more details on the initial human 
dose projections. 
The planned starting dose in Part A is 5 mg of LY3522348. When adjusted for body surface area, 
this dose is at least 60-fold lower than the rat NOAEL dose and 150-fold lower than the dog 
NOAEL dose. The human exposure at the starting dose is predicted to cover the IC10 for 
approximately 24 hours and is greater than 200-fold lower than the observed exposure at the dog 
NOAEL. Doses in the SAD study will be escalated until the mean predicted AUC reaches 
approximately 10-fold lower than the Day 1 exposure AUC observed in the male rat in the 1-
month GLP toxicology study(25.5 µg∙h/mL), which is approximately 7.5-fold lower than the 
exposure observed at the rat NOAEL. A dose of 400 mg is predicted to result in this exposure, at 
which the plasma concentrations are predicted to approach the target IC90, and will provide the 
opportunity to fully explore the efficacious dose range in human. 
The starting dose in the MAD study will be no higher than a tolerated dose at which the 
predicted exposure has been assessed in the SAD study. Because the cause of the morbidity and 
early termination in the animal studies was not fully established, the proposed high dose in the 
MAD study was selected to maintain adequate projected exposure multiples to both the NOAEL 
as well as the effect levels that caused early termination. Doses in the MAD study will be 
escalated until the mean predicted AUC reaches 19.1 µg∙h/mL, which is 1/10th of the exposure at 
the NOAEL in rats (30 mg/kg) in the 1-month toxicity study. This exposure is 15.4-fold lower 
than the exposure associated with clinical observations in the rat that resulted in early 
termination and 10-fold lower and 4.2-fold lower than the exposure observed at the rat and dog 
NOAELs, respectively. A dose of 300 mg once daily is predicted to result in this exposure. The 
accumulation ratio is predicted to be approximately 2-fold. 
Table 1 shows the dose multiples and exposure multiples between the planned clinical dose 
levels and relevant endpoints in toxicity studies with LY3522348. 
For the DDI assessment, a 200-µg dose of midazolam was chosen to determine a CYP3A-
mediated interaction. This subtherapeutic dose is sufficiently measurable in plasma, but should 
avoid the sedative effect of midazolam (Cannady et al. 2015). 
 
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Table 1.  
Margin of Safety for Oral Administration of LY3522348 Based on 
Administered Dose and Predicted Human Exposure 
 
Dose 
(mg/kg) 
Dose 
(mg/m2) 
Dose 
Multiple
a 
AUC  
(ng·hr/mL) 
Exposure Multiple
b  
Human Start Dose (5 
mg)c 
0.0714 
2.64 
- 
312 
- 
Rat NOAEL
e 
30 
180 
68 
191000 
612 
Dog NOAEL
f 
20 
400 
152 
80800 
259 
 
 
 
 
 
 
Human Maximum Dose 
in the SAD (400 mg)d 
5.71 
211 
- 
25500g 
- 
Rat NOAEL
e 
30 
180 
0.9 
191000 
7.5 
Dog NOAEL
f 
20 
400 
1.9 
80800 
3.2 
 Rat Dose > MTDe 
250 
1500 
7.1 
294000 
11.5 
 Dog Dose > MTDf 
60 
1200 
5.7 
222000 
8.7 
 
 
 
 
 
 
Human Maximum Dose 
in the MAD (300 mg)d 
4.3 
159 
- 
19100h 
- 
Rat NOAEL
e 
30 
180 
1.1 
191000 
10 
Dog NOAEL
f 
20 
400 
2.5 
80800 
4.2 
 Rat Dose > MTDe 
250 
1500 
9.4 
294000 
15.4 
 Dog Dose > MTDf 
60 
1200 
7.5 
222000 
11.6 
Abbreviations: AUC = area under the concentration versus time curve; MAD = multiple-ascending dose; MTD = 
maximum tolerated dose; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect level; QD = 
daily dosing; SAD = single-ascending dose. 
a Dose multiple is the dose in animals/dose in humans based on mg/m2. Doses were converted from mg/kg to 
mg/m2 using a km conversion factor of 6 for the rat, 20 for the dog, and 37 for a 70-kg human. 
b Exposure multiple is the calculated AUC in animals/predicted AUC in humans.  
c Clinical starting dose is based on IC10 (5 mg QD). 
d Maximum clinical dose proposed in SAD and MAD.  
e NOAEL and Dose > MTD in rat 4-week repeat-dose toxicity study (Study 8415214). Average of male and 
female rat AUC on Day 29 (NOAEL) or Day 1 (Dose > MTD).  
f NOAEL and Dose > MTD in dog 4-week repeat-dose toxicity study (Study 8415213). Average of male and 
female dog AUC on Day 29 for NOAEL and average of male and female dog AUC on Day 15 for Dose > MTD.  
g AUC(0-inf). 
h AUC(0-24). 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all required 
phases of the study including the last scheduled procedure shown in the SoA. As such, it is 
planned that each cohort will achieve 
• 8 completers per cohort in Part A, and  
• 8 completers per cohort in Part B. 
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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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5. 
Study Population 
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Participants enrolled in Part A will not be allowed to participate in Part B of the study. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply at 
screening: 
Informed Consent 
1. Capable of giving signed informed consent as described in Section 10.1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol 
2. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures including dietary requirements 
Participant Characteristics 
3. Are overtly healthy as determined through medical evaluation including medical history 
and physical examination 
4. Are male, regardless of fertility status, or female, not of childbearing potential, aged from 
18 to 65 years inclusive, at the time of signing the informed consent 
Note: Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For contraception 
requirements of this protocol, see Section 10.4 
5. Have a body mass index of ≥18.5 and ≤40 kg/m2 
6. Have had a stable weight for the 1 month prior to screening and enrollment (<5% body 
weight change) and have not received dietary intervention in the 1 month prior to 
screening and enrollment 
7. Have safety laboratory test results within normal reference range for the population or 
investigative site, or results with acceptable deviations that are judged to be not clinically 
significant by the investigator 
8. Have venous access enough to allow for blood sampling as per the protocol 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply at screening: 
 
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Medical Conditions 
9. Have an abnormality in the 12-lead ECG at screening that, in the opinion of the 
investigator, increases the risks associated with participating in the study or may 
confound ECG data analysis 
10. Have blood pressure of >160/90 mmHg and pulse rate <50 or >100 bpm, supine (at 
screening), or with minor deviations judged to be acceptable by the investigator 
11. Have a significant history of or current CV (e.g., myocardial infarction, congestive heart 
failure, cerebrovascular accident, venous thromboembolism), respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological (including platelet count ≤150,000/mcL), or 
neurological disorders capable of  
• significantly altering the absorption, metabolism, or elimination of the study 
intervention including bariatric surgery  
• constituting a risk while taking the study intervention, or 
• interfering with the interpretation of data 
12. Have a history of fructosuria. 
13. Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis. 
14. Have AST or ALT, ALP, or TBL ≥1.5x ULN. Participants with Gilbert’s syndrome can 
be enrolled with TBL of <2x ULN. 
15. Have estimated glomerular filtration rate <60 mL/min/1.73 m2. 
Prior/Concomitant Therapy 
16. Intend to use over-the-counter or prescription medication including herbal medications 
such as St. John’s wort and vitamin/mineral supplements within 14 days prior to dosing. 
17. Use of any drugs or substances that are known strong inducers or inhibitors of CYP3A is 
specifically excluded within 14 days prior to the first administration of study intervention 
and during the study. 
Prior/Concurrent Clinical Study Experience 
18. Are currently enrolled in a clinical study involving an investigational product or any 
other type of medical research judged not to be scientifically or medically compatible 
with this study. 
19. Have completed or withdrawn from this study or any other study investigating 
LY3522348 and have previously received the study intervention. 
20. Are currently enrolled in or past participation, within the 30 days prior to screening, in a 
clinical study involving a study intervention for which at least 5 half-lives or 30 days 
(whichever is longer) have not passed. 
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Diagnostic Assessments 
21. Regularly use known drugs of abuse and/or positive urine drug screen at screening or 
check-in. 
22. Show evidence of HIV infection and/or positive human HIV antibodies. 
23. Show evidence of hepatitis B and positive hepatitis B surface antigen. 
24. Show evidence of hepatitis C and/or positive hepatitis C antibody. 
Other Exclusions 
25. Smoke >10 cigarettes per day or the equivalent or are unable or unwilling to refrain from 
nicotine during investigative site admission. 
26. Have either moderate or severe alcohol consumption. Moderate alcohol consumption is 
defined as 1 drink per day for women and 2 standard drinks per day for men, whereby, 1 
standard drink is equivalent to 12 ounces of beer (5% alcohol) or 5 ounces of wine (12% 
alcohol), or 1.5 ounces of distilled spirits (40% alcohol). 
27. Have known allergies to LY3522348, related compounds, or any components of the 
formulation, or a history of significant atopy. 
28. For participants in Cohorts 3 and 4 of Part B, have known allergies to midazolam or its 
metabolites. 
29. Are investigative site personnel directly affiliated with this study and their immediate 
families. Immediate family is defined as a spouse, biological or legal guardian, child, or 
sibling. 
30. Are Lilly or investigative site employees. 
31. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
5.3. 
Lifestyle Considerations 
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. 
5.3.1. 
Meals and Dietary Restrictions 
Participants should be fasted for 8 hours prior to predose blood sampling and performing ECGs. 
As such, participants in Part B do not need to fast on Days 3, 5, 6, and Days 8 to 13. On days of 
midazolam drug-drug interaction assessment (Part B Cohorts 3 and 4), participants should fast 
overnight prior to midazolam administration and abstain from food for 2 hours and fluid for 1 
hour after midazolam administration. 
Within 14 days prior to the first dose of any study intervention until discharge from the study, 
participants should not consume 
• 
herbal supplements 
• 
grapefruits or grapefruit-containing products 
• 
Seville oranges or Seville orange-containing products 
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• 
star fruits or star fruit-containing products, pomelo, or 
• 
commercial apple juice or orange juice. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
Participants will be encouraged to maintain their regular caffeine consumption. 
Nicotine use is not permitted at the investigative site. 
Alcohol consumption is not permitted from 48 hours prior to admission and while resident at the 
investigative site. 
5.3.3. 
Activity 
Participants should avoid strenuous exercise immediately prior to the screening visit and should 
avoid strenuous exercise 3 days prior to each admission and while at the investigative site. 
Participants should maintain their normal levels of activity at other times. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened. Repeating of vital signs and laboratory tests during the screening period or repeating 
screening assessments to comply with the protocol-designated screening period does not 
constitute rescreening. However, participants who are eligible for inclusion in previous cohorts, 
but who are not randomized for nonmedical reasons, may be re-assessed for inclusion in 
subsequent cohorts. 
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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 a study participant according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
LY3522348 or placebo will be administered orally with approximately 240 mL of room 
temperature water in the morning on Day 1 in Part A and Days 1 to 14 in Part B. Participants in 
Cohorts 3 and 4 of Part B will receive an additional dose of either LY3522348 or placebo on Day 
15. 
Doses should be administered while the participant is in sitting position. Participants will not be 
allowed to lie supine for 2 hours after dosing, unless clinically indicated or for study procedures. 
Participants in Cohorts 3 and 4 will be administered midazolam orally on Days -1 and 15. On 
Day -1, participants will receive midazolam alone. On Day 15, participants will receive 
midazolam co-administered with either LY3522348 or placebo. Midazolam administration 
should occur within 15 minutes of LY3522348 administration. 
Study Intervention Name 
LY3522348  
Placebo 
Midazolam 
Dosage Formulation 
Capsules 
Capsules 
Oral solution 
Dose Strength 
5 and 50 mg 
- 
200 μg 
Route of Administration 
Oral 
Oral 
Oral 
The investigator or designee is responsible for 
• 
explaining the correct use of the study interventions to the site personnel 
• 
verifying that instructions are followed properly 
• 
maintaining accurate records of study intervention dispensing and collection, and 
• 
returning all unused medications to the sponsor or its designee at the end of the study. 
Note: In some cases, the investigative site may destroy the material if, during the investigative 
site selection, the evaluator has verified and documented that the site has appropriate facilities 
and written procedures to dispose of the clinical materials. 
6.1.1. 
Packaging and Labeling 
Clinical trial materials will be labeled according to the country’s regulatory requirements. 
Each capsule of LY3522348 will contain 5 or 50 mg of active ingredient. Placebo capsules will 
resemble LY3522348 capsules in appearance. 
LY3522348 and placebo capsules will be supplied to the investigator by the sponsor for 
dispensing by unblinded pharmacy staff. 
Midazolam will be sourced locally by the investigative site. 
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6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive investigational products or study materials, 
and only authorized site staff may supply or administer investigational products. All 
investigational products should be stored in an environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Instructions. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Blinding will be maintained throughout the conduct of the study as described in the separate 
blinding plan. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
CRP for the participant to continue in the study 
Method of treatment assignment 
Participants will be randomized to a treatment using a computer-generated randomization 
schedule. 
Unblinded site pharmacist 
The unblinded pharmacist or designee will prepare the study intervention. 
Participants will be randomly assigned in the ratio determined at randomization to receive study 
intervention. Investigators will remain blinded to each participant’s assigned study intervention 
throughout the course of the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization and dispensing have been 
done accurately. 
Blind break 
Emergency codes will be available to the investigator. A code, which reveals the treatment for a 
specific study participant, may be opened during the study only if the participant’s well-being 
requires knowledge of the participant’s treatment assignment. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
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participant’s safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify the sponsor as soon as possible. 
Upon completion of the study, all codes must be returned to the sponsor or its designee. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the CRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing by 
a member of the site personnel other than the person administering the study intervention. Site 
personnel will examine each participant’s mouth to ensure that the study intervention was 
ingested. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency for concomitant therapy of special 
interest 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) before the start of study intervention until completion of the follow-up visit, unless, in 
the opinion of the investigator and sponsor, the medication will not interfere with the study. 
Vitamin/mineral supplements are not allowed during the study. 
Acetaminophen, at doses of ≤3 g/day, is permitted for use any time during the study. Other 
concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the sponsor’s medical monitor. 
Drugs that are known strong inducers or inhibitors of CYP3A are specifically excluded. For 
more information, refer to Section 10.7. 
6.6. 
Dose Modification 
By nature of being a dose-escalation study, cumulative safety data will be evaluated on an 
ongoing basis until the highest tolerated dose has been administered. 
Safety and tolerability data will be the primary criteria for the dose escalation. No dose decision 
can occur without prior discussion and agreement between the investigator and the sponsor. 
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Any available PK data may be used to guide dose selection or to determine if the number of 
doses to be studied may be reduced. 
After review of these data, an agreement on the appropriate dose will be made by the investigator 
and sponsor for the next cohort/dose level. A lower dose may be administered; dose levels may 
be repeated provided that it is not the result of a safety finding; or the magnitude of dose 
escalations may be reduced following data review, provided that subsequent escalations do not 
increase by more than approximately 3-fold (a half-log increment). 
6.6.1. 
Dose Decision/Escalation 
Dose Decision 
Pharmacokinetics (PK) data will be reviewed for each cohort to inform the next dose level prior 
to dose escalation and to ensure the predicted mean exposure AUC(0-inf) will not exceed 25.5 
µg∙h/mL in Part A and the predicted mean steady-state exposure (AUC0-24) will not exceed 19.1 
µg∙h/mL in Part B. 
Dose escalation 
For dose-escalation decisions in Part A, the following must occur: 
• 
All planned participants in current cohort must have been dosed. 
• 
Clinical assessment is done through Day 3 for at least 6 participants. 
• 
Safety laboratory tests, including ECG measurements, are obtained through Day 3 for at 
least 6 participants. 
• 
Pharmacokinetics (PK) data will be reviewed for each cohort prior to dose escalation  
For dose-escalation decisions in Part B, the following must occur: 
• 
All planned participants in current cohort must have been dosed. 
• 
Clinical assessment is done through Day 7 for at least 6 participants. 
• 
Safety laboratory tests, including ECG measurements, are obtained through Day 7 for at 
least 6 participants. 
Pharmacokinetics (PK) data will be reviewed for each cohort prior to dose escalation. If any of 
the following scenarios occur, dosing at the current level and further dose escalation will be 
interrupted until further sponsor’s decision: 
1. One or more participants on active drug experience an SAE considered to be related to 
LY3522348. 
2. One or more participants on active drug experience 2 clinically significant events related 
to LY3522348 defined as moderate to severe symptoms, clinical signs, and clinical 
laboratory findings that could cause harm to health. The clinically significant events will 
be determined by the investigator or the sponsor  
3. CP and may include findings that do not fulfill the criteria for SAEs. 
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6.6.2. 
Data Review during the Study 
Trial level safety reviews of safety and tolerability data are scheduled to occur after every dosing 
session. PK data will be included in these reviews. The purpose of these reviews are to guide 
dose selection for the next dosing session, and/or to inform the design of subsequent studies. The 
investigator and the sponsor will make the determination regarding dose escalation, based upon 
their review of the data. The investigator will remain blinded, and the sponsor will be unblinded 
during these reviews. 
6.7. 
Intervention after the End of the Study 
Not applicable. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 
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 remain in the study to be evaluated for early discontinuation procedures. At the 
discretion of the investigator, participants may be requested to return to the investigative site for 
safety monitoring at additional visits following completion of the early discontinuation 
procedures. Assessments may include, but will not be limited to, those presented for the follow-
up visit with the addition of safety laboratory tests. 
See the SoA 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. 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula after enrollment), the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
Discontinuation of a participant from a study intervention should be considered if there is a 
marked prolongation of the QT/QTc interval during the study. Prolongation is defined as an 
increase in QT/QTc of greater than 500 ms in more than 1 ECG. 
7.1.1. 
Hepatic Criteria for Discontinuation 
In Part B, discontinuation of the investigational product for abnormal liver test results should be 
considered by the investigator when a participant meets 1 of the following conditions, after 
consultation with the Lilly-designated medical monitor: 
• 
ALT or AST >8X ULN 
• 
ALT or AST >5X ULN sustained for more than 2 weeks or 
• 
ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio >1.5 or 
• 
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
ALP >3X ULN 
• 
ALP >2.5X ULN and TBL >2X ULN 
• 
ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
creatine kinase >5X ULN. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study 
• 
at any time at his/her own request 
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• 
at the request of his/her designee (e.g., 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 investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
• 
if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent 
Participation in the study needs to be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP. As such, a participant may withdraw from 
the study if he or she experiences 
• 
any TEAE or SAE considered possibly or probably related to study intervention that is 
severe or medically significant but not immediately life threatening; or where 
hospitalization or prolongation of hospitalization is indicated; or is disabling; or limits 
self-care activities of daily living, or 
• 
any TEAE or SAE regardless of attribution to study intervention that has life-threatening 
consequences or urgent intervention is indicated. 
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 and 
safety follow-up should be performed as outlined in Section 1.3, Section 8.2, and Section 8.3 of 
the protocol. 
7.2.2. 
Discontinuation of the Study 
The study will be discontinued if the sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
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A safety investigation will be triggered to determine if the study should be terminated early 
based on the following criteria: 
• 
Three study participants develop the same TEAE or SAE considered possibly or probably 
related to study intervention that 
o is severe or medically significant, but not immediately life threatening 
o requires hospitalization or prolongation of hospitalization 
o is disabling, or 
o limits self-care activities of daily living; OR 
• 
Two study participants develop any TEAE or SAE regardless of attribution to study 
intervention that has life-threatening consequences or requires urgent intervention; OR 
• 
Death of any study participant at any time related to AE. 
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 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. Protocol waivers or exemptions 
are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
The specifications in this protocol for the timings of safety, PK, and PD sampling are given as 
targets to be achieved within reasonable limits. Modifications may be made to the time points 
based upon the safety and PK information obtained. The scheduled time points may be 
participant to minor alterations; however, the actual time must be correctly recorded in the eCRF. 
Failure or being late (i.e. outside stipulated time allowances) to perform procedures or obtain 
samples within the stipulated time allowances due to legitimate clinical issues will not be 
considered protocol deviations. Legitimate clinical issues include 
• 
equipment technical problems 
• 
venous access difficulty, or 
• 
participant defaulting or turning up late on an agreed scheduled procedure. 
However, the investigative site will still be required to notify the sponsor in writing to account 
for missing samples to facilitate data reconciliation. 
8.1. 
Efficacy Assessments 
Not applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
Physical examinations and routine medical assessments including body temperature will be 
conducted as specified in Section 1.3 and as clinically indicated. 
From Day 1 until 4 days after the last dose of study intervention, participants will be advised to 
wear sunglasses, hats, and sunscreen during sun exposure. During physical examination, 
treatment-emergent ocular and dermal photosensitivity events will also be assessed by asking the 
participant for any abnormal eye or skin irritation, redness, itching, burning sensation in daylight 
or on exposure to sunlight. The participant will be examined for abnormal skin erythema and 
hyperemia in exposed areas, hyperemia, scleritis, and conjunctivitis. 
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8.2.2. 
Vital Signs 
For each participant, vital sign measurements should be conducted according to Section 1.3. If 
warranted, additional vital signs may be measured. 
Blood pressure and pulse rate should be measured after at least 5 minutes supine. When possible, 
measurements of blood pressure and pulse rate should be performed at approximately the same 
time of day at each scheduled time point. 
If orthostatic measurements are required, participants should be supine for at least 5 minutes and 
stand for at least 2 minutes. 
If the participant feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Additional vital signs may be measured during each study period if 
warranted. 
8.2.3. 
Electrocardiograms 
For each participant, single and triplicate ECGs should be collected according to Section 1.3. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
participant receives the first dose of study intervention should be reported to the sponsor, or its 
designee, as an AE via eCRF. 
ECGs must be recorded before collecting any blood samples. Participants must be supine for 
approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG 
collection. Consecutive replicate ECGs will be obtained at approximately 1-minute intervals. 
Electrocardiograms may be obtained at additional times, when deemed clinically necessary. 
ECGs will be interpreted by the investigator (a physician or qualified designee) at the site as 
soon after the time of ECG collection as possible, and ideally while the participant is still 
present, to determine whether the participant meets entry criteria at the relevant visit(s) and for 
immediate participant management should any clinically relevant findings be identified. 
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the participant for symptoms (e.g., palpitations, near 
syncope, syncope) to determine whether the participant can continue in the study. The 
investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document his/her review of the ECG printed at the time of 
evaluation from at least 1 of the replicate ECGs from each time point. 
Single ECGs will be recorded and stored at the investigational site. Triplicate digital ECGs will 
be electronically transmitted to a central ECG laboratory designated by the sponsor. The central 
ECG laboratory will perform a basic quality control check (e.g., demographics and study details) 
then store the ECGs in a database. At a future time, the stored ECG data may be overread at the 
central ECG laboratory for further evaluation of machine-read measurements or to meet 
regulatory requirements. 
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used). 
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8.2.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for the 
timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 14 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
• 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
• 
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s 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 the results must be recorded in the CRF. 
8.2.5. 
Body Temperature 
Body temperature will be measured as specified in the Section 1.3 and as clinically indicated. 
8.2.6. 
Safety Monitoring 
The sponsor’s CP or CRP/scientist will monitor safety data throughout the course of the study. 
The sponsor will review SAEs within time frames mandated by company procedures. The 
sponsor’s CP or CRP will periodically review 
• 
trends in safety data 
• 
laboratory analytes, and 
• 
AEs. 
When appropriate, the sponsor’s CP or CRP will consult with the functionally independent 
Global Patient Safety therapeutic area physician or clinical research scientist. 
If the safety monitoring procedure uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the site personnel 
included in the unblinding/blinding plan. 
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8.2.6.1. 
Hepatic Safety 
Close hepatic monitoring 
Laboratory tests (Section 10.6), 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 1 or more of these conditions 
occur: 
If a participant with baseline results of... 
 develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for patients with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.  
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (e.g., 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 
1 or more of these conditions occur: 
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If a participant with baseline 
results of... 
 develops the following elevation: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or ALT or AST 
≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or ALT or AST 
≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a 
Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined earlier, 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 (e.g., ultrasound or computed tomography scan). 
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for 
• 
hepatitis D virus 
• 
cytomegalovirus 
• 
Epstein-Barr virus 
• 
acetaminophen levels 
• 
acetaminophen protein adducts 
• 
urine toxicology screen 
• 
Wilson’s disease 
• 
blood alcohol levels 
• 
urinary ethyl glucuronide, and 
• 
plasma phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for a 
• 
hepatologist or gastroenterologist consultation 
• 
magnetic resonance cholangiopancreatography 
• 
endoscopic retrograde cholangiopancreatography 
• 
cardiac echocardiogram, or a 
• 
liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver test results during the study 
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
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1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
a. In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests 
2. Elevation of TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
a. In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
a. In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study intervention due to a hepatic event 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events and Serious Adverse Events 
AEs 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 the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Medical occurrences that begin before the start of study intervention but after signing the ICF 
will be recorded on the Adverse Event CRF. 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the patient has signed the ICF and has received study 
intervention. However, if an SAE occurs after signing the ICF, but prior to receiving study 
intervention, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures. 
All SAEs will be collected from the signing the ICF the follow-up visit at the time points 
specified in Section 1.3. 
All AEs will be collected from the signing the ICF until participation in study has ended. 
Adverse events that begin before the start of study intervention but after signing the ICF will be 
recorded on the Adverse Event CRF. 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the participant has signed the ICF and has received study 
intervention. However, if an SAE occurs after signing the ICF, but prior to receiving study 
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intervention, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias while detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed up until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up as defined in Section 7.3. 
Further information on follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (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. 
8.3.5. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study intervention) does not meet the definition of 
an AE. However, to fulfill regulatory requirements, any pregnancy should be reported following 
the SAE process described in Section 10.4.3 to collect data on the outcome for both mother and 
fetus. 
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• 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 90 days after 
the last dose of study intervention. 
• 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Complaint Handling 
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 
trial intervention. 
Sponsor collects product complaints on investigational products and drug delivery systems used 
in clinical studies to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements. 
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study intervention so that the situation can be assessed. 
Note: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.3 and Section 10.3 of the protocol. 
8.3.6.1. 
Time Period for Detecting Product Complaints 
Product complaints that result in an AE will be detected, documented, and reported to the 
sponsor during all periods of the study in which the drug is used. 
If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a drug provided 
for the study, the investigator will promptly notify the sponsor. 
8.3.6.2. 
Prompt Reporting of Product Complaints to Sponsor 
Product complaints will be reported to the sponsor within 24 hours after the investigator becomes 
aware of the complaint. 
The Product Complaint Form will be sent to the sponsor by the method provided in the form. If 
the primary method is unavailable, then an alternative method provided in the form should be 
utilized. 
8.3.6.3. 
Follow-up of Product Complaints 
Follow-up applies to all participants, including those who discontinue study intervention. 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the product complaint. 
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator and submitted to the sponsor. 
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8.4. 
Treatment of Overdose 
For the purposes of this study, an overdose of LY3522348 is considered any dose higher than the 
dose assigned through randomization. 
Refer to the LY3522348 IB for more details. 
In the event of an overdose, the investigator or treating physician should 
1. contact the medical monitor immediately. 
2. closely monitor the participant for any AE/SAE and laboratory abnormalities until 
LY3522348 can no longer be detected systemically. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
Samples will be collected at the visits and times specified in Section 1.3. The actual date and 
time (24-hour clock time) of each sampling will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded site personnel until the study has been unblinded. 
8.5.1. 
Bioanalysis 
Plasma and urine samples will be analyzed at a laboratory approved by the sponsor and stored at 
a facility designated by the sponsor. 
The retention period for bioanalytical samples collected to measure LY3522348 concentrations 
is provided in Section 10.1.10. During this time, samples remaining after the bioanalyses may be 
used for exploratory analyses, such as metabolism and/or protein-binding work. 
8.5.2. 
LY3522348 Measurement 
A maximum of 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 blood samples will be provided by the sponsor. 
Plasma and urine concentrations of LY3522348 will be assayed using a validated liquid 
chromatography tandem mass spectrometry method. Analyses of samples collected from 
placebo-treated participants are not planned. 
8.5.3. 
Drug-Drug Interaction with Midazolam 
Midazolam will be administered to Cohorts 3 and 4 in Part B as indicated in Section 1.3 on 
Days -1 and 15. Blood samples will be collected to determine the plasma concentrations of 
midazolam and its metabolite, 1ʹ-hydroxymidazolam.  
Plasma concentrations of midazolam and its metabolite, 1ʹ-hydroxymidazolam, will be analyzed 
using validated liquid chromatography tandem mass assay. Analyses of samples collected from 
LY3522348- and placebo-treated participants are planned. 
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8.5.4. 
Renal Clearance 
Urine samples will be collected for the characterization of renal clearance. Total urine output for 
the appropriate period after study intervention administration will be collected, pooled, and 
refrigerated. At the end of the collection period, the total urine volume will be recorded. Urine 
samples will be used to determine creatinine, quantification of LY3522348, and exploratory 
metabolite identification. 
Assessment of renal clearance will be an exploratory assessment; therefore, failure to collect 
samples or analyze all collected samples will not be a deviation. Samples will be analyzed using 
a validated fit-for-purpose liquid chromatography tandem mass assay.  
At the visits and times specified in Section 1.3, venous blood samples will be collected to 
determine serum creatinine measurements. 
8.6. 
Pharmacodynamics 
Fructose tolerance test 
Three meals (breakfast, lunch, and dinner) will be served at approximately 20 minutes, 6 hours, 
and 12 hours after dose with low fructose content. A beverage will be served with each of the 3 
meals on Day 1 in Part A (SAD) and Days 1 and 14 in Part B (MAD). The beverage contains a 
mixture of approximately 30.25 g of fructose and 24.75 g of glucose in approximately 300 to 500 
mL of non-caloric solution. The beverage should be served after a portion of the meal has been 
consumed.  The meals should start at the defined time (20 minutes, 6 hours, and 12 hours post 
dose). 
Blood samples for the analysis of fructose will be collected into appropriately labeled tubes 
containing ethylene diamine tetra acetic acid at the time points specified in  
Section 1.3. Sample handling and shipment to the central laboratory will occur per instructions 
given to the investigative site. 
The retention period for PD samples is provided in Section 10.1.10. 
8.7. 
Genetics 
A blood sample will be collected and stored from participants. 
See Section 10.5 for information regarding genetic research and Section 10.1.10 for details about 
sample retention and custody. 
8.8. 
Biomarkers 
8.8.1. 
Fasting Insulin and Adiponectin 
At the visits and times specified in Section 1.3, venous blood samples will be collected to 
determine the blood concentrations of fasting insulin and adiponectin. 
8.8.2. 
Coproporphyrins 
At the visits and times specified in the SoA (Section 1.3.2), venous blood samples will be 
collected and stored to determine the plasma concentrations of coproporphyrins 1 and 3. 
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Instructions for the collection and handling of blood samples will be provided by the sponsor. 
The actual date and 24-hour clock time of each sampling will be recorded. 
Clinical study data indicate that the endogenous coproporphyrins can be used to detect in vivo 
inhibition of hepatic OATPs; therefore, coproporphyrins 1 and 3 are being explored in this study 
as potential biomarkers of OATP function (Lai et al. 2016). If in vitro transporter inhibition data 
indicate potential in vivo OATP inhibition by LY3522348, the coproporphyrin samples may be 
analyzed. 
8.8.2.1. 
Bioanalysis 
Samples may be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of coproporphyrins may be assayed using a validated liquid chromatography 
tandem mass spectrometry method. Samples collected from both LY3522348- and placebo-
treated participants may be analyzed. 
8.8.3. 
Nonpharmacogenetic Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements. 
Blood samples for nonpharmacogenetic biomarker research will be collected at the times 
specified in Section 1.3, where local regulations allow. 
Samples will be used for research on the 
• 
drug target 
• 
disease process 
• 
variable response to LY3522348 
• 
effect of LY3522348 on enzymes/transporters 
• 
pathways associated with targeted indication and/or comorbidities 
• 
potential mechanism of action of LY3522348 and/or research method 
• 
for validating diagnostic tools or assays related to indication and/or comorbidities, or the 
• 
potential mechanism of action of LY3522348. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the site personnel. 
The retention period for biomarker samples is provided in Section 10.1.10. This retention period 
enables use of new technologies, response to regulatory questions, and investigation of variable 
response that may not be observed until later in the development of LY3522348 or after 
LY3522348 is commercially available. 
8.9. 
Immunogenicity Assessments 
Not applicable. 
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8.10. 
Health Economics 
Not applicable 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The primary objectives of this study are to evaluate the safety and tolerability of LY3522348 in 
healthy participants. No statistical hypotheses will be tested for this objective. 
9.2. 
Sample Size Determination 
The sample size for Parts A and B of the study was chosen to provide sufficient data for 
evaluating safety, tolerability, and PK parameters, as well as PD and other exploratory objectives 
of this study. 
A maximum of 100 participants will be randomly assigned to study intervention such that 
approximately 
• 
48 evaluable participants complete Part A, and 
• 
32 evaluable participants complete Part B the study. 
Participant replacement 
To ensure that enough participants complete the study, participants who discontinue from the 
study, for reasons other than an AE suspected to be related to study intervention, may be 
replaced as agreed between the sponsor and investigator. The replacement participant will 
assume the randomization schedule of the discontinued participant. 
9.3. 
Populations for Analyses 
9.3.1. 
Study Participant Disposition 
A detailed description of participant disposition will be provided at the end of the study. 
9.3.2. 
Study Participant Characteristics 
The participant’s age, sex, race, weight, height, and other demographic characteristics will be 
summarized. 
9.4. 
Statistical Analyses 
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
PK/PD analyses will be conducted on data from all participants who receive at least 1 dose of the 
study intervention and have evaluable PK and PD data. 
Safety analyses will be conducted for all enrolled participants, irrespective of the completion of 
all protocol requirements. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Additional 
exploratory analyses of the data, other than the ones outlined in these subsections, may be 
conducted as deemed appropriate. 
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9.4.1. 
Safety Analyses 
9.4.1.1. 
Clinical Evaluation of Safety 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology. 
The incidence of symptoms for each study intervention will be presented by severity and by 
association with the study intervention as perceived by the investigator. Symptoms reported to 
occur prior to enrollment will be distinguished from those reported as new or increased in 
severity during the study. Each symptom will be classified by the most suitable term from the 
Medical Dictionary for Regulatory Activities. 
The number of study intervention-related SAEs will be reported. 
9.4.1.2. 
Statistical Evaluation of Safety 
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 
ECG parameters. All laboratory values will be reported in both absolute values and changes from 
baseline. The parameters will be listed and summarized using standard descriptive statistics. 
Analyses may be performed to determine the effects of LY3522348 concentrations on QTc. A 
concentration-response analysis will be performed according to the ICH-E14 (the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic 
drugs) guidelines. 
Additional analysis will be performed if warranted upon review of the data. 
9.4.2. 
Pharmacokinetic Analyses 
9.4.2.1. 
Pharmacokinetic Parameter Estimation 
PK parameter estimates for LY3522348 will be calculated using standard noncompartmental 
methods of analysis in Parts A and B. 
Pharmacokinetic parameter estimation in Parts A and B 
The primary parameters for LY3522348 analysis will be 
• 
Cmax 
• 
tmax 
• 
AUC 
Other noncompartmental parameters, such as t1/2, apparent clearance, and apparent volume of 
distribution may be reported. 
Pharmacokinetic parameter estimation in Part A only 
Renal clearance of LY3522348 will be calculated as the ratio of total amount excreted/plasma 
AUC(0-inf) in Part A only. The amount excreted is calculated as AUC(0-t), where t is the time 
interval over which urine is collected. This will be compared to the unbound glomerular filtration 
rate, which is estimated using creatinine. 
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Pharmacokinetic parameter estimation in Part B only 
Accumulation ratio for LY3522348 based on AUC(0-24) and Cmax may be reported. 
The primary parameters for analysis for midazolam and its metabolite, 1ʹ-hydroxymidazolam, 
will be AUC(0-tlast) and Cmax. Other parameters, including tmax, t1/2, CL/F, apparent volume of 
distribution during the terminal elimination phase (Vz/F), metabolite ratios based on AUC(0-
tlast) will be calculated as appropriate. 
9.4.2.2. 
Pharmacokinetic Statistical Inference 
The descriptive statistics for the PK parameters will be provided for each dose level. Where 
appropriate, geometric mean and coefficient of variation will be reported. The dose 
proportionality for LY3522348 will be assessed for AUC and Cmax using a power model. The 
power parameter will be evaluated to determine the dose proportionality. 
Comparisons of PK parameters between different treatments on the PK sampling days will be 
performed with appropriate statistical models. Test significance (unadjusted p-values) and 90% 
confidence intervals will be reported. The analyses will be detailed in a separate statistical 
analysis plan. 
9.4.3. 
Pharmacodynamic Analyses 
9.4.3.1. 
Pharmacodynamic Parameter Estimation 
The primary PD effect will be evaluated using FTT for fructose. Area under the curve over times 
sampled for FTT will be calculated using trapezoid methods. Other biomarkers including low- 
and high-density lipoproteins, cholesterol, and triglycerides will be determined if appropriate. 
9.4.3.2. 
Pharmacodynamic Statistical Inference 
PD data will be summarized using descriptive statistics. Where appropriate, geometric mean and 
coefficient of variation will be reported. Comparison of FTT and biomarker measurements 
between different treatments over time will be performed with appropriate statistical models. 
Test significance (unadjusted p-values) and 90% confidence intervals will be reported. The 
analyses will be detailed in a separate statistical analysis plan. 
9.4.4. 
Pharmacokinetic/Pharmacodynamic Analyses 
PK/PD modeling may be employed to characterize the exposure-response relationships between 
LY3522348 concentrations and various PD endpoints, provided enough data are available. 
9.5. 
Interim Analyses 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended. 
The ongoing safety reviews planned for this study are described in Section 6.6.2. 
9.6. 
Data Monitoring Committee (DMC) 
Not applicable. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• 
Applicable ICH GCP Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
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 the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. 
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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 and is kept on file. 
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 that would make the participant identifiable will not be transferred. 
The participant must be informed that his/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 their data to be used as 
described in the informed consent. 
The participant must be informed that his/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. 
10.1.5. 
Dissemination of Clinical Study Data 
Communication of suspended for 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 the sponsor to all investigators (e.g., through 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 the sponsor personnel prior to any further planned dosing. If a dose is planned 
imminently, the sponsor 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. 
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10.1.6. 
Data Quality Assurance 
Investigator responsibilities 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the sponsor or designee electronically (e.g., 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. 
Data monitoring and management 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g., contract 
research organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the investigative site. The study may be audited by the 
sponsor or its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
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An electronic data capture system will be used in this study. The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system. 
Data collected via the sponsor-provided data capture system(s) will be stored by third parties. 
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s). Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports 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 the 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. 
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 investigative site or terminate the study at 
any time for any reason at the sole discretion of the sponsor. Investigative sites will be closed 
upon study completion. An investigative 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 investigative 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 an investigative 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 
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regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.9. 
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. 
10.1.10. 
Long-Term Sample Retention 
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of LY3522348 or after LY3522348 becomes commercially available. 
The following table lists the maximum retention period for sample types. The retention period 
begins after the last participant visit for the study. 
The maximum retention times may be shorter, if specified in local regulations and/or if 
ERBs/IRBs impose shorter time limits. 
Any samples remaining after the specified retention period will be destroyed. 
The sample retention facility will be selected by the sponsor or its designee. 
Sample Type 
Custodian 
Retention Period after Last Patient Visita 
Biomarkers 
Sponsor or designee 
15 years 
PK 
Sponsor or designee 
2 years 
PD 
Sponsor or designee 
1 year 
Genetics 
Sponsor or designee 
15 years 
a 
Retention periods may differ locally. 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 2 will be performed by the central laboratory or by the local 
laboratory. 
• 
Local laboratory results are required only in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered into the CRF. 
• 
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. 
• 
Pregnancy testing will occur as indicated in Section 1.3. 
Investigators must document their review of each laboratory safety report. 
Laboratory and analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel. 
Table 2. 
Clinical Laboratory Tests 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Magnesium 
Platelets 
Glucose 
Differential WBC (absolute counts of): 
Creatinine 
• 
Neutrophils 
Blood urea nitrogen (BUN) 
• 
Lymphocytes 
Lipid panel 
• 
Monocytes 
Total protein 
• 
Eosinophils 
Albumin 
• 
Basophils 
Total bilirubin level 
 
Alkaline phosphatase (ALP) 
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Urinalysis 
Aspartate aminotransferase (AST) 
Specific gravity 
Alanine aminotransferase (ALT) 
pH 
Gamma-glutamyl transferase (GGT) 
Protein 
 
Glucose 
Ethanol testinga,b 
Ketones 
Urine drug screena,b 
Bilirubin 
Hepatitis B surface antigena 
Urobilinogen 
Hepatitis C antibodya 
Blood 
HIV 
Nitrite 
 
  
Pregnancy testc 
Thyroid-stimulating hormonea 
FSHa,d 
Abbreviations: FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell. 
a 
Performed at screening only. 
b 
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities. 
c 
Serum pregnancy test will be performed at screening and urine pregnancy test will be performed at all other 
specified time points. 
d 
Performed in 40- to 55-year-old females to confirm their postmenopausal status. 
10.2.1. 
Blood Sampling Summary 
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. 
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Protocol J2U-MC-YBAA Sampling Summary for Part A 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
45 
1 
45 
Serum pregnancy test 
3.5 
1 
3.5 
Clinical laboratory testsa 
12 
6 
72 
Serum creatinine 
2.5 
4 
10 
Pharmacokinetics 
2 
15 
30 
Pharmacodynamics, including fructose 
tolerance test 
2 
13 
26 
Pharmacogeneticsb 
10 
1 
10 
Fasting biomarker samples 
(nonpharmacogenetic) 
11.5 
(4 mL plasma; 7.5 mL 
serum) 
2 
23 
Total 
 
 
219.5 
Total for clinical purposes (rounded up to the nearest 10 mL) 
 
220 
a Additional samples may be drawn if needed for safety purposes. 
b Only 1 pharmacogenetic sample is needed for each participant. 
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Protocol J2U-MC-YBAA Sampling Summary for Part B – Cohorts 1 and 2 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
45 
1 
45 
Serum pregnancy test 
3.5 
1 
3.5 
Clinical laboratory testsa 
12 
7 
84 
LY3522348 pharmacokinetics 
2 
25 
50 
Adiponectin 
2.5 
2 
5 
Fasting insulin and adiponectin 
2 
2 
4 
Pharmacodynamics, including fructose 
tolerance test 
2 
26 
52 
Pharmacogenetics 
10 
1 
10 
Fasting biomarker samples 
(nonpharmacogenetic) 
11.5 
(4 mL plasma; 7.5 mL 
serum) 
3 
34.5 
Coproporphyrin (stored) 
3 
11 
33 
Total 
  
  
348 
Total for clinical purposes (rounded up to the nearest 10 mL) 
350 
a Additional samples may be drawn if needed for safety purposes. 
 
 
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Protocol J2U-MC-YBAA Sampling Summary for Part B – Cohorts 3 and 4 
Purpose 
Blood Volume per 
Sample (mL) 
Number of 
Blood Samples 
Total 
Volume 
(mL) 
Screening testsa 
45 
1 
45 
Serum pregnancy test 
3.5 
1 
3.5 
Clinical laboratory testsa 
12 
7 
84 
LY3522348 pharmacokinetics 
2 
34 
68 
Adiponectin 
2.5 
2 
5 
Fasting insulin  
2 
2 
4 
Pharmacodynamics, including fructose 
tolerance test 
2 
26 
52 
Midazolam pharmacokinetics 
2 
18 
36 
Pharmacogenetics 
10 
1 
10 
Fasting biomarker samples 
(nonpharmacogenetic) 
11.5 
(4 mL plasma; 7.5 mL 
serum) 
3 
34.5 
Coproporphyrin (stored) 
3 
20 
60 
Total 
 
 
402 
Total for clinical purposes (rounded up to the nearest 10 mL) 
410 
a 
Additional samples may be drawn if needed for safety purposes. 
 
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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 patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
• 
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Events Not Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
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• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of preexisting 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 earlier, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An 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 preexisting 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 (e.g., 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 
f. Other situations: 
• 
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 1 of the other 
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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. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostic reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
 
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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• 
The investigator will consider any AEs, SAEs, and clinically important laboratory 
abnormalities as related to the study intervention unless there is clear evidence that the 
event is not related. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/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 the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE 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. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the sponsor or designee within 24 
hours of receipt of the information. 
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10.3.4. 
Reporting of SAEs 
SAE Reporting via SAE Report 
• 
Facsimile transmission of the SAE Report is the preferred method to transmit this 
information to the sponsor or designee. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Report within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in the SAE Report. 
10.3.5. 
Sponsor Surveillance Process for Dose Escalation or Cohort Expansion 
The sponsor has systematic and robust internal processes in place that ensure safety surveillance 
of development compounds in line with the Food and Drug Administration’s expectations for 
safety assessment committees (FDA 2012, 2015, 2018a, 2018b). This includes processes with 
clearly described roles and responsibilities that are owned by the sponsor’s Global Patient Safety 
organization. These processes are designed to monitor the evolving safety profile (i.e., review of 
cumulative SAEs, other important safety information) by designated cross-functional teams in a 
timely manner at predefined intervals or on an ad hoc basis. In addition, a dedicated process may 
be used to perform unblinded comparisons of event rates for SAEs as necessary. 
This system ensures that the accumulating safety data derived from individual and multiple trials 
across a development program is reviewed on a regular basis and that important new safety 
information such as the need for protocol modification or other relevant safety related material is 
identified and communicated to regulators and investigators appropriately and in a timely 
manner. An internal review of aggregate safety data occurs on at least a quarterly basis or more 
frequently, as appropriate. Any serious adverse reactions are reported within the required 
timeline for expedited reporting. 
In addition to annual periodic safety updates and to further inform investigators, a line listing 
report of suspected unexpected serious adverse reactions is created and distributed to 
investigators on a biannual (twice yearly) basis. Any significant potential risk-safety concerns 
that are being monitored as well as any results being reported in other periodic reports for the 
compound; safety assessment committee decisions; and other significant safety data (e.g., 
nonclinical, clinical findings, removal of serious adverse reactions) are included in the report. 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Female of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be considered. 
Female NOT of Childbearing Potential 
Females in the following categories are not considered females of childbearing potential: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
• 
Tubal ligation 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female is defined as, females who are 
• 
at least aged 40 years with an intact uterus, not on hormone therapy, who has cessation of 
menses for at least 1 year without an alternative medical cause, AND a follicle-
stimulating hormone >40 mIU/mL; or 
• 
aged 55 years or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea; or 
• 
at least aged 55 years with a diagnosis of menopause prior to starting hormone 
replacement therapy. 
10.4.2. 
Contraception Guidance 
Female participants 
Female participants of childbearing potential are excluded from this study. 
Female participants who are not of childbearing potential may participate in this study. 
 
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Male participants 
Male participants (regardless of their fertility status) with nonpregnant female partners of 
childbearing potential must agree to either 
• 
remain abstinent (if this is their preferred and usual lifestyle), 
• 
use condoms as well as 1 additional highly effective method of contraception, or 
• 
use condoms as well as 1 additional effective contraception method (such as diaphragms 
with spermicide or cervical sponge). 
Male participants with pregnant partners should use condoms during intercourse from the 
entirety of the study, plus 90 days thereafter, which corresponds to 4 months after the last 
investigational product dose. 
Male participants who chose to remain abstinent (if this is their preferred and usual lifestyle) 
must adhere to the contraception requirements indicated above should their circumstances 
change. 
Male participants should refrain from sperm donation from the entirety of the study, plus 90 days 
thereafter, which corresponds to 4 months after the last investigational product dose. 
Contraception methods 
Abstinence 
Participants who are abstinent (if this is complete abstinence, as their preferred and usual 
lifestyle) must agree to either remain abstinent without sexual relationships with the opposite 
sex. 
Same-sex relationships 
Participants who are in a same-sex relationship (as part of their preferred and usual lifestyle) 
must agree to stay in a same-sex relationship without sexual relationships with the opposite sex. 
Participants who are in exclusively same-sex relationships (as their preferred and usual lifestyle) 
are not required to use contraception. 
 
 
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Highly effective and effective contraception methods 
Highly effective methods of contraception (less than 1% failure rate) 
Combined oral contraceptive pill and mini-pill 
Intrauterine device (such as Mirena® and ParaGard®) 
NuvaRing® 
Contraceptive patch – ONLY women less than 198 pounds 
(90 kg) 
Implantable contraceptives 
Vasectomy – for men in clinical trials 
Injectable contraceptives (such as Depo-
Provera®) 
Fallopian tube implants (Essure®) if confirmed by 
hysterosalpingogram 
Total abstinence 
  
  
Effective methods of contraception (use 2 forms combined except where noted) 
Male condom with spermicidea 
Diaphragm with spermicide 
Female condom with spermicidea 
Cervical sponge 
Cervical cap with spermicide 
a 
Due to a high failure rate, male and female condoms should not be used in combination. 
Unacceptable contraception methods 
Unacceptable methods of contraception include 
• 
periodic abstinence, such as 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation methods 
• 
declaration of abstinence just for the duration of the trial, and 
• 
withdrawal. 
10.4.3. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive LY3522348. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed up to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
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delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• 
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant’s pregnancy. 
• 
The participant will be followed up to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• 
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at >20 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in  
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. The discontinued participant should follow the standard 
discontinuation process and continue directly to the follow-up visit. 
 
 
 
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10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
Genetic variation may impact a participant’s response to study intervention, susceptibility to, and 
severity and progression of disease. Variable response to study intervention may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease being 
treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected 
for DNA analysis from consenting participants. 
DNA samples will be used for research related to LY3522348 or NAFLD, NASH, and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related to 
LY3522348 and interventions of this drug class, NAFLD, and NASH. Genetic research may 
consist of the analysis of 1 or more candidate genes or the analysis of genetic markers throughout 
the genome or analysis of the entire genome, as appropriate. 
Additional analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to LY3522348 or study interventions of this class to understand study disease or 
related conditions. 
The results of genetic analyses may be reported in the CSR or in a separate study summary. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained while research on LY3522348, similar study interventions of this 
class, or NAFLD and NASH continue but no longer than 15 years or other period as per local 
requirements. 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
See Section 8.2.6.1 for guidance on appropriate test selection. 
The sponsor-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 level 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
Lymphocytes 
Creatine kinase (CK) 
Monocytes 
Other Chemistry 
Basophils 
Acetaminophen 
Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Prothrombin time, international normalized ratio (PT-
INR) 
Ethyl alcohol (EtOH) 
Serology 
Haptoglobin 
Hepatitis A virus (HAV) testing: 
Immunoglobulin (Ig)A (quantitative) 
HAV total antibody 
IgG (quantitative) 
HAV IgM antibody 
IgM (quantitative) 
Hepatis B virus (HBV) testing: 
Phosphatidylethanol (PEth) 
Hepatitis B surface antigen (HBsAg) 
Urine Chemistry 
Hepatitis B surface antibody (anti-HBs) 
Drug screen 
Hepatitis B core total antibody (anti-HBc) 
Ethyl glucuronide (EtG) 
Hepatitis B core IgM antibody 
Other Serology 
Hepatitis B core IgG antibody 
Anti-nuclear antibody (ANA) 
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HBV DNAa 
Anti-smooth muscle antibody (ASMA)b 
Hepatis C virus (HCV) testing: 
Anti-actin antibodyc 
HCV antibody 
Epstein-Barr virus (EBV) testing: 
HCV RNAa 
EBV antibody 
Hepatitis D virus (HDV) testing: 
EBV DNAa 
HDV antibody 
Cytomegalovirus (CMV) testing: 
Hepatitis E virus (HEV) testing: 
CMV antibody 
HEV IgG antibody 
CMV DNAa 
HEV IgM antibody 
Herpes simplex virus (HSV) testing: 
HEV RNAa 
HSV (Type 1 and 2) antibody 
Microbiologyd 
HSV (Type 1 and 2) DNAa 
Culture: 
Liver kidney microsomal type 1 (LKM-1) 
antibody 
Blood 
  
Urine 
  
a 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
b 
Not required if anti-actin antibody is tested. 
c 
Not required if anti-smooth muscle antibody (ASMA) is tested. 
d 
Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
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10.7. 
Appendix 7: Excluded Concomitant Medications 
Strong CYP3A inhibitors 
Strong CYP3A inducers 
Boceprevir 
apalutamide 
Clarithromycin 
avasimibe 
Cobicistat 
carbamazepine 
Conivaptan 
enzalutamide 
danoprevir and ritonavir 
fosphenytoin (see also phenytoin) 
Diltiazem 
ivosidenib 
elvitegravir and ritonavir 
lumacaftor 
grapefruit juice 
mitotane 
Idelalisib 
phenobarbital 
indinavir and ritonavir 
phenytoin 
Itraconazole 
rifabutin 
Ketoconazole 
rifampicin (rifampin) 
lopinavir and ritonavir 
rifapentine 
Nefazodone 
St. John’s wort 
Nelfinavir 
  
Posaconazole 
  
Ribociclib 
  
Ritonavir 
  
saquinavir and ritonavir 
  
Telithromycin 
  
tipranavir and ritonavir 
  
Viekira Pak® (paritaprevir and ritonavir and ombitasvir and/or dasabuvir) 
  
Voriconazole 
  
Abbreviation: CYP = cytochrome P450. 
Note: This list may be updated at the investigator’s discretion. 
 
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10.8. 
Appendix 8: Abbreviations 
Term 
Definition 
AE 
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC(0-24) 
AUC from time zero to 24 hours 
AUC(0-tlast) 
AUC from time zero to time t, where t is the last time point with a measurable 
concentration 
AUC(0-inf) 
AUC from time zero to infinity 
blinding 
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s). Unless otherwise specified, blinding will remain in effect until final 
database lock. 
A single-blind study is one in which the investigator and/or his personnel are aware of 
the treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his personnel and the participant are not. A double-
blind study is one in which neither the participant nor any of the investigator or sponsor 
personnel who are involved in the treatment or clinical evaluation of the participants are 
aware of the treatment received 
CL/F 
apparent clearance of drug 
Cmax 
maximum observed drug concentration 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
confirmation 
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate. Confirmation will either occur immediately after initial testing or will require 
that samples be held to be re-tested at some defined time point, depending on the steps 
required to obtain confirmed results. 
CP 
clinical pharmacologist 
CRF 
case report form 
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. 
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CV 
Cardiovascular 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
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. 
ERB 
ethical review board 
FTT 
fructose tolerance test 
GCP 
good clinical practice 
GLP 
Good Laboratory Practice 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
IC90 
90% maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
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.  
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigator 
A person responsible for the conduct of the clinical study at an investigative site. If a 
study is conducted by a team of individuals at an investigative site, the investigator is the 
responsible leader of the team and may be called the principal investigator. 
IRB 
institutional review board 
KHK 
Ketohexokinase 
legal representative 
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective participant, to the participant’s participation in the clinical study. 
MAD 
multiple-ascending dose 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no-observed-adverse-effect level 
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noninvestigational 
product 
A product that is not being tested or used as a reference in the clinical study, but is 
provided to participants and used in accordance with the protocol, such as concomitant or 
rescue/escape medication for preventative, diagnostic, or therapeutic reasons, medication 
to ensure adequate medical care, and/or products used to induce a physiological response. 
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 
PK/PD 
pharmacokinetic(s)/pharmacodynamic(s) 
QTc 
corrected QT 
randomize 
The process of assigning participants to an experimental group on a random basis. 
SAD 
single-ascending dose 
SAE 
serious adverse event 
screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SoA 
Schedule of Activities 
study intervention 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to gain 
further information about the authorized form. 
TBL 
total bilirubin level 
TEAE 
treatment-emergent adverse event: Any untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship with 
this treatment  
tmax 
time of Cmax 
ULN 
upper limit of normal 
 
 
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10.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]: (09-Sep-2020) 
Overall Rationale for the Amendment: 
The protocol was amended to  
• address FDA comments received during the review of the Initial Investigational New 
Drug Application for LY3522348 and 
• correct minor typo errors which are not reflected in the table below. 
The following table describes the changes made for Amendment (a). 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema 
Changes to this section were made to 
reflect the changes made in Section 
4.1.1-Part A and Section 4.1.2-Part B. 
Adjustments to the study design for the single-
ascending dose (SAD) part of the study 
(PART A) were made to account for timeline 
and design element changes following 
implementation of specific design elements 
that were agreed upon with FDA during the 
initial IND review, such as sentinel dosing 
and mandatory PK after each cohort. Sentinel 
dosing requires 1 placebo and 1 LY to be 
dosed prior to dosing of the other participants. 
With only 1 placebo per cohort as proposed in 
the original SAD design, this would have led 
to unblinding of the investigator. Therefore, 
Lilly changed the design to include 2 placebo 
participants per cohort in the SAD. Mandatory 
PK analysis after each SAD cohort prior to 
dose escalation imposes additional time 
between cohorts. With the re-randomization 
design, this would have required participants 
to stay in the study for a significantly longer 
time. Therefore, the SAD design has been 
changed to a sequential parallel design 
without re-randomization from the originally 
proposed sequential cross-over design with re-
randomization. Consequently, 40-48 
participants (instead of 21) will complete part 
A of the study. 
Section 1.3. 2 
Schedule of 
Activities for Part B 
In the multiple-ascending dose (MAD) 
part of the study, Part B, triplicate ECG 
monitoring was added on Day 18 for 
Cohorts 1 and 2 and on Day 19 for 
Cohorts 3 and 4. 
Response to FDA comment 
Section 4.1.1 Part A 
Changes in Part A are:  
• Removed study intervention 
sequence progression 
Response to FDA comment 
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Section # and Name 
Description of Change 
Brief Rationale 
• Added sentinel dosing for 
Cohorts 4, 5, and 6 anticipated 
to result in the exposure(s) 
between 8.1 μg hr/mL and 
25.5 μg hr/mL. 
• Added 7-day in-patient stay to 
allow intensive monitoring for 
Cohorts 1 to 6. 
• Added dose escalation will not 
proceed if the predicted mean 
exposure, AUC(0-inf), in the 
next cohort is higher than 25.5 
μg hr/mL.  
• Cohort 6 was changed into an 
optional cohort. 
Section 4.1.2 Part B 
Changes in Part B are:  
• Added sentinel dosing for 
Cohorts 3 and 4, anticipated to 
result in the exposure(s) 
between 8.1 μg hr/mL and 
19.1 μg hr/mL. 
• Added 20-day in-patient stay for 
Cohorts 1 and 2. 
• Added 21-day in patient stay to 
allow intensive monitoring for 
Cohorts 3 and 4. 
• Added dose escalation will not 
proceed if the predicted mean 
exposure, AUC(0-24), in the 
next cohort is higher than 19.1 
μg hr/mL, which is 1/10th of 
the AUC at the NOAEL (30 
mg/kg) in the 4-week rat 
study. 
Response to FDA comment 
Section 4.3 
Justification for Dose 
Added dose escalation in the SAD 
study will not proceed if the predicted 
mean exposure, AUC(0-inf), in the next 
cohort is higher than 25.5 μg hr/mL. 
Updated mean predicted AUC criteria 
(Part B) to 19.1 µg∙hr/mL, which is 
1/10th of the AUC at the NOAEL (30 
mg/kg) in the 4-week rat study. 
Response to FDA comment 
Section 5.2 Exclusion 
Criteria 
Changes in Exclusion Criteria are to: 
• Exclude participants with a 
platelet count ≤150,000/mcL. 
• Exclude all participants who 
have undergone bariatric 
surgery. 
Response to FDA comment 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6.1 Dose 
Decision/Escalation 
Changes to this section are:  
• dose escalation in the SAD 
study will not proceed if the 
predicted mean exposure, 
AUC(0-inf), in the next cohort 
is higher than 25.5 μg hr/mL. 
• Updated mean predicted AUC(0-
24) criteria (Part B) to 
19.1 µg∙hr/mL. 
• pharmacokinetics (PK) data will 
be reviewed after completion 
of each cohort prior to dose 
escalation in both Parts A and 
B. 
Response to FDA comment 
Section 10.4.2 
Contraception 
Guidance 
Added use of condoms as well as 1 
additional effective contraception 
method (such as diaphragms with 
spermicide or cervical sponge). 
Added this information as it was inadvertently 
missed previously. 
Amendment [b]: (04-Mar-2021) 
Overall Rationale for the Amendment: 
The protocol was amended to  
• revise the Schedule of Activities for MAD part of the study “Fructose Tolerance Test 
Assay” by removing time points 5 and 20 hours and adding time points 7 and 13 hours on 
Days 1 and 14 to better capture the pharmacokinetic profile of fructose following oral 
administration and 
• revise additional language for clarification as follows: 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.3.1. 
Schedule of 
Activities for Part A 
• Meal for Fructose Tolerance Test is changed to 
Low Fructose Meal. 
• 0.3 hour is changed to 20 minutes for Low 
Fructose Meal. 
• 0.3 hour is changed to 20 minutes for Fructose 
Beverage (for FTT). 
To provide more clarity 
Section 1.3.2. 
Schedule of 
Activities for Part B 
• Additional language is added in Midazolam PK 
sampling “Sampling times are based on 
midazolam administration”. 
• Meal for Fructose Tolerance Test is changed to 
Low Fructose Meal. 
• 0.3 hour is changed to 20 minutes for Low 
Fructose Meal on Days 1 and 14. 
• 0.3 hour is changed to 20 minutes for Fructose 
Beverage (for FTT) on Days 1 and 14. 
To provide more clarity 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.3.2. 
Schedule of 
Activities for Part B 
Timepoints are revised for “Fructose Tolerance Test 
Assay” by removing time points 5 and 20 hours and 
adding time points 7 and 13 hours on Days 1 and 14. 
To better capture the 
pharmacokinetic profile of 
fructose following oral 
administration 
Section 1.3.2. 
Schedule of 
Activities for Part B 
Added additional text on Day 2 and Days 15 to 17 
FTT Assay “predose sample on Day 2 and pre-meal 
for C1 and C2 and predose and premeal for C3 and C4 
on Days 15 - 17”. 
To provide more clarity 
Section 5.2. 
Exclusion Criteria 
Revised exclusion criteria 23 to remove hepatitis B 
core antibody. 
To provide more clarity, 
(hepatitis B antigen is tested 
but hepatitis B core antibody is 
not tested at screening) 
Section 5.3.1. Meals 
and Dietary 
Restrictions 
Added additional text about midazolam administration 
“On days of midazolam drug-drug interaction 
assessment (Part B Cohorts 3 and 4), participants 
should fast overnight prior to midazolam 
administration and abstain from food for 2 hours and 
fluid for 1 hour after midazolam administration”. 
To provide more clarity 
Section 8.2.6.1. 
Hepatic Safety 
serum phosphatidylethanol is changed to plasma 
phosphatidylethanol 
Lab prefers to analyze in 
plasma. 
Section 8.6. 
Pharmacodynamics – 
Fructose tolerance 
test 
Additional language has been added about beverage 
timing “The beverage should be served after a portion 
of the meal has been consumed.  The meals should 
start at the defined time (20 minutes, 6 hours, and 12 
hours postdose).” 
To provide more clarity 
Section 10.2. 
Appendix 2: Clinical 
Laboratory Tests 
Superscript “a” is added to Thyroid-stimulating 
hormone. 
To provide more clarity 
 
 
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