Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 31
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to assess the effect of Pirtobrutinib (LOXO-305) on the heart rate-corrected QT (QTc) interval and to conduct blood tests to measure how much pirtobrutinib (LOXO-305) is in the bloodstream and how the body handles and eliminates pirtobrutinib. The study will also evaluate the safety and tolerability of pirtobrutinib. The study will last up to 71 days, including screening.

Detailed description:

Arms:
arm 1: Pirtobrutinib a single oral dose on Day 1, 12 and 23 following a fast of at least 8 hours prior to and 6 hours after dosing. arm 2: Placebo (matched to Pirtobrutinib) a single oral dose on Day 1, 12 and 23 following a fast of at least 8 hours prior to and 6 hours after dosing. arm 3: Moxifloxacin a single oral dose on Day 1, 12 and 23 following a fast of at least 8 hours prior to and 6 hours after dosing.

Interventions: intervention 1: Pirtobrutinib intervention 2: Placebo intervention 3: Moxifloxacin
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol document:
Prot_000.pdf: 
Protocol LOXO-BTK-20011
A Phase I, Single-Dose, Randomized, Partially Double-Blind, Placebo- and 
Positive-Controlled, 3-Way Crossover Study to Evaluate the Effect of LOXO-305 
on QTc Interval in Healthy Subjects
NCT06215521  
Approval date: 01-Dec-2020


TITLE PAGE 
Protocol 
A Phase I, Single-Dose, Randomized, Partially Double-Blind, Placebo- and 
Positive-Controlled, 3-Way Crossover Study to Evaluate the Effect of LOXO-305 on 
QTc Interval in Healthy Subjects  
Protocol Status: Final 
Protocol Date: 30 November 2020 
Protocol Version: 1.0  
Investigational Medicinal Product: LOXO-305 
Protocol Reference Number: LOXO-BTK-20011 
Covance Study Number: 8419690 
IND Number: 139876 
Sponsor: 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and 
Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Coordinating Investigator Study Site: 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA  
Up to 2 additional sites in the United States 
may be utilized. 
Sponsor Signatory: 
Coordinating Investigator: 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 
PPD
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Protocol 
CONFIDENTIAL 
Covance Study: 8419690 
Protocol Reference: LOXO-BTK-20011 
Protocol Version 1.0, 30 November 2020 
Page 2 of 79 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
 
Date 
01-Dec-20 | 06:54:53 PST
PPD


Protocol 
Covance Stndy: 8419690 
CONFIDENTIAL 
Protocol Reference: LOXO-BTK-20011 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the stndy as described herein. 
Protocol Version 1.0, 30 November 2020 
Date 
Page 3 of79 
PPD


Protocol 
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Covance Study: 8419690 
Protocol Reference: LOXO-BTK-20011 
Protocol Version 1.0, 30 November 2020 
Page 4 of 79 
STUDY IDENTIFICATION 
Sponsor 
Loxo Oncology, Inc. 
A wholly owned subsidiary of Eli Lilly and Company 
701 Gateway Boulevard, Suite 420 
South San Francisco, California 94080 
USA 
Tel (main): 
 
Sponsor’s Study Contact 
 
 
Loxo Oncology, Inc. 
Tel (mobile): 
 
Tel (alternative contact): 
 
Email: 
 
Sponsor’s Medical Contact 
 
Consulting to Loxo Oncology, Inc. 
Tel (mobile): 
 
Email: 
 
Serious Adverse Event Reporting 
Email: SAEIntake@covance.com 
Study Site(s) 
Coordinating Investigator Study Site 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
Up to 2 additional sites in the United States may be 
utilized. 
Coordinating Investigator 
 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, WI 53704 
USA 
Tel: 
 
Tel (after hours): 
 
Sub-investigator(s) 
Obtain information from Form FDA 1572s 
Clinical Laboratory(s) 
Meriter Laboratories 
36 South Brooks Street 
Madison, WI 53715 
USA  
Each additional site will use their local laboratory for 
safety analyses. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Protocol 
CONFIDENTIAL 
Covance Study: 8419690 
Protocol Reference: LOXO-BTK-20011 
Protocol Version 1.0, 30 November 2020 
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Cardiodynamic Analysis 
 
ERT  
150 Allens Creek Road,  
Rochester, New York 14618 
USA 
Email: michael.hirschman@ert.com 
Bioanalytical Laboratory 
Alturas Analytics, Inc. 
1324 Alturas Drive 
Moscow, Idaho 83843 
USA 
Tel (main): (208) 883-3400 
Email: jzimmer@alturasanalytics.com 
Statistician 
 
Covance 
Tel: 
 
Email: 
 
Protocol Medical Writer 
 
Covance 
Tel: 
 
Email: 
 
PPD
PPD
PPD
PPD
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Protocol 
CONFIDENTIAL 
Covance Study: 8419690 
Protocol Reference: LOXO-BTK-20011 
Protocol Version 1.0, 30 November 2020 
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SYNOPSIS 
Study Title 
A Phase I, Single-Dose, Randomized, Partially Double-Blind, Placebo- And 
Positive-Controlled, 3-Way Crossover Study to Evaluate the Effect of LOXO 305 on QTc 
Interval in Healthy Subjects 
Objectives 
The primary objective of the study is to evaluate the effect of a supratherapeutic dose of 
LOXO-305 on the QTc interval corrected for heart rate (HR) compared with placebo in 
healthy subjects. 
The secondary objectives of the study are: 
• to assess the effect of a single supratherapeutic dose exposure of LOXO-305 on other 
electrocardiogram (ECG) parameters (HR, PR, and QRS intervals) and on T-wave 
morphology changes compared with placebo in healthy subjects. 
• to demonstrate assay sensitivity of the study to detect a small QTc effect using 
400 mg oral moxifloxacin as a positive control in healthy subjects.  
• to evaluate the pharmacokinetics (PK) of a single supratherapeutic dose of 
LOXO-305 in healthy subjects.  
• to evaluate the safety and tolerability of a single supratherapeutic dose of LOXO-305 
in healthy subjects. 
Study Design  
This is a single-dose, randomized, partially double-blind (for LOXO-305 only, not 
moxifloxacin), placebo- and positive-controlled, 3-way crossover design study.  
All subjects will participate in 3 treatment periods (Treatment Periods 1, 2, and 3); in each 
treatment period, subjects will receive either a single oral dose of 900 mg LOXO-305 
(Treatment A), a single oral dose of 900 mg LOXO-305 matched placebo (Treatment B), or a 
single oral dose of 400 mg moxifloxacin (Treatment C). All subjects will receive Treatments 
A, B, and C on 1 occasion during the study. There will be a washout period of at least 
10 days between dosing in each period. 
Subjects will be randomly assigned to 1 of 6 treatment sequences (eg, ABC), according to the 
randomization scheme generated by Covance. A total of 30 subjects will be randomized, such 
that 5 subjects will be assigned to each treatment sequence.  
Each treatment (A, B, and C) will be administered orally in the mornings of Day 1, Day 12, 
and Day 23 following a fast of at least 8 hours prior to and 6 hours after dosing. 
Blood samples for the analysis of plasma concentrations of LOXO-305 will be collected for 
96 hours after administration of LOXO-305 (Treatment A) and LOXO-305 matched placebo 
(Treatment B), and for 
 (Treatment C). 
Additional blood samples will be collected for 96 hours after administration of LOXO-305 
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(Treatment A) and LOXO-305 matched placebo (Treatment B) and will be stored for future 
potential and/or exploratory analysis. 
Blood samples from Treatment A will be analyzed for concentrations of LOXO-305 in 
plasma through 96 hours after administration of LOXO-305. Blood samples from Treatment 
B will be analyzed for concentrations of LOXO-305 in plasma only at the single timepoint 
taken 2 hours after administration of LOXO-305 matched placebo. Blood samples from 
Treatment C will be analyzed for concentrations of moxifloxacin in plasma 
 
 Cardiodynamic sampling will be obtained for 24 hours 
after administration of each dose in all treatments (A, B, and C). 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until End of 
Treatment (EOT) on Day 33 upon completion of all PK and safety assessments or Early 
Termination (ET) if the subject discontinues. Subjects will be dosed on Day 1, Day 12, and 
Day 23. A follow-up phone call will occur for all subjects who received at least 1 dose of 
study drug (including subjects who are terminated early) 7 days (± 2 days) after EOT or ET.  
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned to receive a dose of study drug; this definition excludes screen failure 
subjects. Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
In this study, physical examinations, standard safety 12-lead ECGs, vital sign measurements, 
How Do You Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation parameters, 
hematology panel, urinalysis (UA; Appendix 2), and recording of concomitant medications 
will be performed at specified times during the study (for specific timepoints and details on 
each study variable, refer to Appendix 4). Adverse events (AEs) and serious adverse events 
(SAEs) will be collected beginning at informed consent. Adverse events will be reported 
throughout the study (ie, from signing of the ICF until End of Study [EOS], or until ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as 
subject medical history (if the event is reported as beginning prior to signing of the ICF or if 
the event occurs prior to study drug administration on Day 1 and is assessed as not related to 
study procedures by the Investigator [or designee]) or as AEs (if the event occurs after 
signing of the ICF but prior to study drug administration on Day 1 and is assessed as related 
to study procedures by the Investigator [or designee], or if the event occurs after study drug 
administration on Day 1 through EOT or ET regardless of relationship to study drug). From 
EOT or ET through EOS, only AEs assessed as related to study drug by the Investigator (or 
designee) are to be reported. All SAEs that develop from the time of ICF signing until EOS 
(or ET, if the subject discontinues from the study and does not complete a follow-up phone 
call) are to be reported. 
Study completion is defined as the time of the last subject’s follow-up phone call. 
Number of Subjects 
A total of up to 30 subjects (5 subjects per treatment sequence) will be enrolled to ensure at 
least 24 evaluable subjects completed all three treatment periods of the study. A sample size 
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of 24 evaluable subjects will provide at least 90% power to exclude that LOXO-305 causes 
more than a 10-msec QTc effect at clinically relevant plasma levels, as shown by the upper 
bound of the 2-sided 90% confidence interval of the model-predicted QTc effect 
(placebo-corrected change from baseline (ΔΔ) QTc [∆∆QTc]) at the observed geometric 
mean maximum observed plasma concentration (Cmax) of LOXO-305 in the study. This 
power is estimated approximately using a paired t-test. The calculation assumes a 1-sided 5% 
significance level, a small underlying effect of LOXO-305 of 3 msec, and a standard 
deviation (SD) of the change from baseline (Δ) QTc (ΔQTc) of 8 msec for both LOXO-305 
and placebo. 
Main Criteria for Inclusion 
Male subjects, and female subjects of non-childbearing potential must meet the following 
criteria: 
● Between 18 and 55 years of age, inclusive, at Screening  
● Within body mass index (BMI) range 18.0 to 32.0 kg/m2, inclusive at Screening  
● In good general health, based on medical history, physical examination findings, vital 
signs, standard safety 12-lead ECG, or clinical laboratory evaluations at Screening 
and/or Check-in (Day -1), as determined by the Investigator (or designee) 
Investigational Medicinal Products, Dose, and Mode of Administration 
Subject will receive each of the following treatments once throughout the study:  
Treatment A: 
• A single oral dose of 900 mg LOXO-305 (36 × 25-mg tablets, over-encapsulated [9 
capsules]), following a fast of at least 8 hours prior to and 6 hours after dosing. 
Treatment B: 
• A single oral dose of placebo to match 900 mg LOXO-305 (9 capsules), following a 
fast of at least 8 hours prior to and 6 hours after dosing. 
Treatment C: 
• A single oral dose of 400 mg moxifloxacin (1 × 400 mg tablet), following a fast of at 
least 8 hours prior to and 6 hours after dosing. 
Duration of Subject Participation in the Study: 
Planned Enrollment/Screening Duration: Approximately 28 days (Days -29 to -2).  
Length of CRU Confinement: Up to 34 days (Days -1 to 33). 
Planned Study Conduct Duration: Approximately 71 days (Screening through follow-up call).  


Protocol 
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Protocol Reference: LOXO-BTK-20011 
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Criteria for Evaluation: 
Pharmacokinetics: 
Blood samples for the analysis of concentrations of LOXO-305 in plasma will be collected 
for 96 hours after administration of LOXO-305 (Treatment A) and LOXO-305 matched 
placebo (Treatment B). Blood samples for analysis of concentrations of moxifloxacin in 
plasma will be collected for 
 (Treatment C). 
Additional blood samples will be collected for 96 hours after administration of LOXO-305 
(Treatment A) and LOXO-305 matched placebo (Treatment B) and will be stored for future 
potential and/or exploratory analysis. 
Blood samples from Treatment A will be analyzed for concentrations of LOXO-305 in 
plasma through 96 hours after administration of LOXO-305. Blood samples from Treatment 
B will be analyzed for concentrations of LOXO-305 in plasma only at the single timepoint 
taken 2 hours after administration of LOXO-305 matched placebo. Blood samples from 
Treatment C will be analyzed for concentrations of moxifloxacin in plasma through 
 
  
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): area under the concentration-time curve 
(AUC) from hour 0 to 24 hours postdose (AUC0-24), AUC from hour 0 to the last measurable 
concentration (AUC0-t), AUC from hour 0 extrapolated to infinity (AUC0-inf), percentage 
extrapolation for AUC0-inf (%AUCextrap), Cmax, time to Cmax (tmax), apparent terminal 
elimination rate constant (λZ), apparent systemic clearance (CL/F), apparent plasma terminal 
elimination half-life (t½), mean residence time (MRT), and apparent volume of distribution 
(Vz/F).  
Cardiodynamic: 
Cardiodynamic sampling will be obtained for 1.5 hours prior to dosing and 24 hours after 
administration of each dose in all treatments (A, B, and C). 
Safety: 
Safety will be monitored with HDYF? inquiries, clinical laboratory evaluations, vital sign 
measurements, standard safety 12-lead ECGs, and physical examinations. 
Statistical Methods 
Pharmacokinetics: 
Plasma concentrations and PK parameters will be summarized with descriptive statistics 
(number, arithmetic mean, SD, coefficient of variation [CV%], geometric mean, geometric 
CV%, median, minimum, and maximum). No formal statistical analysis is planned. 
Cardiodynamic: 
The primary QTc analysis will be based on concentration-QTc modeling of the relationship 
between the plasma concentrations of LOXO-305 and change-from-baseline QTc using 
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Fridericia’s method (∆QTcF) or ΔQTc corrected, with the method chosen as primary if a 
substantial HR effect is observed. The intent is to exclude an effect of placebo-corrected 
ΔQTc (ΔΔQTc) > 10 msec at clinically relevant plasma levels. If a substantial HR effect (ie, 
the largest least squares mean ∆∆HR > 10 bpm in the by-time point analysis) is observed, the 
QT interval will be corrected using several methods (QTcF, individualized heart 
rate-corrected QT interval [QTcS], and optimized heart rate-corrected QT interval [QTcI]) 
and the primary endpoint will be ΔQTc with the method that removes the heart rate 
dependency of QTc in the best way. Placebo-corrected ΔHR, ΔPR, ΔQRS and ∆QTc (ΔΔHR, 
ΔΔPR, ΔΔQRS and ∆∆QTc) will also be evaluated at each post-dosing timepoint ('by 
timepoint' analysis). An analysis of categorical outliers will also be performed as secondary 
analyses for changes in HR, PR, QRS, QTc, T-wave morphology and U-wave presence. 
Safety: 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and standard safety 12-lead 
ECGs, will be tabulated, and summarized where possible, using descriptive methodology by 
treatment and, as needed, by timepoint. Unless otherwise specified, baseline value is defined 
as the last non-missing measurement before administration of study drug on Days 1, 12, and 
23. No formal statistical analyses are planned for the safety data. All safety data will be listed 
by subject. 
The specific procedures will be documented in the Statistical Analysis Plan. 


Protocol 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES AND FIGURES........................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................14 
1. 
INTRODUCTION ...........................................................................................................17 
1.1. Background ................................................................................................................17 
1.2. Nonclinical Pharmacokinetics and Toxicology Summary ........................................17 
1.3. Potential for Drug-drug Interactions ..........................................................................19 
1.4. Summary of Clinical Experience ...............................................................................20 
1.4.1. 
Safety ...........................................................................................................21 
1.4.2. 
Pharmacokinetics .........................................................................................22 
1.5. Study Rationale ..........................................................................................................25 
1.6. Risk Assessment ........................................................................................................26 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................27 
2.1. Objectives ..................................................................................................................27 
2.1.1. 
Primary Objective ........................................................................................27 
2.1.2. 
Secondary Objectives ...................................................................................27 
2.2. Endpoints ...................................................................................................................27 
2.2.1. 
Primary Endpoint .........................................................................................27 
2.2.2. 
Secondary Endpoints ...................................................................................27 
3. 
INVESTIGATIONAL PLAN ..........................................................................................29 
3.1. Overall Study Design and Plan ..................................................................................29 
3.2. Discussion of Study Design .......................................................................................31 
3.3. Selection of Doses in the Study .................................................................................31 
3.3.1. 
LOXO-305 ...................................................................................................31 
3.3.2. 
Moxifloxacin ................................................................................................32 
4. 
SELECTION OF STUDY POPULATION .....................................................................33 
4.1. Screening Procedures .................................................................................................33 
4.2. Check-in Procedures (Day -1) ...................................................................................33 
4.3. Inclusion Criteria .......................................................................................................34 
4.4. Exclusion Criteria ......................................................................................................36 
4.5. Subject Number and Identification ............................................................................40 
4.6. Removal of Subjects from Study Participation .........................................................41 
5. 
STUDY TREATMENTS .................................................................................................43 
5.1. Description, Storage, Packaging, and Labeling .........................................................43 


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5.2. Study Treatment Administration ...............................................................................43 
5.3. Randomization ...........................................................................................................44 
5.4. Blinding .....................................................................................................................45 
5.4.1. 
Procedures for Breaking the Blind Prior to Study Completion ...................45 
5.4.2. 
Revealing of Randomization........................................................................46 
5.5. Treatment Compliance ...............................................................................................46 
5.6. Drug Accountability ..................................................................................................46 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................47 
6.1. Concomitant Therapies ..............................................................................................47 
6.2. Diet, Fluid, and Activity Control ...............................................................................47 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................49 
7.1. Pharmacokinetic Assessments ...................................................................................49 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing ........................49 
7.1.2. 
Analytical Methodology ..............................................................................49 
7.2. Cardiodynamic Assessments .....................................................................................49 
7.2.1. 
Cardiodynamic ECGs (Holter Monitoring) .................................................49 
7.3. Safety and Tolerability Assessments .........................................................................51 
7.3.1. 
Adverse Events ............................................................................................52 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................53 
7.3.3. 
Vital Signs ....................................................................................................53 
7.3.4. 
Standard Safety 12-lead Electrocardiogram ................................................53 
7.3.5. 
Physical Examination...................................................................................54 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................55 
8.1. Determination of Sample Size ...................................................................................55 
8.1.1. 
Determination of Sample Size for Assay Sensitivity ...................................55 
8.2. Analysis Populations .................................................................................................55 
8.2.1. 
Study Populations ........................................................................................55 
8.3. Cardiodynamic Analysis ............................................................................................56 
8.3.1. 
Baseline ........................................................................................................56 
8.3.2. 
QT Correction Methods ...............................................................................56 
8.3.3. 
Evaluation for QT-RR Correction Methods ................................................57 
8.3.4. 
Concentration-QTc Analysis (Primary Analysis) ........................................57 
8.3.5. 
Assay Sensitivity ..........................................................................................59 
8.3.6. 
By-timepoint Analysis (Secondary Analysis) ..............................................59 
8.3.7. 
Categorical Analysis ....................................................................................59 
8.4. Pharmacokinetic Analysis .........................................................................................60 
8.4.1. 
Descriptive Analysis ....................................................................................61 
8.5. Safety Analysis ..........................................................................................................61 
8.6. Data Handling and Record Keeping ..........................................................................61 
8.7. Quality Control and Quality Assurance .....................................................................62 


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9. 
ADMINISTRATIVE ASPECTS .....................................................................................63 
9.1. Change in Protocol ....................................................................................................63 
9.2. Site Initiation Visit/Investigator Meeting ..................................................................63 
9.3. Disclosure ..................................................................................................................63 
9.4. Monitoring .................................................................................................................63 
9.5. Institutional Review Board ........................................................................................63 
9.6. Informed Consent ......................................................................................................64 
9.7. Records ......................................................................................................................64 
9.8. Reference to Declaration of Helsinki/Basic Principles .............................................64 
9.9. Financing and Insurance ............................................................................................65 
10. REFERENCES ................................................................................................................66 
11. APPENDICES .................................................................................................................68 
Appendix 1: Adverse Event Reporting ...............................................................................69 
Appendix 2: Clinical Laboratory Evaluations .....................................................................73 
Appendix 3: Total Blood Volume .......................................................................................74 
Appendix 4: Schedule of Assessments ...............................................................................75 
 
LIST OF TABLES AND FIGURES 
Table 1: Pharmacokinetic Parameters of LOXO-305 in Cancer Patients 
(Study LOXO-BTK-18001) at Steady State (Cycle 1 Day 8) .............................23 
Table 2: Study Drugs .........................................................................................................43 
Table 3: Treatment Sequences ...........................................................................................45 
 
Figure 2: Dose-Exposure Correlation Assessed by AUC0-8 vs Dose for Cycle 1 Day 8 ...25 
Figure 3: Study Design Schematic .....................................................................................30 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
%AUCextrap 
percentage extrapolation for area under the concentration-time curve 
from hour 0 extrapolated to infinity 
∆ 
change from baseline 
∆∆ 
placebo-corrected change from baseline 
ADL 
Activities of Daily Living 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from hour 0 to 24 hours 
postdose 
AUC0-inf 
area under the concentration-time curve from hour 0 extrapolated to 
infinity 
AUC0-t 
area under the concentration-time curve from hour 0 to the last 
measurable concentration 
AV 
atrioventricular 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BSEP 
bile salt exporter pump 
BTK 
Bruton’s tyrosine kinase 
CFR 
Code of Federal Regulations 
CI 
confidence interval(s) 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent systemic clearance 
Cmax 
maximum observed plasma concentration 
COVID-19 
SARS-CoV-2 
C-QT 
concentration-QT 
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FDA 
Food and Drug Administration 


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FSH 
follicle-stimulating hormone 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDYF? 
How Do You Feel? 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone-replacement therapy 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
IC90 
concentration required for 90% inhibition 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IgM 
immunoglobulin M 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
LFT 
liver function test 
LOWESS 
Locally weighted scatter plot smoothing 
LS 
least squares 
MATE 
multidrug and toxin extrusion protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
MRT 
mean residence time 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OCT 
organic cation transporter 
PCR 
polymerase chain reaction 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
PR interval of the ECG 
QD 
once daily 
QRS 
QRS interval of the ECG 
QT 
QT interval of the ECG 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 


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QTcI 
Optimized heart rate-corrected QT interval 
QTcS 
Individualized heart rate-corrected QT interval 
RBC 
red blood cell(s) 
RP2D 
recommended Phase 2 dose 
RR 
RR interval of the ECG 
SAD 
single ascending dose 
SAE 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDD 
spray-dried dispersion 
SE 
standard error 
SOC 
system organ class 
SOP 
SUSAR 
Standard Operating Procedure 
suspected unexpected serious adverse reaction  
SSS 
sum of squared slopes 
t1/2 
apparent plasma terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum observed plasma concentration 
TQT 
thorough QT 
TSH 
thyroid-stimulating hormone 
UA 
urinalysis 
Vz 
volume of distribution 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
λZ 
apparent terminal elimination rate constant 


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1. INTRODUCTION 
Refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product, LOXO-305.1  
1.1. 
Background 
LOXO-305 (also known as LY3527727) is a selective inhibitor of the Bruton’s tyrosine 
kinase (BTK) being developed by Loxo Oncology. LOXO-305 is distinct from the approved 
BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) in several important ways 
including on the basis of its selectivity, favorable absorption, distribution, metabolism, and 
excretion properties, and non-covalent binding mode.2 These features enable LOXO-305 to 
achieve pharmacokinetic (PK) exposures that exceed the BTK concentration resulting in 90% 
inhibition (IC90) at trough, and thus deliver tonic BTK target inhibition throughout the dosing 
period, regardless of the intrinsic rate of BTK turnover. Moreover, the non-covalent binding 
mode of LOXO-305 is unaffected by BTK C481 substitutions, a common mechanism of drug 
resistance described for all available covalent inhibitors.3,4,5,6,7 Finally, LOXO-305 is also a 
highly selective molecule that is more than 300-fold more selective for BTK versus 370 other 
kinases tested with no significant inhibition of non-kinase off-targets at 1 µM, thus limiting 
the potential for off-target mediated toxicities. Collectively, these unique properties of 
LOXO-305 are expected to deliver more potent, continuous, and selective inhibition of BTK 
in a variety of settings, potentially resulting in increased efficacy. Of note, the activity of 
LOXO-305 in diverse preclinical model systems supports this underlying hypothesis.2 
LOXO-305 is a small molecule that was designed to block the adenosine triphosphate (ATP) 
binding site of the BTK kinase competitively. There is no evidence of irreversible binding. 
LOXO-305 has a molecular weight of approximately 500 g/mol. LOXO-305 will be supplied 
as an immediate-release tablet containing 25 mg or 100 mg of drug substance. 
1.2. 
Nonclinical Pharmacokinetics and Toxicology Summary 
LOXO-305 had high permeability in vitro, but low aqueous solubility. To reduce the 
variability in oral absorption, a spray-dried dispersion (SDD) tablet formulation was 
developed that showed consistent oral bioavailability of approximately 50% in rats and 80% 
in dogs. The bioavailability of the SDD formulation was also not dependent on feeding state 
in dogs. 
As is common in rodents, oral exposure of LOXO-305 was consistently much higher in 
female rats than in males given the same dose of LOXO-305. The sex difference was also 
apparent after intravenous (IV) administration of LOXO-305. There was no difference in the 
PK of LOXO-305 between sexes of dog, and none is expected in other non-rodent species, 
including humans.  
The volume of distribution (Vz) of LOXO-305 ranged from approximately 2 L/kg in the dog 
to 5 L/kg in the male rat, which indicates that LOXO-305 distributes into tissues. LOXO-305 
had protein binding of approximately 95% in human plasma. A somewhat lower extent of 
binding (approximately 82% to 92%) was observed across mouse, rat, rabbit, and dog. 


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LOXO-305 was metabolized slowly by human microsomal fractions and hepatocytes. The 
low rates of metabolism in both these human in vitro systems suggest that LOXO-305 will 
have low clearance in humans. In vitro data with clone expressed cytochrome P450 (CYP) 
enzymes and human liver microsomes indicate that CYP3A4 is the primary CYP enzyme that 
metabolizes LOXO-305. It is also a substrate for direct glucuronidation. 
In long-term hepatocyte incubations, LOXO-305 was metabolized by both oxidation and 
glucuronidation. Inhibition of oxidative metabolism by addition of the P450 inhibitor 
1-aminobenzotriazole showed that oxidative metabolism is CYP dependent. All metabolites 
formed by human hepatocytes were also formed in rat and/or dog hepatocytes supporting the 
use of rat and dog for nonclinical safety assessment. 
Renal clearance of LOXO-305 in male and female rats was negligible. No data on renal 
clearance are available in other species; however, the renal excretion pathway is often 
conserved across species, and therefore no renal clearance would be expected in humans. 
In a Good Laboratory Practice (GLP) in vitro assay for human ether-à-go-go-related gene 
(hERG) activity, the concentration resulting in 50% inhibitory concentration (IC50) for the 
inhibitory effects of LOXO-305 on hERG potassium currents was 
 μM, which is 
approximately 
 higher than the maximum unbound concentration of LOXO-305 in 
patients treated with the dose of 200 mg once daily (QD). There were no LOXO-305-related 
changes in any cardiovascular endpoints including QTc at single doses up to 60 mg/kg in the 
GLP cardiovascular study in the conscious telemetry-instrumented dog. The maximum 
observed plasma concentration (Cmax) for this dose was 10000 ng/mL, which is 
approximately 
above the predicted Cmax 
 ng/mL) at the proposed clinical 
therapeutic dose of 200 mg QD. Furthermore, there were no LOXO-305-related 
abnormalities in rhythm or waveform morphology in the GLP 28-day repeated-dose toxicity 
study in dogs at the low and mid-dose groups based on comparison of predose and postdose 
electrocardiogram (ECG) recordings. The high dose (90/60 mg/kg/dose twice daily [BID]) 
was not evaluated as animals in this group were moribund/debilitated and were terminated on 
Day 13. Mean QTc interval was statistically significantly prolonged (+ 6%; + 15 msec) on 
Day 26 of the dosing phase in males administered 30/10 mg/kg/dose BID compared with 
controls. The prolongation in QTc for males was below the 10% increase or the threshold 
reported for canines exposed to therapeutic concentrations of drugs known to cause QT 
prolongation in humans.8 Therefore, the QTc changes were considered physiologically 
unimportant, and thus not deemed to be adverse. Together, these data indicate that 
LOXO-305 has a low risk of inducing delayed ventricular repolarization, prolongation of the 
QTc interval, and unstable arrhythmias in patients. 
There were no LOXO-305-related findings on the central nervous system when evaluated in 
rat functional observational battery tests and locomotor activity assessments after 4 weeks of 
dosing or during recovery at doses of up to 500 mg/kg/dose BID in male rats and 
175 mg/kg/dose BID in female rats as part of the GLP 28-day repeat-dose study.  
LOXO-305 had no effect on respiration rate in the dog at doses up to 10 mg/kg/dose BID.  
Targets of toxicity were characterized in repeated-dose studies conducted in 2 relevant 
toxicity species. Certain targets (the hematopoietic and lymphoid systems) were found in 
both the rat and the dog. Rat-specific changes in the pancreas are species-specific and seen 
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with other BTK inhibitors. Dog-specific changes in lung and large intestine were lesions 
contributing to moribundity in high-dose animals in the 28-day study. Doses evaluated in 
the 28-day dog study demonstrated a steep dose-response curve for toxicity and pronounced 
changes in hematologic parameters at high exposures. Additionally, in dogs treated for 
3 months, 2 male dogs at 5 mg/kg BID (the highest dose tested) were observed to have eye 
lesions via both ophthalmic and microscopic examination. Findings were observed in both 
eyes of these animals and consisted of very slight to slight multifocal or focal areas of corneal 
opacity in the center of the cornea along with constellation histopathological findings 
suggestive of minimal to mild corneal injury. The time of onset of these effects is unknown, 
as ophthalmic exams were only performed prior to the start of dosing and during the last 
week of the study; however, no eye effects were observed in the previous 28-day study. No 
ocular findings were observed in females. See the IB for additional details.1 
LOXO-305 was not mutagenic in 2 bacterial reverse mutation assays and was negative in a 
non-GLP micronucleus assay using Chinese hamster ovary cells. LOXO-305 was positive for 
the induction of micronuclei via an aneugenic mechanism in the absence and presence of the 
exogenous metabolic activation system in a GLP in vitro micronucleus assay in human 
peripheral blood lymphocytes. However, LOXO-305 was negative in a GLP in vivo 
micronucleus assay in rats at doses up to and including a dose of 
 mg/kg. The Cmax at the 
no observed effect level of 
 mg/kg was 
 ng/mL for males and 
 ng/mL for 
females. 
LOXO-305 was not found to be phototoxic when evaluated in an in vitro neutral red uptake 
phototoxicity assay. 
1.3. 
Potential for Drug-drug Interactions 
LOXO-305 showed no detectable inhibition (IC50 > 
) of CYP1A2, CYP2B6, 
CYP2C19, and CYP2D6, and weak inhibition of CYP2C8, CYP2C9, and CYP3A4 in human 
liver microsomes. After pre-incubation of microsomes with LOXO-305 and nicotinamide 
adenine dinucleotide phosphate prior to addition of CYP450 probe substrate, the CYP3A4 
inhibitory potency of LOXO-305 was increased, suggesting the potential for time-dependent 
inhibition of CYP3A4. Further kinetic evaluation confirmed that LOXO-305 is a 
time-dependent inhibitor of CYP3A4. 
In an in vitro hepatocyte assay, LOXO-305 induced messenger RNA (mRNA) for CYP3A4, 
CYP3A5, CYP2B6, and CYP2C19. For both CYP2B6 and CYP2C19, an increase in activity 
was seen. For CYP3A4, LOXO-305 did not cause an increase in activity, likely due to 
concurrent inhibition of CYP3A4 by LOXO-305. LOXO-305 caused a decrease in mRNA for 
CYP1A2 but did not lead to a reduction of CYP1A2 activity. In the study, CYP2D6, 
CYP2C8, and CYP2C9 mRNA were not induced. 
In vitro LOXO-305 inhibited P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), 
multidrug and toxin extrusion protein (MATE) 1, and MATE2K. LOXO-305 did not inhibit 
organic anion transporter (OAT) 1 and weakly inhibited organic anion transporting 
polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, OAT3, and 
bile salt exporter pump (BSEP). 
LOXO-305 is a substrate of P-gp and BCRP. It is not a substrate of the hepatic transporters 
OCT1, OATP1B1, OATP1B3, or BSEP.  
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1.4. 
Summary of Clinical Experience 
LOXO-305 is currently being studied in an ongoing global Phase 1/2 first-in-human study, 
LOXO-BTK-18001 (the BRUIN Study), in patients with previously treated chronic 
lymphocytic leukemia/ small lymphocytic lymphoma or non-Hodgkin lymphoma. The 
starting dose of LOXO-305 was 25 mg QD. 
As of September 27, 2020, safety data were available from a total of 330 patients treated in 
the LOXO-BTK-18001 study. This includes 324 patients treated at doses ranging from 25 mg 
QD to 300 mg QD in Phase 1/2 Monotherapy cohorts, and 6 patients treated in Phase 1b 
Combination Arm A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after ramp-up] 
Section 1.4.1).  
As of September 30, 2020, PK data were available from 181 patients enrolled in the 
LOXO-BTK-18001 study (Section 1.4.2). 
As of November 23, 2020, LOXO-305 had been recently investigated in 1 study in healthy 
volunteers (LOXO-BTK-20014), which was completed. LOXO-BTK-20014 was a pilot 
food-effect crossover study evaluating the effects of food and a proton pump inhibitor 
(omeprazole) on the PK of LOXO-305 where 10 healthy volunteers were given 200 mg of 
LOXO-305 on 3 separate days, each followed by a washout period.  
As of November 23, 2020, four additional studies were ongoing in healthy volunteers 
(LOXO-BTK-20006, LOXO-BTK-20017, LOXO-BTK-20007, and LOXO-BTK-20008).  
LOXO-BTK-20006 is a drug-drug interaction study evaluating the effects of a strong 
CYP3A4 inhibitor (itraconazole) and a strong CYP3A4 inducer (rifampin) on the PK of 
LOXO-305 where, at the time of this protocol’s development, 3 healthy volunteers were 
given 1 dose of 200 mg of LOXO-305, 12 healthy volunteers were given 200 mg of 
LOXO-305 on 2 separate days (1 of which was co-administered with itraconazole), each 
followed by a washout period, and 12 healthy volunteers were given 200 mg of LOXO-305 
on 3 separate days (2 of which were co-administered with rifampin), each followed by a 
washout period.  
LOXO-BTK-20017 is a single ascending dose (SAD) study evaluating the safety and 
tolerability of LOXO-305 at 300 mg, 600 mg, 800 mg, and 900 mg doses, where, at the time 
of this protocol’s development, 6 healthy volunteers were given a single dose of 300 mg 
LOXO-305, 6 healthy volunteers were given a single dose of 600 mg LOXO-305, 6 healthy 
volunteers were given a single dose of 800 mg LOXO-305, and 6 healthy volunteers were 
given a single dose of 900 mg LOXO-305.  
LOXO-BTK-20007 is a 2-part study of the absorption, metabolism, excretion, and the 
absolute bioavailability of [14C]-LOXO-305 where, at the time of this protocol’s 
development, 4 subjects were given a single oral dose of 200 mg of [14C]-LOXO-305 
(containing ~200 µCi) as an oral solution and 5 subjects were given a single oral dose of 
200 mg LOXO-305 as 2 × 100-mg tablets followed 2 hours later by a single dose of < 100 µg 
of [14C]-LOXO-305 (containing ~1 µCi of radioactivity [microtracer]) administered as an IV 
push over approximately 2 minutes.  


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LOXO-BTK-20008 is a drug-drug interaction study evaluating the effects of LOXO-305 on 
the PK of a sensitive CYP3A4 substrate (midazolam) where, at the time of this protocol’s 
development, 15 healthy volunteers were given 200 mg QD of LOXO-305 on 13 consecutive 
days (1 day of which was co-administered with IV midazolam and 1 day of which was 
co-administered with oral midazolam). 
1.4.1. 
Safety 
As of September 27, 2020, 330 patients were treated in the LOXO-BTK-18001 study and 
received LOXO-305. This includes 324 patients treated at doses ranging from 25 mg QD to 
300 mg QD in Phase 1/2 Monotherapy cohorts, and 6 patients treated in Phase 1b 
Combination Arm A (LOXO-305 200 mg QD plus venetoclax 400 mg QD [after venetoclax 
ramp-up]). A full summary of treatment-emergent adverse events (TEAEs) for patients in the 
study is provided in the LOXO-305 IB and the Investigator is directed to the safety 
information described in that document.1 A summary of safety for LOXO-305 given as 
monotherapy to patients in the LOXO-BTK-18001 study is provided below.  
• In the 324 patients in the Phase 1/2 Monotherapy cohorts, TEAEs reported in ≥ 10% 
of patients (n = 33 or more) were fatigue (20.1% total, 8.3% related), diarrhea (17.0% 
total, 8.6% related), and contusion (13.0% total, 9.0% related). Drug-related TEAEs 
were reported in 156 of 324 patients (48.1%) in the Phase 1/2 Monotherapy cohorts. 
The most frequently reported drug-related TEAEs for LOXO-305 (those in > 5% of 
patients overall) were contusion (9.0%), diarrhea (8.6%), and fatigue (8.3%). All 
other drug-related TEAEs were reported in < 5% of patients (ie, < 17 patients each). 
Treatment-emergent AEs of severity Grade 3 or 4 were reported in 87 of 324 patients 
(26.9%) in the Phase 1/2 Monotherapy cohorts, with 41 (12.7%) of these Grade 3 or 4 
AEs reported as related to study drug.  
• On-study death (death within 28 days of the last dose of study drug) due to a Grade 5 
(fatal) AE was reported in 4 of 324 patients (1.2%) in the Phase 1/2 Monotherapy 
cohorts. One Grade 5 AE, Enterococcus faecium-related septic shock, was considered 
to be related to study drug (further details are provided in the LOXO-305 IB).1 All 
other Grade 5 AEs were considered to be not related to study drug; these included 
pneumonia fungal, shock, and pleural effusion. 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20014 study (headache, nausea, and vomiting), were all Grade 1 in 
severity and considered to be related to LOXO-305. All 3 events were reported by 1 subject 
and resolved within 1 to 1.5 days.  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20006 study (intermittent belching, bloating, insect bite, aphthous ulcer, 
nausea, intermittent diarrhea [x2], muscle twitch), were all Grade 1 in severity, and bloating, 
1 instance of intermittent diarrhea, and intermittent belching were considered to be related to 
LOXO-305 and rifampin. All 7 AEs were reported by 3 subjects and all events resolved prior 
to End of Treatment (EOT; preliminary data on file at the time of this protocol’s 
development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20017 study (headache [observed at the 300 mg LOXO-305 dose], and 


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headache [x2], intermittent headache, and petechial rash left thigh [observed at the 900 mg 
LOXO-305 dose]), were all Grade 1 in severity. One instance of headache observed at the 
300 mg LOXO-305 dose and 1 instance observed at the 900 mg LOXO-305 dose, the 
intermittent headache, and the petechial rash left thigh were considered to be related to 
LOXO-305. All five AEs were reported by 4 subjects and resolved within 2 hours to 5 days 
of onset (preliminary data on file at the time of this protocol’s development). 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in Part 1 of the LOXO-BTK-20007 study (bloody nose, headache, loose stool [x2], red 
bumps on left knee, small abrasion to right elbow), were all Grade 1 in severity and headache 
was considered to be related to LOXO-305. All 7 AEs were reported by 4 subjects and all 
events resolved within 1 to 2 days (preliminary data on file at the time of this protocol’s 
development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in Part 2 of the LOXO-BTK-20007 study (tenderness at left venipuncture site [x2], bruising 
to left antecubital secondary to phlebotomy [x2], bruising to right antecubital secondary to 
phlebotomy, and allergic reaction), were all Grade 1 in severity and no events were 
considered to be related to LOXO-305. All 6 AEs were reported by 4 subjects and all events 
resolved within 1 to 2 days (preliminary data on file at the time of this protocol’s 
development).  
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20008 study (injection site pain, nasal congestion, flatulence, 
constipation, increased urinary frequency, facial rash, and skin tear from tape at IV site), were 
all Grade 1 in severity, and flatulence, constipation, and increased urinary frequency were 
considered to be related to LOXO-305. All 7 AEs were reported by 3 subjects and all events 
resolved within 1 to 8 days (preliminary data on file at the time of this protocol’s 
development).  
As part of each clinical trial conducted in patients or healthy volunteers, ECG and vital signs 
are performed at intervals specified by protocol. For study LOXO-BTK-18001 conducted in 
patients, no clinically significant findings of QTc prolongation have been identified in 330 
patients as of September 27, 2020 (LOXO-305 IB1). In addition, there have been no clinically 
significant abnormal findings in vital signs and ECG data in the studies investigating 
LOXO-305 conducted in healthy volunteers as of November 23, 2020 (preliminary data on 
file at the time of this protocol’s development). 
1.4.2. 
Pharmacokinetics 
As of September 30, 2020, PK data were available from 181 patients enrolled in the 
LOXO-BTK-18001 study. Steady-state PK parameters of LOXO-305 in these cancer patients 
could be derived from data collected on Cycle 1 Day 8 (Figure 1), and are shown in Table 1. 
These data show that LOXO-305 is absorbed after oral administration with a median time to 
maximum observed plasma concentration (tmax) of approximately 2 hours and low clearance 
(Table 1). Due to the limited sampling interval (0-8 hours), imputation for the 24-hour sample 
was made from Cycle 1 Day 8 predose sample, leading to an estimated plasma half-life of 
approximately 20 hours. Maximum observed plasma concentration and area under the plasma 
concentration-time curve (AUC) of LOXO-305 showed increase proportional to dose 


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(Figure 2). Following administration of the recommended Phase 2 dose (RP2D) 200 mg QD, 
mean trough plasma levels of LOXO-305 exceeded the concentration required for 96% 
inhibition of BTK in vitro (IC50 = 
, IC96 = 
). Further details may be 
found in the IB.1 
Pharmacokinetic data following oral administration of a 200-mg dose of LOXO-305 in tablet 
form in healthy volunteers in the LOXO-BTK-20014 study indicate that there was little effect 
of either a standard meal or the proton pump inhibitor omeprazole on the PK of LOXO-305. 
Table 1: Pharmacokinetic Parameters of LOXO-305 in Cancer Patients 
(Study LOXO-BTK-18001) at Steady State (Cycle 1 Day 8) 
Dose Level 
N 
Cmax 
(ng/mL) 
Geo 
mean 
(%CV) 
tmax (h) 
Median 
(min, max) 
AUC0-8 
(ng*h/ 
mL) 
Geo 
mean 
(%CV) 
AUC0-24 
(ng*h/mL) 
Geo mean 
(%CV) 
CL/F (L/h) 
Geo mean 
(%CV) 
t1/2 (h) 
Geo 
mean 
(%CV) 
Ratio 
AUC0-8  
Day 
8/Day 1 
Geo mean 
(%CV) 
25 mg QD 
5 
734 
(11.0%) 
2 (1, 8) 
4240 
(12.4%) 
9800 (25.8%) 
1.55a 
(69.6%) 
18.2a 
(60.1%) 
1.44 
(23.0%) 
50 mg QD 
6 
1420 
(19.2%) 
1.5 (1, 4) 
8660 
(24.7%) 
20100 
(34.9%) 
2.62b 
(36.7%) 
17.6b 
(39.6%) 
1.51 
(25.9%) 
100 mg QD 
9 
3910 
(35.6%) 
2 (1, 4) 
22000 
(37.2%) 
52400 
(39.7%) 
0.968c 
(63.0%) 
22.2c 
(33.9%) 
1.88 
(42.8%) 
150 mg QD 
20 
4680 
(29.1%) 
2 (1, 8) 
28000 
(29.6%) 
64400 
(39.6%) 
1.36d 
(66.7%) 
18.1d 
(51.8%) 
1.74 
(24.9%) 
200 mg QD 
99 
5770 
(47.7%) 
2 (1, 8) 
36900 
(40.8%) 
91000 
(42.0%) 
1.14e 
(61.8%) 
19.9e 
(56.2%) 
1.69h 
(29.6%) 
250 mg QD 
25 
8100 
(28.1%) 
2 (1, 4) 
49700 
(31.3%) 
111000 
(38.7%) 
1.26f 
(1.08%) 
17.4f 
(50.6%) 
1.68 
(24.5%) 
300 mg QD 
17 
10700 
(26.6%)  
2 (1, 4) 
65800 
(35.9%) 
158000 
(49.2%) 
1.63g 
(42.5%) 
30.1g 
(102%) 
2.15 
(31.2%) 
Abbreviations: AUC0-8 = area under the concentration-time curve from time 0 to 8 hours; AUC0-24 = area under 
the concentration-time curve from time 0 to 24 hours; CL/F = apparent oral clearance; Cmax = maximum drug 
concentration; Geo mean = Geometrical mean; N = number of subjects; QD = once daily; CV = coefficient of 
variation; t1/2 = half-life; tmax = time of maximal plasma concentration. 
a N= 4, b N= 5, c N= 8, d N= 18, e N= 64, f N= 21, g N= 16, h N= 73 
SDTM Transfer: September 30, 2020 
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SDTM Transfer: September 30, 2020 
1.5. 
Study Rationale 
Cardiac safety is a major factor in clinical development given that the effects of new drugs in 
delaying cardiac repolarization are a common cause for drug withdrawal from the market and 
delays in, or denial of, regulatory approval for marketing. The potential effect of a drug on 
cardiac repolarization can be measured as prolongation of the QT interval on 
electrocardiographic recordings. 
Regulatory guidance (International Council for Harmonisation [ICH] E14) has emphasized 
the need to obtain clear robust data on the effect of new chemical entities on ECG parameters 
with focus on cardiac repolarization as measured by the QTc duration.9 Most clinical trials 
due to insufficient sample size, infrequent sampling of ECG data, or the lack of placebo or 
positive pharmacologic controls are not adequately powered to overcome the high rate of 
spontaneous change in QTc duration. The most recent R3 Q&A document updating the ICH 
E14 guidance10, specifies that concentration-response analysis, in the correct setting, may 
serve as the primary basis for decisions to classify the proarrhythmic risk of a new drug.  
The study design includes the use of a placebo, a supratherapeutic dose of LOXO-305 (to 
mimic the exposure in healthy subjects that may occur in the target population under the most 
extreme circumstances and to assess the effect on cardiac repolarization), and a positive 
control, moxifloxacin. Modeling the concentration-QT (C-QT) relationship observed during 
this study will characterize the QT prolongation effect over the observed drug concentration 
at a supratherapeutic dose of LOXO-305 to assess the drug cardiac effect at therapeutic 
doses. 
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1.6. 
Risk Assessment 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatments, although there may 
also be some discomfort from collection of blood samples and other study procedures.  
The therapeutic dose of LOXO-305 is 200 mg QD which at steady state has a geometric 
mean Cmax of 
. It is expected that the worst-case scenario during maximal 
CYP3A4 inhibition will be an increase in the Cmax of < 2 fold. Thus, the study will target a 
dose of LOXO-305 that achieves a Cmax of 
. The supratherapeutic dose of 
900 mg LOXO-305 selected for this study is anticipated to result in a mean Cmax of 
approximately 
 based on the data to date from the SAD study 
(LOXO-BTK-20017) and is not anticipated to induce any potential risk to subjects 
participating in this study. More information about the known and expected benefits, risks, 
and reasonably anticipated AEs associated with LOXO-305 may be found in the IB.1  
Moxifloxacin hydrochloride (HCl) is a synthetic C-8-methoxy-fluoroquinolone antimicrobial 
agent. The recommended oral dose is 400 mg QD for 5 to 21 days, depending on the specific 
infection.11 Following administration of the usual therapeutic dose (400 mg), peak plasma 
levels occur at approximately 1.5 hours and the elimination half-life of moxifloxacin is about 
13 hours. Moxifloxacin prolongs QT interval duration and is used as a positive control in 
most thorough QT (TQT) studies to determine study sensitivity. The most common AEs seen 
with moxifloxacin are nausea, diarrhea, headache, and dizziness. The moxifloxacin dosing 
regimen for this study is within the Food and Drug Administration (FDA)-approved dosing 
regimen and the risk of moxifloxacin-induced Torsade de Pointes is expected to be minimal 
when the drug is administered at the recommended dose.  
The safety monitoring practices employed will include AE reporting, vital sign 
measurements, standard safety 12-lead ECGs, clinical laboratory evaluations, and physical 
examinations, and are considered adequate to protect the subjects’ safety. 
 
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2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is: 
• to evaluate the effect of a supratherapeutic dose of LOXO-305 on the QTc interval 
corrected for heart rate (HR) compared with placebo in healthy subjects.  
2.1.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• to assess the effect of a single supratherapeutic dose exposure of LOXO-305 on other 
ECG parameters (HR, PR, and QRS intervals) and on T-wave morphology changes 
compared with placebo in healthy subjects. 
• to demonstrate assay sensitivity of the study to detect a small QTc effect using 
400 mg oral moxifloxacin as a positive control in healthy subjects. 
• to evaluate the PK of a single supratherapeutic dose of LOXO-305 in healthy subjects. 
• to evaluate the safety and tolerability of a single supratherapeutic dose of LOXO-305 
in healthy subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
2.2.1.1. 
Cardiodynamic 
• Placebo-corrected change from baseline (ΔΔ) QTc interval (ΔΔQTc). The default will 
be ΔΔQTcF with QTc interval corrected for HR using the Fridericia method (QTcF). 
If a substantial HR effect is observed (ie, the largest least squares [LS] mean ΔΔHR is 
greater than 10 bpm in the by-time point analysis), other correction methods such as 
optimized HR-corrected QT interval (QTcI), and individual HR-corrected QT interval 
(QTcS) will be explored and compared. The method that removes the HR dependence 
of the QT interval most efficiently will be chosen as the primary correction method 
for this primary endpoint. 
2.2.2. 
Secondary Endpoints 
2.2.2.1. 
Cardiodynamic 
• Change from baseline (Δ) QTcF, HR, PR, QRS intervals (ΔQTcF, ∆HR, ∆PR, and 
∆QRS) 
• If a substantial HR effect is observed: Change-from-baseline QTcS, and QTcI 
(ΔQTcS, and ΔQTcI) 
• Placebo-corrected change from baseline HR, PR, and QRS (ΔΔHR, ΔΔ PR, ΔΔQRS) 


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• If a substantial HR effect is observed: Placebo-corrected ΔQTcF, and/or ∆QTcS, 
and/or ∆QTcI (ΔΔQTcF, ∆∆QTcS, ∆∆QTcI) if not selected as the primary endpoint 
• Categorical outliers for QTcF (and QTcS, and QTcI if a substantial HR effect is 
observed), HR, PR, and QRS 
• Frequency of treatment-emergent changes of T-wave morphology and U-wave 
presence. 
2.2.2.2. 
Pharmacokinetic 
The following PK parameters will be calculated, whenever possible, based on the plasma 
concentrations of LOXO-305 (as appropriate): 
• AUC from hour 0 to 24 hours postdose (AUC0-24) 
• AUC from hour 0 to the last measurable concentration (AUC0-t) 
• AUC from hour 0 extrapolated to infinity (AUC0-inf) 
• percentage extrapolation for AUC0-inf (%AUCextrap) 
• apparent systemic clearance (CL/F) 
• Cmax 
• apparent plasma terminal elimination half-life (t½) 
• tmax 
• apparent terminal elimination rate constant (λZ) 
• apparent volume of distribution at the terminal phase (Vz/F) 
• mean residence time (MRT) 
In addition, concentrations of moxifloxacin in plasma will be assessed 
 
. 
2.2.2.3. 
Safety 
Safety and tolerability will be assessed by monitoring AEs, performing physical examinations 
and clinical laboratory evaluations, measuring vital signs, and recording standard safety 
12-lead ECGs. 
 
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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is a single-dose, randomized, partially double-blind (for LOXO-305 only, not 
moxifloxacin), placebo- and positive-controlled, 3-way crossover design study.  
All subjects will participate in 3 treatment periods (Treatment Periods 1, 2, and 3); in each 
treatment period, subjects will receive either a single oral dose of 900 mg LOXO-305 
(Treatment A), a single oral dose of 900 mg LOXO-305 matched placebo (Treatment B), or a 
single oral dose of 400 mg moxifloxacin (Treatment C). All subjects will receive Treatments 
A, B, and C on 1 occasion during the study. There will be a washout period of at least 
10 days between dosing in each period. 
Subjects will be randomly assigned to 1 of 6 treatment sequences (eg, ABC), according to the 
randomization scheme issued by Covance. A total of 30 subjects will be randomized, such 
that 5 subjects will be assigned to each treatment sequence (see Table 3 for treatment 
sequences).  
Each treatment (A, B, and C) will be administered orally in the mornings of Day 1, Day 12, 
and Day 23 following a fast of at least 8 hours prior to and 6 hours after dosing. 
Blood samples for the analysis of plasma concentrations of LOXO-305 will be collected for 
96 hours after administration of LOXO-305 (Treatment A) and LOXO-305 matched placebo 
(Treatment B), and 
 (Treatment C). Additional 
blood samples will be collected for 96 hours after administration of LOXO-305 (Treatment 
A) and LOXO-305 matched placebo (Treatment B) and will be stored for future potential 
and/or exploratory analysis. 
Blood samples from Treatment A will be analyzed for concentrations of LOXO-305 in 
plasma through 96 hours after administration of LOXO-305. Blood samples from Treatment 
B will be analyzed for concentrations of LOXO-305 in plasma only at the single timepoint 
taken 2 hours after administration of LOXO-305 matched placebo. Blood samples from 
Treatment C will be analyzed for concentrations of moxifloxacin in plasma through 
 
. Cardiodynamic sampling will be obtained for 24 hours 
after administration of each dose in all treatments (A, B, and C). 
The schematic of the study design is displayed in Figure 3.  
The start of the study is defined as the date the first subject who is enrolled in the study signs 
an Informed Consent Form (ICF). Note that enrolled subjects are defined as those subjects 
who are assigned to receive a dose of study drug; this definition excludes screen failure 
subjects. Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number. 
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Figure 3: Study Design Schematic 
 
To assess their eligibility to enter the study, potential subjects will be screened within 28 days 
(Days -29 to -2) and be admitted to the Clinical Research Unit (CRU) on Day -1 (Check-in). 
Subjects will be confined at the CRU from the time of Check-in (Day -1) until EOT on 
Day 33 upon completion of all PK and safety assessments or Early Termination (ET) if the 
subject discontinues. Subjects will be dosed on Days 1, 12, and 23. A follow-up phone call 
will occur for all subjects who received at least 1 dose of study drug (including subjects who 
are terminated early) 7 days (± 2 days) after EOT or ET. The duration of participation is 
expected to be approximately 71 days (Screening through follow-up phone call). 
In this study, physical examinations, standard safety 12-lead ECGs, vital sign measurements, 
How Do You Feel? (HDYF?) inquiries, clinical chemistry panel, coagulation parameters, 
hematology panel, urinalysis (UA; Appendix 2), and recording of concomitant medications 
will be performed at specified times during the study (for specific timepoints and details on 
each study variable, refer to Appendix 4).  
Adverse events and serious adverse events (SAEs) will be collected beginning at informed 
consent. Adverse events will be reported throughout the study (ie, from signing of the ICF 
until End of Study [EOS], or until ET if the subject discontinues from the study and does not 
complete a follow-up phone call), either as subject medical history (if the event is reported as 
beginning prior to signing of the ICF or if the event occurs prior to study drug administration 
on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) 
or as AEs (if the event occurs after signing of the ICF but prior to study drug administration 
on Day 1 and is assessed as related to study procedures by the Investigator [or designee], or if 
the event occurs after study drug administration on Day 1 through EOT or ET regardless of 
relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to 
study drug by the Investigator (or designee) are to be reported. All SAEs that develop from 
the time of ICF signing until EOS (or ET, if the subject discontinues from the study and does 
not complete a follow-up phone call) are to be reported. 


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A Schedule of Assessments is presented in Appendix 4. Study completion is defined as the 
time of the last subject’s follow-up phone call. 
3.2. 
Discussion of Study Design 
The study design includes the use of a placebo, a supratherapeutic dose of LOXO-305 to 
mimic the exposure in healthy subjects that may occur in the target population under the most 
extreme circumstances and to assess the effect on cardiac repolarization and a positive 
control, moxifloxacin. Modeling the C-QT relationship observed during this study will 
characterize the QT prolongation effect over the observed drug concentration of a 
supratherapeutic dose of LOXO-305 to assess the drug cardiac effect at therapeutic doses. 
A randomized crossover design has been selected to minimize assignment bias and to allow 
each subject to serve as his or her own control, which improves the precision of the estimated 
treatment differences as well as decreasing the overall number of subjects needed for the 
study. It will be a partially double-blind study with respect to LOXO-305 and LOXO-305 
matched placebo because blinding eliminates confounding by concomitant interventions and 
biased safety findings, thus eliminating the possibility that the observed effects of 
intervention are because of differential use of other treatments or biased expectations 
regarding safety. 
Placebo has been chosen as the control treatment to assess whether any observed effects are 
treatment-related or simply reflect the study conditions. Moxifloxacin as a single 400-mg 
dose is a standard positive control to be used in QT studies to assess assay sensitivity. This 
product has been shown to produce a peak QTc prolongation ranging from 10 to 15 msec in 
crossover design studies,12,13 with a mean QTc prolongation of about 5 msec. Hence, 
moxifloxacin-induced changes in ventricular repolarization, when compared to the placebo 
treatment in healthy subjects, will be used to evaluate assay sensitivity.13,11 
The sampling scheme is expected to adequately characterize the LOXO-305 
exposure-response relationship including hysteresis and late effects and diurnal variability, 
and the washout period of at least 10 days between each treatment period is considered 
sufficient to prevent carryover effects of the treatments. 
Conducting the study in healthy adult subjects mitigates the potential confounding effects of 
the disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
3.3.1. 
LOXO-305 
A single dose of LOXO-305 (900 mg) has been selected as a supratherapeutic dose to provide 
a single-dose Cmax that is approximately 2-fold greater than that of the steady-state Cmax of 
LOXO-305 at its RP2D in cancer patients, specifically 12860 ng/mL. This target 
concentration of 12860 ng/mL is 2-fold greater than the geometric mean of 
 from 
the dosage of 200 mg QD as shown in Table 1. The approximate 2-fold greater Cmax planned 
for this study, relative to the steady-state Cmax in cancer patients, is to account for factors that 
may reduce the clearance and increase the levels of LOXO-305, for example disease states, or 
concomitant use of drugs that inhibit the metabolism of LOXO-305. LOXO-305 is 
metabolized by CYP3A4; emerging data at the time of development of this protocol indicate 
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that the strong CYP3A4 inhibitor itraconazole caused an approximate 34% increase in 
LOXO-305 exposure (AUC0-t), but other factors such as hepatic impairment or other settings 
could make the increase in LOXO-305 exposure larger. Testing plasma concentrations 
approximately 2-fold higher than geometric mean Cmax in cancer patients is therefore 
anticipated to represent a “worst case” supra-therapeutic exposure. The dose of 900 mg 
LOXO-305 was selected based upon data from the ongoing LOXO-BTK-20017 SAD Study 
and is expected to achieve a mean Cmax of approximately 
. 
Single doses of 300 mg, 600 mg, 800 mg, and 900 mg LOXO-305 have been administered to 
healthy volunteers in Study LOXO-BTK-20017. Preliminary safety and tolerability analysis 
showed no clinically significant abnormal findings in vital signs and ECG data. 
Treatment-emergent AEs reported following LOXO-305 administration in healthy volunteers 
in the LOXO-BTK-20017 study (headache [observed at the 300 mg LOXO-305 dose], and 
headache [x2], intermittent headache, and petechial rash left thigh [observed at the 900 mg 
LOXO-305 dose]), were all Grade 1 in severity. One instance of headache observed at the 
300 mg LOXO-305 dose and 1 instance observed at the 900 mg LOXO-305 dose, the 
intermittent headache, and the petechial rash left thigh were considered to be related to 
LOXO-305. All five AEs were reported by 4 subjects and resolved within 2 hours to 5 days 
of onset (preliminary data on file at the time of this protocol’s development). 
3.3.2. 
Moxifloxacin 
A single 400-mg dose is a standard positive control to be used in QT studies. This product 
has been shown to produce a peak QTc prolongation ranging from 10 to 15 msec in crossover 
design studies12,13, with a mean QTc prolongation of approximately 5 msec which is the 
threshold of regulatory concern. Hence, moxifloxacin-induced changes in ventricular 
repolarization, when compared to the placebo treatment in healthy subjects, will be used to 
evaluate assay sensitivity.13,11 If the slope of the moxifloxacin plasma concentration/∆QTc 
relationship is statistically significant at the 10% level in a 2-sided test and the lower bound 
of the 2-sided 90% confidence interval (CI) of the predicted QT effect at the observed 
geometric Cmax of the 400 mg dose is above 5 msec, assay sensitivity will be deemed to have 
been demonstrated. The dosing regimen for moxifloxacin in this study is within the 
FDA-approved dosing regimen. 
 
 
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4. SELECTION OF STUDY POPULATION 
4.1. 
Screening Procedures 
The following screening procedures will be performed for all potential subjects at a visit 
conducted within 28 days of study entry (ie, prior to Check-in [Day -1]): 
1. Inclusion/Exclusion criteria 
2. Informed consent 
3. Demographic data 
4. Medical history (including review of medication[s]) 
5. Height, weight, and body mass index (BMI) 
6. Standard safety 12-lead ECG measured after the subject has been resting in the supine 
position for at least 10 minutes (Section 7.3.4) 
7. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine blood pressure [BP] and pulse rate [measured after the subject 
has been supine for at least 5 minutes]; Section 7.3.3) 
8. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.3.1) 
9. Clinical laboratory evaluations (Section 7.3.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
10. Screens for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HBsAg), 
hepatitis B virus (HBV) immunoglobulin M (IgM) core antibody, human 
immunodeficiency virus (HIV) antibody, and SARS-CoV-2 (COVID-19) via 
polymerase chain reaction (PCR) testing or equivalent (Appendix 2) 
11. Hemoglobin A1c (HbA1c) test (Appendix 2) 
12. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen 
(breath or urine; Appendix 2) 
13. Estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 2) 
14. Serum pregnancy test (for female subjects only; Appendix 2) 
15. Follicle-stimulating hormone (FSH) test (for post-menopausal female subjects only; 
Appendix 2) 
16. Thyroid-stimulating hormone (TSH) test (Appendix 2) 
4.2. 
Check-in Procedures (Day -1) 
At Check-in (Day -1), subjects will report to the CRU and the following procedures will be 
performed: 
1. Review of inclusion/exclusion criteria 
2. Interim medical history, including concomitant medication(s) 
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4. Complete physical examination (Section 7.3.5) 
5. Standard safety 12-lead ECG measured after the subject has been resting in the supine 
position for at least 10 minutes (Section 7.3.4) 
6. Vital sign measurements (including body temperature, respiratory rate, oxygen 
saturation, and supine BP and pulse rate [measured after the subject has been supine 
for at least 5 minutes]; Section 7.3.3) 
7. HDYF? inquiry, AE, SAE, and concomitant medication evaluations (Section 7.3.1) 
8. Clinical laboratory evaluations (Section 7.3.2; clinical chemistry panel [fasted at least 
8 hours], coagulation parameters, hematology panel, and UA; Appendix 2) 
9. Screen for COVID-19 via PCR test (or equivalent; Appendix 2) 
10. Urine drug screen for selected drugs of abuse (including cotinine) and alcohol screen 
(breath or urine; Appendix 2) 
11. eGFR calculated using the CKD-EPI equation (Appendix 2) 
12. Serum pregnancy test (for female subjects only; Appendix 2) 
13. Compliance with concomitant medications and exclusionary restrictions (Section 6) 
For subjects to continue their participation in the study, the inclusion/exclusion criteria must 
continue to be met at Check-in (Day -1 [as appropriate; #1, Section 4.2]). In addition, 
continued compliance with concomitant medication and other restrictions will be verified. 
The Sponsor will review medical history and all screening evaluations for potential subjects 
prior to Check-in (Day -1). Prior to dosing, the Sponsor will provide approval of subjects 
selected for enrollment by the Investigator (or designee). 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria apply 
will be eligible to be enrolled into the study. Safety evaluations may be repeated at the 
discretion of the Investigator (or designee) or Sponsor. 
4.3. 
Inclusion Criteria 
Subjects who meet the following criteria at Screening and Check-in (Day -1), unless 
otherwise specified, may be included in the study: 
1. Males, and females of non-childbearing potential, between 18 and 55 years of age, 
inclusive, at Screening. 
2. Within BMI range 18.0 to 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, standard safety 12-lead ECG, vital sign measurements, or 
clinical laboratory evaluations (Appendix 4) at Screening and/or Check-in (Day -1) as 
assessed by the Investigator (or designee). 
4. Female subjects of non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy, or confirmed tubal occlusion more than 6 months prior to Day 1) or 
post-menopausal (defined as at least 12 months post-cessation of menses without an 


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alternative medical cause). Post-menopausal status will be confirmed with a screening 
serum FSH level consistent with post-menopausal status per the laboratory’s reference 
ranges. All female subjects must have a negative qualitative serum pregnancy test 
(serum human chorionic gonadotropin; serum quantitative human chorionic 
gonadotropin tests may be used for confirmation as needed) at Screening and 
Check-in (Day -1). Female subjects are required to refrain from donation of ova from 
Check-in (Day -1) until 6 months after Day 23 (or last administration of study drug if 
subject terminates from the study early). 
5. Male subjects who are capable of fathering a child must agree to use 1 of the 
following methods of contraception:  
a. Male sterilization, with documented confirmation of surgical success. Male 
subjects will be surgically sterile for at least 90 days prior to Check-in 
(Day -1), or 
b. If documentation of surgical sterilization is not available, male subjects must 
follow 1 of the contraception methods below from Day 1 through 6 months 
after Day 23 (or last administration of study drug if subject terminates from 
the study early): 
i. Male condom with spermicide, or 
ii. A male subject must ensure that their female partner meets 1 of the 
following criteria: 
1. intrauterine device (IUD) (hormonal IUD; eg, Mirena®). 
Copper IUDs are acceptable (eg, ParaGard®); or 
2. established use of oral, implanted, injected, transdermal, 
intravaginal, or hormonal method of contraception associated 
with inhibition of ovulation; or 
3. non-childbearing potential, defined as being permanently sterile 
(ie, due to hysterectomy, bilateral tubal ligation, bilateral 
salpingectomy, bilateral oophorectomy, or confirmed tubal 
occlusion more than 6 months prior to Day 1 for male partner); 
or 
4. be post-menopausal with amenorrhea for at least 1 year prior to 
Day 1 and FSH serum levels consistent with post-menopausal 
status. 
Male subjects who practice true abstinence because of a lifestyle choice (ie, do not 
become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements. Periodic abstinence by a female partner (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. If a male subject is abstinent at the time of signing the ICF 
but becomes sexually active from Check-in (Day -1) through 6 months after Day 23 
(or last administration of study drug if subject terminates from the study early), he 
must agree to use contraception as described above. 
For male subjects, sexual intercourse with female partners who are pregnant, or 
breastfeeding should be avoided from Check-in (Day -1) through 6 months after 
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early), unless the male subject uses a condom with spermicide. Male subjects are 
required to refrain from donation of sperm from Check-in (Day -1) until 6 months 
after Day 23 (or last administration of study drug if subject terminates from the study 
early). 
For subjects who are exclusively in same-sex relationships, contraceptive 
requirements do not apply. 
6. Able to swallow multiple capsules. 
7. Able to understand and provide written informed consent. 
8. Able to comply with all study procedures, including the 33-night stay at the CRU and 
follow-up phone call. 
4.4. 
Exclusion Criteria 
 
The following will exclude potential subjects from the study: 
1. History or presence of any of the following, deemed clinically significant by the 
Investigator (or designee), and/or Sponsor: 
a. allergy to band aids, adhesive dressing, or medical tape 
b. seizure(s) 
c. liver disease 
d. pancreatitis 
e. peptic ulcer disease 
f. intestinal malabsorption 
g. cholecystectomy  
h. gastric reduction surgery 
i. history or presence of clinically significant cardiovascular disease: 
i. 
myocardial infarction or cerebrovascular thromboembolism or 
transient ischemic attack, pacemaker within 6 months prior to Day 1 
ii. 
symptomatic angina pectoris or unstable angina within 6 months 
prior to Day 1 
iii. 
congestive heart failure ≥ stage 2 per New York Heart Association 
Classification, cardiomyopathy, or pulmonary hypertension within 
6 months prior to Day 1 
iv. 
cardiac surgery revascularization (coronary artery bypass grafting or 
percutaneous transluminal coronary angioplasty) 
v. 
atrial fibrillation, flutter, non-sustained or sustained ventricular 
tachycardia, other arrhythmias, or ventricular fibrillation sick sinus 
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vi. 
personal or family history of sudden death or congenital prolonged 
QT syndrome; unexplained syncope or syncope within the last 
3 years regardless of etiology; or history of Torsade’s de Pointes 
vii. 
ventricular pre-excitation syndrome (Wolff-Parkinson White 
syndrome) 
viii. 
arrhythmia (excluding benign sinus arrhythmia) or history of 
arrhythmia requiring medical intervention within 6 months prior to 
Day 1 
ix. 
ECG abnormalities at Screening*, Check-in (Day -1), or predose on 
Day 1, including, but not limited to: 
1. complete left bundle-branch block or right bundle branch block 
or intraventricular conduction delay with QRS > 110 msec 
2. second degree atrioventricular (AV) block, type 2, or 
third-degree AV block 
3. QTcF is > 440 msec 
4. QRS interval > 110 msec; result will be confirmed by manual 
over-read 
5. PR interval > 220 msec 
6. HR < 50 bpm or > 90 bpm 
7. Electrographically significant abnormalities that might interfere 
with ECG analysis including evidence of a previous myocardial 
infarction, left ventricular hypertrophy, flat T waves 
(particularly in the inferior leads) or more than minor 
non-specific ST-T wave changes. 
*Subjects with out-of-range ECG values or abnormal ECG 
findings that are not clinically significant will be permitted to 
have ECGs repeated up to 2 times at Screening only to confirm 
eligibility for study participation, if the repeat value(s) are 
normal/fall outside of the ranges stated above. 
2. Subjects with out-of-range, at-rest (ie, supine for at least 5 minutes) vital sign 
measurements at Screening, Check-in (Day -1), or prior to dosing on Day 1. 
Out-of-range vital sign measurements are defined as:  
a. body temperature > 37.5°C; 
b. pulse rate < 50 or > 90 beats per minute (bpm); 
c. systolic BP < 89 or > 139 mmHg; 
d. diastolic BP < 50 or > 89 mmHg; 
e. oxygen saturation < 95% (room air). 
Subjects with out-of-range values for these parameters that are not clinically 
significant will be permitted to have vital sign measurements repeated up to 2 times 
during Screening, Check-in (Day -1), and predose on Day 1 to confirm eligibility for 


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study participation if the repeat value(s) are normal/fall outside of the ranges stated 
above. 
3. History or presence of clinically significant medical or psychiatric condition or 
disease in the opinion of the Investigator (or designee), or mentally or legally 
incapacitated or has significant emotional problems at the time of the Screening visit 
or expected during the conduct of the study. 
4. Clinically significant abnormality, as determined by the Investigator (or designee), 
from physical examination at Check-in (Day -1). 
5. Abnormal laboratory values (hematology panel, UA, clinical chemistry panel [fasted 
at least 8 hours]) that are clinically significant excluding those further defined in 
exclusion criteria #6, #7, #8, #9, #10, #11, and #12 at Screening and/or Check-in 
(Day -1). Subjects with out-of-range clinical laboratory results that are not clinically 
significant (excluding those further defined in exclusion criteria #6, #7, #8, #9, #10, 
#11, and #12) may have laboratory assessments repeated at the Investigator (or 
designee)’s discretion up to 2 times during Screening and Check-in (Day -1) to 
confirm eligibility for study participation if the repeat value(s) fall within normal 
ranges or are stabilizing.  
6. Abnormal liver function tests (LFTs) as defined by aspartate aminotransferase, 
alanine aminotransferase, and serum (total and direct) bilirubin, as well as amylase, or 
lipase above the upper limit of the normal range per the laboratory’s reference ranges 
at Screening or Check-in (Day -1). Subjects with out-of-range LFTs, amylase, and 
lipase values above the upper limit of normal that are not clinically significant will be 
permitted to have LFTs, amylase, or lipase assessments repeated up to 2 times during 
Screening and Check-in (Day -1) to confirm eligibility for study participation if the 
repeat value(s) fall within normal ranges. 
7. Creatine kinase values above the upper limit of the normal range per the laboratory’s 
reference ranges that are clinically significant at Screening or Check-in (Day -1). 
Subjects with out-of-range creatine kinase values that are not clinically significant 
will be permitted to have the creatine kinase assessments repeated up to 2 times 
during Screening and Check-in (Day -1) to confirm eligibility for study participation 
if the repeat value(s) are stable or normalizing. 
8. Estimated glomerular filtration rate (eGFR) ≤ 80 mL/minute/1.73m2 calculated using 
the CKD-EPI equation at Screening or Check-in (Day -1). Subjects with out-of-range 
eGFR values that are not clinically significant will be permitted to have eGFR 
assessments repeated up to 2 times during Screening and Check-in (Day -1) to 
confirm eligibility for study participation if the repeat value(s) fall above the range 
stated above. 
9. Hemoglobin below the lower limit of normal range per the laboratory’s reference 
ranges at Screening or Check-in (Day -1). Subjects with out-of-range hemoglobin that 
is not clinically significant will be permitted to have hemoglobin assessments 
repeated up to 2 times during Screening and Check-in (Day -1) to confirm eligibility 
for study participation if the repeat value(s) fall above the lower limit of normal range 
or are normalizing. 
10. Potassium values < 4.0 mEq/L at Screening or Check-in (Day -1). Subjects with 
potassium values < 4.0 mEq/L that are not clinically significant will be permitted to 


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have potassium assessments repeated up to 2 times during Screening and Check-in 
(Day -1) to confirm eligibility for study participation if the repeat value(s) fall above 
the range stated above or are normalizing. 
11. Calcium values < 8.5 mg/dL at Screening or Check-in (Day -1). Subjects with 
calcium values < 8.5 mg/dL that are not clinically significant will be permitted to 
have calcium assessments repeated up to 2 times during Screening and Check-in 
(Day -1) to confirm eligibility for study participation if the repeat value(s) fall above 
the range stated above or are normalizing. 
12. Magnesium levels < 2.0 mEq/L at Screening or Check-in (Day -1). Subjects with 
magnesium values < 2.0 mEq/L that are not clinically significant will be permitted to 
have magnesium assessments repeated up to 2 times during Screening and Check-in 
(Day -1) to confirm eligibility for study participation if the repeat value(s) fall above 
the range stated above or are normalizing.  
13. HbA1c ≥ 6.5% at Screening. Subjects with out-of-range HbA1c values that are not 
clinically significant will be permitted to have HbA1c assessments repeated up to 2 
times during Screening to confirm eligibility for study participation if the repeat 
value(s) fall below the range stated above.  
14. Positive serologic test for HBsAg, HBV IgM core antibody, HCV antibody, or HIV 
antibody at Screening. Subjects who are positive for HBV IgM core antibody or HCV 
antibody require confirmation by PCR before enrollment to detect presence of active 
virus. Subjects who are HBV core antibody or HCV antibody positive or for whom a 
PCR is unable to be obtained will not be eligible. 
15. Positive PCR test (or equivalent) for COVID-19 at Screening or Check-in (Day -1). 
Further details regarding COVID-19 testing (including procedures for subjects who 
test positive at any time throughout CRU confinement) are specified in a separate 
document. 
16. History of congenital non-hemolytic hyperbilirubinemia (eg, Gilbert’s syndrome). 
17. Significant history or clinical manifestation of any allergic, dermatological, biliary, 
hepatic, gastrointestinal, renal, metabolic, hematological, pulmonary, cardiovascular 
(including any prior history of cardiomyopathy or heart failure), neurological, or 
psychiatric disorder (as determined by the Investigator [or designee]), or cancer 
within the past 5 years (except localized basal cell, squamous, or in situ cancer of the 
skin). Note: subjects with a history of appendectomy and/or hernia repairs will be 
acceptable. 
18. History or presence, upon clinical evaluation, of any illness that, in the opinion of the 
Investigator (or designee), would interfere with the ability to provide informed 
consent or comply with study instructions, or that might confound the interpretation 
of the study results, or put the subject at undue risk. 
19. History of a major surgical procedure within 30 days prior to Screening. 
20. Known ongoing alcohol and/or drug abuse within 2 years prior to Screening, or 
evidence of such abuse as indicated by the laboratory assays for drugs of abuse 
(including cotinine and alcohol) conducted during Screening and/or at Check-in 
(Day -1). Tests for drugs of abuse must be negative at both Screening and Check-in 
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21. Use of tobacco, smoking-cessation products, or products containing nicotine and 
e-cigarettes (nicotine and non-nicotine), within 3 months prior to Screening and 
through EOT or ET. 
22. Use or intention to use any prescription or over-the-counter medications (including 
but not limited to any moderate or strong CYP3A4 and/or CYP3A5 inhibitors or 
inducers [including herbal products such as St. John’s wort], CYP2C8 substrates, 
strong P-gp inhibitors, proton pump inhibitors, antacids, H2-receptor antagonists, and 
drugs that prolong QT/QTc interval [with the exception of moxifloxacin administered 
for the purposes of this study/in accordance with the protocol], vitamin supplements, 
herbal products, natural or herbal supplements, and hormone-replacement therapy 
[HRT]) from 14 days prior to Day 1 or 5 half-lives (if known, whichever is longer) 
through EOT or ET, unless deemed acceptable by the Investigator (or designee) and 
Sponsor. 
23. Consumption of grapefruit/grapefruit juice or Seville oranges or its juice within 
7 days prior to Check-in (Day -1) and through EOT or ET. 
24. Consumption of alcohol- or caffeine-containing foods or beverages within 5 days 
prior to Check-in (Day -1) and through EOT or ET. 
25. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
26. Has been on a diet incompatible with the on-study diet, in the opinion of the 
Investigator (or designee), within the 30 days prior to Day 1 and through EOT or ET. 
27. Participation in any other investigational study drug trial involving administration of 
any investigational drug in the past 30 days or 5 half-lives (if known), whichever is 
longer, prior to Day 1. 
28. Has previously received LOXO-305 in any other study investigating LOXO-305, 
within 30 days prior to Day 1. 
29. History within the past 2 months of strenuous exercise (eg, marathon running) and is 
unwilling to refrain from strenuous exercise from 7 days prior to Day -1 (Check-in) 
through EOT or ET.  
30. Poor peripheral venous access. 
31. Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks 
prior to Screening. 
32. Receipt of blood products within 2 months prior to Check-in (Day -1). 
33. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
4.5. 
Subject Number and Identification 
Subject numbers will consist of 6 digits in which the first set of 3 digits will identify the site 
and the second set of 3 digits will identify the subject (eg, 001-101).  
For subjects who are withdrawn by the Investigator (or designee) or voluntarily withdraw 
prematurely from the study, replacement subjects will be enrolled only if deemed necessary 
by the Sponsor.  


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If necessary, as determined by the Sponsor, subjects who fail to complete the treatment or 
have insufficient PK data may be replaced. Replacement subjects will be assigned a subject 
number by adding 200 to the last 3 digits of the subject number for the subject they are 
replacing (eg, Subject Number 001-301 replaces Subject Number 001-101). 
Subjects who are determined to be screen failures are permitted to be re-screened if the 
Investigator (or designee), with agreement from the Sponsor, feels that the subject may meet 
eligibility criteria upon re-screen. Re-screened subjects will be provided a new subject 
number as defined above. 
4.6. 
Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and for 
any reason. The Investigator (or designee) may remove a subject from the study if, in the 
Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to continue 
the study. Subjects may be withdrawn because of the following:  
• change in compliance with inclusion/exclusion criterion that is clinically relevant and 
affects subject safety 
• occurrence of AEs 
• QTcF interval > 500 msec, and on recheck within 30 minutes and confirmed by the 
core ECG laboratory, on any scheduled standard safety ECG or at any time an 
unscheduled ECG for safety was deemed necessary by the Investigator (or designee), 
or an increase > 75 msec from baseline not associated with significant hypokalemia 
• occurrence of pregnancy 
• non-compliance with study restrictions  
• intake of non-permitted concomitant medication that might affect subject safety or 
study assessments/objectives, etc. 
Notification of withdrawal will immediately be made to the Sponsor. In case of withdrawal, 
efforts will be made to perform all ET assessments (Appendix 4). The date the subject is 
withdrawn from the study and the reason for withdrawal will be recorded on the subject’s 
electronic Case Report Form (eCRF). All withdrawn subjects with AEs that are assessed as 
related to study drug and which are ongoing at ET may continue to be followed until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the Investigator (or 
designee) and confirmed by the Sponsor. 
The entire study may be discontinued at the discretion of the Investigator (or designee) or 
Sponsor, based on the occurrence of the following: 
• AEs unknown to date with respect to their nature, severity, and/or duration 
• increased frequency and/or severity and/or duration of known AEs 
• medical or ethical reasons affecting the continued performance of the study 
• difficulties in the recruitment of subjects 
• cancellation of drug development 


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In the event that the study is terminated early, the Sponsor or its designee will provide 
specific guidance to the CRU regarding the EOS procedures. 
 
 


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5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of LOXO-305. Covance will procure adequate quantities of LOXO-305 matched 
placebo, capsules to over-encapsulate LOXO-305 and for LOXO-305 matched placebo, and 
moxifloxacin.  
Table 2: Study Drugs 
Study Drug 
LOXO-305 
Moxifloxacin 
LOXO-305 Matched 
Placebo 
Forma 
Tabletb 
Tablet 
Powder-filled Capsuleb 
Strength 
25 mg 
400 mg 
N/A 
Supplier 
Loxo Oncology, Inc. 
Covance 
Covance 
Manufacturer 
Bend Research, Inc. 
To be confirmedc 
Covance 
a Specific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with 
the study drug(s). 
b Tablets will be over-encapsulated and matching capsules will be filled with placebo powder by Covance to 
maintain study blind. 
c The manufacturer will be confirmed by the site at the time of drug procurement.  
The tablets containing 25 mg LOXO-305 will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificate of Analysis. It will be provided in 
high-density polyethylene bottles and will be stored according to the instructions on the label.  
LOXO-305 matched placebo powder and moxifloxacin will be supplied by Covance and 
stored according to the instructions in the package insert and/or label. 
Size 0 light blue capsules to over-encapsulate LOXO-305 tablets and LOXO-305 matched 
placebo powder will be supplied by Covance.  
LOXO-305 tablets will be over-encapsulated (with 4 tablets of LOXO-305 being placed in 
each capsule) and LOXO-305 matched placebo powder will be encapsulated according to 
Covance CRUs Standard Operating Procedures (SOPs) and relevant processes. 
Study drugs will be stored at the CRU in a location that is locked with restricted access. 
The bulk drug container and unit dose containers will be labeled in accordance with national 
laws and regulations. The study drugs will be stored in accordance with the labeling. The 
study drugs will be transferred from bulk supplies into the subject’s dose container by 
qualified CRU employees. Each unit dose container will be appropriately labeled. 
5.2. 
Study Treatment Administration 
Subjects will receive each of the following treatments once throughout the study:  


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Treatment A: 
• A single oral dose of 900 mg LOXO-305 (36 × 25-mg tablets, over-encapsulated [9 
capsules]), following a fast of at least 8 hours prior to and 6 hours after dosing. 
Treatment B: 
• A single oral dose of placebo to match 900 mg LOXO-305 (9 capsules), following a 
fast of at least 8 hours prior to and 6 hours after dosing. 
Treatment C: 
• A single oral dose of 400 mg moxifloxacin (1 × 400 mg tablet), following a fast of at 
least 8 hours prior to and 6 hours after dosing. 
All study drugs will be administered with approximately 240 mL of water. An additional 
volume of up to approximately 240 mL of water may be administered if needed. Water will 
be restricted for 1-hour predose and 1-hour postdose, with the exception of water 
administered for dose administration.  
Each unit dose will be prepared by qualified CRU staff.  
Appropriate unit dose(s), as described above, will be administered to subjects. Although the 
timing of events requires that each subject will be administered the appropriate dose at a 
specific time, the exact dose time of subjects may be staggered to obviate the need to have all 
subjects on precisely the same study schedule. For each dose, the subject’s actual dose time 
will be recorded in the source documents and transcribed into the eCRF. 
Subjects will be instructed not to crush, split, or chew the study drugs. 
Following dosing, subjects will remain lying down or sitting and awake for the first 7 hours 
of the 24-hour postdose cardiodynamic ECG monitoring period, as the QT-RR relationship is 
different during sleep. Subjects will be required to lie quietly in a supine position with 
minimal movement and minimal exposure to noise and other environmental stimuli (ie, TV, 
loud radio, interactions with other subjects, etc.) for at least 10 minutes before and 5 minutes 
during the ECG extraction to allow for quality ECG extraction. In the event that an AE(s) 
occurs at any time during cardiodynamic ECG recordings, subjects may be placed in an 
appropriate position or will be permitted to lie down on their right side.  
5.3. 
Randomization 
Subjects will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned 
a unique randomization identification number (in accordance with the requirements in 
Section 4.5 and the randomization scheme generated by Covance) prior to the time of the first 
dose, different from the screening number, and will receive the corresponding product 
according to the randomization scheme generated by Covance.  
Subjects will be randomly assigned to 1 of 6 treatment sequences (Table 3), according to the 
randomization scheme issued by Covance.  


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Table 3: Treatment Sequences 
  
Treatment Period 
1 
2 
3 
Treatment 
Sequence 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
A 
C 
B 
5 
C 
B 
A 
6 
B 
A 
C 
The randomization scheme and corresponding subject assignment will be available only to 
the CRU pharmacy staff that is preparing the doses of LOXO-305, LOXO-305 matched 
placebo, and moxifloxacin. These CRU pharmacy staff will not be involved in any other 
aspect of the study including administration of the doses to subjects. The randomization 
scheme and corresponding subject assignment will also be available to the bioanalytical 
laboratory as sample analysis will be treatment-dependent (ie, different method, and dilutions 
depending on the treatment). It will not be made available to the Sponsor, subjects, members 
of the CRU staff responsible for the monitoring and evaluation of safety assessments 
(including the members of the CRU staff responsible for ECG reading). 
5.4. 
Blinding 
This is a partially double-blind study with respect to LOXO-305 and LOXO-305 matched 
placebo, of which LOXO-305 will be supplied as tablets, which will be over-encapsulated by 
the CRU pharmacy staff and placebo will be supplied as a powder to fill capsules by the CRU 
pharmacy staff to maintain the blind. Moxifloxacin treatment (positive control) will be 
administered in an open-label fashion.  
5.4.1. 
Procedures for Breaking the Blind Prior to Study Completion 
One set of sealed envelopes containing the randomization code will be supplied to the 
Investigator (or designee) at each site at the start of the study. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the subject.  
In the event of a medical emergency, it is requested that the Investigator (or designee) make 
every effort to contact the Sponsor prior to breaking the blind. If breaking the blind is 
required because of a medical emergency, the treatment identity would be revealed by the 
Investigator (or designee) for that subject only. In the event that the medical emergency is 
one in which it appears that the other subjects may be at imminent risk, the blind may be 
broken for all subjects who have received study drug(s). The unblinding will be properly 
documented in the study file. 
In all cases where the randomization code is broken, the Investigator (or designee) should 
record the date and reason for code breaking. 
At the end of the study, envelopes will be retained or destroyed according to relevant 
Covance CRU SOPs and procedures unless specified otherwise by the Sponsor. 


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5.4.2. 
Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered in the database, edits checks are performed, queries closed, 
and the database is officially locked.  
Preliminary data and any data received from the bioanalytical laboratory prior to the clinical 
database lock will be blinded (using dummy IDs). 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified CRU staff. 
• Immediately after oral dose administration, a visual inspection of the mouth and 
hands will be performed for each subject. 
• At each dose preparation occasion, a predose and postdose inventory of LOXO-305, 
LOXO-305 matched placebo, and moxifloxacin, as appropriate, will be performed. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies (including LOXO-305 tablets, excipient [for LOXO-305 matched placebo], capsules 
to over-encapsulate LOXO-305 and excipient [for LOXO-305 matched placebo powder], and 
moxifloxacin tablets) received from the Sponsor or procured by Covance. In addition, an 
accurate drug disposition record will be kept, specifying the amount dispensed to each subject 
and the date of dispensing. This drug accountability record will be available for inspection at 
any time. At the completion of the study, the original drug accountability record will be 
available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused LOXO-305 tablets will be disposed of by the CRU 
in accordance with the CRU’s SOPs and local/state/federal guidelines governing waste 
disposal of investigational drugs, following the Sponsor’s written authorization. Placebo 
powder and moxifloxacin tablets and will be disposed of by the CRU in accordance with the 
CRU’s SOPs. 
 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurs within 5 half-lives (if known) or 30 days, 
whichever is longer, prior to Day 1. 
All prescription medications and over-the-counter medications, including but not limited to: 
moderate or strong CYP3A4 and/or CYP3A5 inhibitors or inducers (including herbal 
products such as St. John’s wort), CYP2C8 substrates, strong P-gp inhibitors, proton pump 
inhibitors, antacids, H2-receptor antagonists, and drugs that prolong QT/QTc interval (with 
the exception of moxifloxacin administered for the purposes of this study/in accordance with 
the protocol), herbal products, vitamin supplements, natural or herbal supplements, and HRT 
are prohibited for 14 days or 5 half-lives (if known), whichever is longer, prior to Day 1 and 
through EOT or ET, unless deemed acceptable by the, Investigator (or designee), and 
Sponsor. Any medication taken by a subject during the course of the study, including details 
of its dosage, administration, and the reason for its use, will be documented in the eCRF. 
The administration of any concomitant medication during the study is prohibited without 
prior approval of the Investigator (or designee) and Sponsor, unless its use is deemed 
necessary in a medical emergency. In this case, the use of the concomitant medication will be 
reported as soon as is practical. 
6.2. 
Diet, Fluid, and Activity Control 
Subjects are required to refrain from use of tobacco, smoking-cessation products, 
nicotine-containing products and e-cigarettes (nicotine and non-nicotine), within 3 months 
prior to Screening through EOT or ET. 
Consumption of foods or beverages containing grapefruit/grapefruit juice or Seville oranges 
or its juice within 7 days prior to Check-in (Day -1) and through EOT or ET will not be 
allowed. 
Consumption of alcohol- or caffeine-containing foods or beverages within 5 days prior to 
Check-in (Day -1) and through EOT or ET will not be allowed. 
On Days 1, 12, and 23, subjects will be fasted for at least 8 hours prior to dosing through 
6 hours postdose. Water will be restricted for 1 hour prior to and 1 hour after dosing, with the 
exception of water administered for dose administration.  
On Days 1, 12, and 23, a light meal will be provided immediately following completion of 
the cardiodynamic ECG recording at the 6-hour postdose timepoint and a full meal will be 
provided immediately after the 12-hour postdose timepoints. A snack can also be given just 
after the 8.5-hour postdose timepoint. Meals and snacks must be scheduled to be completed at 
least 90 minutes prior to any scheduled ECG (ie, standard safety 12-lead ECG, or 
cardiodynamic ECG). Otherwise, while confined at the CRU, subjects will receive a standard 
diet at scheduled times that do not conflict with other study-related activities. 
Fasting requirement in relation to dosing are described in Section 3.1 and Section 5.2. 


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Subjects should not have a history within the past 2 months of strenuous exercise (eg, 
marathon running) and will refrain from strenuous exercise from 7 days prior to Check-in 
(Day -1) and during the period of confinement at the CRU and will otherwise maintain their 
normal level of physical activity through EOT or ET (ie, should not begin a new exercise 
program or participate in any unusually strenuous physical exertion). 
 
 


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7. STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for PK analysis of plasma concentrations of LOXO-305, LOXO-305 matched 
placebo, moxifloxacin plasma levels, and for future potential and/or exploratory analysis will 
be collected at the timepoints specified in Appendix 4. The exact time of the study drug 
administration and the actual time of blood sampling for PK analysis will be recorded on the 
eCRF. 
Processing, storage, and shipping instructions for these PK blood samples and for blood 
samples collected for future potential and/or exploratory analysis will be provided in a 
separate Laboratory Manual. The number of blood samples and total blood volume required 
for PK testing is presented in Appendix 3. 
7.1.2. 
Analytical Methodology 
Concentrations of LOXO-305 and moxifloxacin in plasma will be determined using validated 
bioanalytical methods. For PK samples collected for LOXO-305 matched placebo, only the 
samples collected 2 hours postdose will be analyzed for concentrations of LOXO-305 or 
moxifloxacin, as appropriate. Specifics of the bioanalytical methods will be provided in a 
separate document. 
7.2. 
Cardiodynamic Assessments 
7.2.1. 
Cardiodynamic ECGs (Holter Monitoring) 
Holter monitors will be used to collect continuous 12-lead ECG data for the purpose of 
collecting cardiodynamic ECGs for approximately 25.5 hours, starting at approximately 
1.5 hours prior to dosing and at least 24 hours postdose. Recording will be started and 
stopped at logistically optimal times to ensure that all scheduled time points are collected. Up 
to 10 replicate 12-lead ECG recordings will be extracted from the continuous Holter 
recording at the timepoints specified in Appendix 4, prior to the collection of blood samples 
for PK analysis.  
Timing and recording technique for ECGs will be standardized for all subjects. Subjects must 
be awakened at least 1 hour prior to the start of the cardiodynamic ECGs on the day of dosing 
and before the ECG recording scheduled at the 24-hour postdose timepoint as specified in 
Appendix 4.  
Following dosing on days where cardiodynamic ECG assessments are performed, subjects 
will remain lying down or sitting and awake for the first 7 hours of the 24-hour postdose 
cardiodynamic ECG monitoring period, as the QT-RR relationship is different during sleep. 
Subjects will be required to lie quietly in a supine position with minimal movement and 
minimal exposure to noise and other environmental stimuli (ie, TV, loud radio, interactions 
with other subjects, etc.) for at least 10 minutes before and 5 minutes during the ECG 
extraction to allow for quality ECG extraction. In the event that an AE(s) occurs at any time 


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during cardiodynamic ECG recordings, subjects may be placed in an appropriate position or 
will be permitted to lie down on their right side.  
All ECG extraction should occur in a 5-minute time window around the scheduled/nominal 
time and always precede the PK draw. If targeted ECG timepoints are artefactual or of poor 
quality, analyzable 10-second ECGs will be extracted as close as possible to the targeted time 
points.  
The 12-lead Holter and ECG equipment will be supplied and supported by ERT. All ECG 
data will be collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG 
continuous 12-lead digital recorder. The continuous 12-lead digital ECG data will be stored 
onto SD memory cards. ECGs to be used in the analyses will be selected by pre-determined 
timepoints as defined in the Appendix 4 and will be read centrally by ERT. 
The following principles will be followed in ERT’s core laboratory: 
• ECG readers are blinded to the subject, visit, and treatment allocation 
• A limited number of readers will be employed for the study 
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same 
lead and will be analyzed by the same reader 
• The primary analysis lead is lead II. If lead II is not analyzable, then primary lead of 
analysis will be changed to another lead for the entire subject data set 
The following is a brief description of ECG analysis methods utilized by ERT’s core 
laboratory. 
7.2.1.1. 
TQT Plus ECG Extraction Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘TQT Plus method’, a computer-assisted and statistical process utilized 
by ERT. The method enables extraction of ECGs with the lowest HR variability and noise 
within the protocol-specified extraction time window (eg, the HR and QT changes from 
beat-to-beat in the range of < 10%). At each protocol-specified timepoint, 10 ECG replicates 
will be extracted from a 5-minute “ECG window” (typically, the last 5 minutes of the 
15-minute period when the subject is maintained in a supine or semi-recumbent quiet 
position). 
7.2.1.2. 
Expert-Precision QT Analysis 
Expert-precision QT analysis will be performed on all analyzable (non-artifact) beats in the 
10 ECG replicates. Statistical quality control procedures are used to review and assess all 
beats and identify “high” and “low” confidence beats using several criteria, including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
• RR values exceeding or below certain thresholds (biologically unlikely) 
• Rapid changes in QT, QTc, or RR from beat-to-beat 


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Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” are performed using COMPAS software. All 
low confidence beats are reviewed manually and adjudicated using pass-fail criteria. The 
final QC assessment is performed by a cardiologist. The beats found acceptable by manual 
review are included in the analysis. The median QT, QTc, and RR value from each extracted 
replicate is calculated, and then the mean of all available medians from a nominal timepoint 
is used as the subject’s reportable value at that timepoint. 
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals will 
be performed manually in 3 of the 10 ECG replicates at each timepoint. Each fiducial point 
(onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) is electronically 
marked. 
For T-wave morphology and U-wave presence, treatment-emergent changes will be assessed, 
ie, changes not present at baseline. For each category of T-wave morphology and of 
U-waves, the category will be deemed as present if observed in any replicate at the timepoint. 
For baseline, the category will be deemed as present if observed in any replicate from all 
timepoints that constitute baseline. Nominal time of the cardiodynamic ECG recording will 
be used for the cardiodynamic analysis. 
Procedures for ECG extraction and Early Precision QT evaluation at the central ECG 
laboratory (ERT) will be provided separately. 
7.3. 
Safety and Tolerability Assessments 
Safety evaluations may be repeated at the discretion of the Investigator (or designee) or 
Sponsor. 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and any other procedures to be performed at the same timepoint. The order of priority for 
scheduling procedures around a timepoint is (in order of priority): 
• dosing 
• ECG extraction (for cardiodynamic assessments) 
• PK blood sampling 
• vital sign measurements * 
• standard safety 12-lead ECGs * 
• blood and urine samples for clinical laboratory evaluations 
• physical examination 
* When vital sign measurements and standard safety 12-lead ECGs are scheduled at the same 
time as PK blood sampling, the PK blood sampling will be obtained at the scheduled 
timepoint, and the vital sign measurements followed by standard safety 12-lead ECGs will be 
obtained prior to and as close as possible to the scheduled PK blood sampling. 


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7.3.1. 
Adverse Events 
Adverse event definitions; assignment of severity, causality, action taken, and outcome; and 
procedures for reporting SAEs are detailed in Appendix 1. 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes 
in your health status since Screening/since you were last asked?” at the timepoints specified 
in Appendix 4 (ie, at Screening [after the ICF is signed], at Check-in [Day -1], at each 
postdose vital sign measurement, and at an appropriate time for all other days). Subjects will 
also be encouraged to voluntarily report AEs occurring at any other time through the EOS. 
Adverse events, whether volunteered, identified by the subject’s responses to HDYF? 
inquiries, or noted on physical examination, standard safety ECG, vital sign measurements, or 
clinical laboratory evaluations, will be recorded throughout the study (ie, from signing of the 
ICF until EOS [or ET if the subject discontinues from the study and does not complete a 
follow-up phone call]), either as subject medical history (if the event is reported as beginning 
prior to signing of the ICF or if the event occurs prior to study drug administration on Day 1 
and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs 
(if the event occurs after signing of the ICF but prior to study drug administration on Day 1 
and is assessed as related to study procedures by the Investigator [or designee], or if the event 
occurs after study drug administration on Day 1 through EOT or ET regardless of relationship 
to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug by 
the Investigator (or designee) are to be reported. All SAEs that develop from the time of ICF 
signing until EOS (or ET, if the subject discontinues from the study and does not complete a 
follow-up phone call) are to be reported. 
Unless a subject withdraws consent or is withdrawn from the study and does not complete the 
follow-up phone call, all subjects must be followed until EOS. Subjects with AEs that are 
assessed as related to study drug by the Investigator (or designee) which are ongoing at EOS 
may continue to be followed until the symptoms or value(s) return to normal, or acceptable 
levels, as judged by the Investigator (or designee) and confirmed by the Sponsor. The 
Investigator (or designee) should use appropriate judgment in ordering additional tests as 
necessary to monitor the resolution of events. The Sponsor may request that additional safety 
tests be performed. 
Subjects will receive a follow-up phone call 7 days (± 2 days) after EOT or ET to determine 
if any SAE or drug-related AE has occurred since the EOT or ET visit. 
At all times, a subject may be required to remain at the CRU for longer at the discretion of 
the Investigator (or designee). 
Any event that meets the criteria of a suspected unexpected serious adverse reaction 
(SUSAR) will be reported to the Institutional Review Board (IRB) according to CRU policy 
by the Investigator (or designee) and to regulatory authorities by the Sponsor (or Sponsor 
designee) according to regulatory authority requirements. Refer to Reference Safety 
Information in the current IB1 for LOXO-305 for additional safety information. 


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7.3.2. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (clinical chemistry panel [fasted at least 8 hours; at ET or the 
day before EOT, subjects are not required to be fasted prior to clinical laboratory 
evaluations], coagulation parameters, hematology panel, TSH [Screening only], HbA1c 
[Screening only], eGFR [Screening and Check-in (Day -1)], and UA) will be collected at the 
timepoints specified in Appendix 4. 
Screens for HCV antibody, HBsAg, HBV IgM core antibody, and HIV antibody will be 
performed at Screening.  
Testing for COVID-19 via PCR (or equivalent) will be performed at the timepoints specified 
in Appendix 4. Testing for COVID-19 may also be conducted periodically during the 
subject’s CRU confinement, at the discretion of the Investigator (or designee). Further details 
regarding COVID-19 testing (including procedures for subjects who test positive at any time 
throughout CRU confinement) are specified in a separate document. 
A urine drug screen for selected drugs of abuse (including cotinine) and an alcohol screen 
(urine or breath) will be performed at Screening and repeated at Check-in (Day -1) for all 
subjects.  
A serum qualitative pregnancy test (female subjects only [serum quantitative may be used for 
confirmation, if needed]) and an FSH test (post-menopausal female subjects only) will be 
performed at the timepoints specified in Appendix 4. 
The number of blood samples and total blood volume required for clinical laboratory 
evaluations are presented in Appendix 3.A list of the specific evaluations is inAppendix 2. 
7.3.3. 
Vital Signs 
Vital sign measurements (including body temperature, respiratory rate, oxygen saturation, 
and supine BP and pulse rate) will be obtained at the timepoints specified in Appendix 4. 
Blood pressure and pulse rate measurements should be performed using the same arm for 
each reading and measurements should be taken after the subject has been resting in the 
supine position for at least 5 minutes. 
When vital sign measurements are scheduled at the same time as PK blood draws, the PK 
blood draws will be obtained at the scheduled timepoint, and the vital sign measurements will 
be obtained prior to and as close as possible to the scheduled PK blood draw. 
7.3.4. 
Standard Safety 12-lead Electrocardiogram 
A standard safety 12-lead ECG (including HR, PR, RR, QRS, and QT interval parameters) 
will be obtained after the subject has been resting for at least 10 minutes in the supine 
position at the timepoints specified in Appendix 4. There will be no significant stimuli such 
as TV, loud radio, interactions with other subjects. The QT interval will be corrected for HR 
by Fridericia’s (QTcF = QT/[RR]1/3) formula. In the event that an AE(s) occur at any time 
during safety ECG recordings, subjects may be placed in an appropriate position or will be 
permitted to lie down on their right side. 


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When standard safety 12-lead ECGs are scheduled at the same time as PK blood draws, the 
PK blood draws will be obtained at the scheduled timepoint, and the standard safety 12-lead 
ECGs will be obtained prior to and as close as possible to the scheduled PK blood draw. 
In all cases in which a standard safety ECG has a potentially concerning finding (eg, QTcF 
> 500 msec, increase from baseline QTcF > 75 msec), or an abnormal and potentially 
clinically significant observation, it will be repeated within 30 minutes and the ECGs will be 
reviewed independently by the ECG core laboratory or, if not feasible, by a cardiac 
electrophysiologist prior to any study disposition decisions that do not constitute a patient 
emergency. The safety ECG data, including all timepoints, will be recorded on the eCRF and 
used for evaluating general safety of the subjects during study and for evaluation of an AE. 
The ECG core laboratory analysis will constitute the ECG analysis used for all study 
decisions as well as the primary ECG analysis for the study. 
7.3.5. 
Physical Examination 
A complete or abbreviated physical examination will be performed at the timepoints specified 
in Appendix 4. Complete physical examinations will evaluate general appearance and the 
following body systems/organs: dermatological; head and eyes; ears, nose, mouth, and throat; 
pulmonary; cardiovascular; abdominal; lymphatic; musculoskeletal/extremities; and 
neurological. Weight and height will be reported (height only reported during Screening). 
Abbreviated physical examinations will evaluate general appearance and the following body 
systems/organs: dermatological; pulmonary; cardiovascular; abdominal; and neurological. 


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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
A total of up to 30 subjects (5 subjects per treatment sequence) will be enrolled to ensure at 
least 24 evaluable subjects completed all three treatment periods of the study. A sample size 
of 24 evaluable subjects will provide at least 90% power to exclude that LOXO-305 causes 
more than a 10-msec QTc effect at clinically relevant plasma levels, as shown by the upper 
bound of the 2-sided 90% CI of the model-predicted QTc effect (∆∆QTc) at the observed 
geometric mean Cmax of LOXO-305 in the study. This power is estimated approximately 
using a paired t-test. The calculation assumes a 1-sided 5% significance level, a small 
underlying effect of LOXO-305 of 3 msec, and a standard deviation (SD) of the ΔQTc of 
8 msec for both LOXO-305 and placebo. The concentration-QTc analysis method is 
supported by Darpo et al14 and Ferber et al15, and is consistent with the experiences from 25 
recent TQT studies. 
8.1.1. 
Determination of Sample Size for Assay Sensitivity  
To demonstrate assay sensitivity with concentration-QTc analysis, it has to be shown that the 
ΔΔQTc of a single dose of 400 mg moxifloxacin exceeds 5 msec (ie, the lower bound of the 
2-sided 90% CI of the predicted QTc effect [ΔΔQTc] should exceed 5 msec). In a similarly 
designed, recent crossover study with 24 healthy subjects (on-file data, ERT), the standard 
error (SE) for the prediction of the QT effect of moxifloxacin based on the concentration-QTc 
analysis was 1.24 msec. The within-subject SD of ΔQTcF in the referred study was 5.4 msec 
based on the by-timepoint analysis. If the effect of moxifloxacin is assumed to be 10 msec, 
the SE of 1.24 msec corresponds to an effect size of (10-5)/(1.24 ×sqrt[24])= 0.82, where the 
effect size is the effect assumed under the alternative hypothesis divided by the SD of the test 
variable. This value should be compared to the effect size of 0.62 required to guarantee a 
power of at least 90% in a paired t-test situation with a sample size of 24 evaluable subjects. 
In other words, based on this calculation, a power of at least 90% for 24 evaluable subjects 
will be obtained as long as the variability of the ΔQTc, as measured by its within-subject SD, 
does not exceed 7.1 msec (ie, 132% [= 0.82/0.62] of the 5.4 msec observed in the referred 
study assuming the ratio of effective sizes is consistent with inverse ratio of within-subject 
SD). The number also agrees with recent recommendations of the FDA, which propose at 
least 20 subjects. 16 
Replacement subjects may be enrolled only if deemed necessary by the Sponsor. 
8.2. 
Analysis Populations 
8.2.1. 
Study Populations 
The QT/QTc population will consist of all subjects who have received 1 dose of study drug 
(LOXO-305, moxifloxacin, and placebo) with measurements at baseline as well as 
on-treatment with at least 1 postdose timepoint with a ΔQTc value. The QT/QTc population 
will be used for the by-timepoint and categorical analysis of cardiodynamic ECG parameters. 
The safety population will consist of all subjects who received 1 dose of study drug. 
Subjects will be classified into groups based on actual treatment received. 


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The PK population will consist of all subjects who received 1 dose of LOXO-305 or 
moxifloxacin, have at least 1 quantifiable plasma concentration of LOXO-305 or its 
metabolites, or moxifloxacin. A subject may be excluded from the PK summary statistics and 
statistical analysis if the subject has an AE of vomiting that occurs at or before tmax. The 
impact of protocol deviations on the PK population will be evaluated on a case-by-case basis. 
The PK/QTc population will consist of all subjects who are in both the QT/QTc and PK 
populations with at least 1 pair of postdose PK concentration and ΔQTc data from the same 
timepoint in at least 1 period as well as subjects in the QT/QTc population who received 
placebo. The PK/QTc population will be used for the concentration-QTc analysis and assay 
sensitivity. PK/QTc population will be defined for LOXO-305, for its metabolites, and for 
moxifloxacin. 
8.3. 
Cardiodynamic Analysis 
8.3.1. 
Baseline 
For all continuous ECG parameters from each period, baseline will be the average of the 
derived ECG intervals from the 3 ECG timepoints prior to treatment administration on Day 1, 
Day 12, and Day 23. For T-wave morphology and U-wave presence from each period, 
baseline includes findings observed in any of the replicates from the 3 timepoints prior to 
dosing on Day 1, Day 12, and Day 23. 
8.3.2. 
QT Correction Methods 
The QT and RR value for each beat will be used for HR correction. Twelve-lead ECGs will 
be extracted in up to 10 replicates from each nominal timepoint. The median value of each 
parameter from the set of evaluable beats in each extracted replicate will be calculated, and 
then the mean of all available medians (minimum 3 medians) from the nominal timepoint will 
be used as the subject’s reportable value at that timepoint. 
If the largest LS mean peak ∆∆HR after dosing with LOXO-305 is < 10 bpm, the HR 
correction method will be the Fridericia method defined as: 
 QTcF (msec) = QT (msec)/[RR (msec)/1000]1/3 
If a substantial HR effect is observed, ie, the largest LS mean ∆∆HR larger than 10 bpm in 
the by-time point analysis, additional QT correction methods may be explored. Since Holter 
recordings are not collected on Day -1, prior to treatment, additional QT correction method 
will be derived from Day 1 of the placebo period during both the timepoints of supine rest 
(QTcS) and from all evaluable QT/RR pairs in the 24-h recording (QTcI). These data will be 
used to obtain RR interval (HR) and QT data to enable derivation of QTcS, and QTcI, as 
follows. 
 An individualized HR-corrected QT interval (QTcS) will be calculated from QT/RR 
data obtained at supine resting timepoints on Day 1 of the placebo period. Based on 
QT/RR pairs from all subjects, the QTcS correction coefficient will be derived from a 
linear mixed-effects model: log(QTij) = log(ai) + b1i × log(RRij) + b2i× genderi + b3i× 
log(RRij) × genderi with gender included as a fixed effect for both intercept and slope, 
and subject included as a random effect for both intercept and slope. The coefficient 


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of log(RR) for each subject, bi =b1i+ b3i × genderi, will then be used to calculate 
QTcS for each subject as follows: QTcS = QT/RRbi. 
 An optimized HR-corrected QT interval (QTcI) will be derived from a broader range 
of HRs by using all QT/RR data on Day 1 of the placebo period. The QT/RR pairs 
from each subject will be used for that subject’s individual correction coefficient, 
which will be derived from a linear regression model: log(QT) = log(a) + b×log(RR). 
The coefficient of log(RR) for each subject, bi, will then be used to calculate QTcI for 
that subject as follows: QTcI = QT/RRbi. 
For QTcS and QTcI, the individual correction coefficients, bi, will be listed and also 
summarized in a table using arithmetic mean, SE, number of subjects, and 90% CI (based on 
t-distribution). 
The method that removes the HR dependence of the QT interval most efficiently will be 
chosen as primary correction method. 
8.3.3. 
Evaluation for QT-RR Correction Methods  
In case a substantial HR effect is observed, defined as a largest ∆∆HR greater than 10 bpm, 
the relationship between QTc (QTcF and, if derived, QTcS [individual], and QTcI 
[optimized]) and RR interval will be investigated using on-treatment data (LOXO-305, 
moxifloxacin, and placebo) by a linear regression model: QTc = c + d x RR. Mean QTc and 
RR values from all nominal time points (including predose) will be used. The RR coefficient 
for each subject, di, will then be used to calculate the average sum of squared slopes (SSS) for 
each of the different QT/RR correction methods. The correction method that results in the 
average on-treatment slope closest to 0 (the smallest average SSS, as described by Tornøe et 
al 201117) for LOXO-305 and placebo will be deemed the most appropriate HR correction 
method. If different methods show similar SSS values on placebo as on LOXO-305, priority 
in the choice will be given to the placebo results. In addition, a scatter plot and quantile plot 
of QTc (QTcF, QTcS, and QTcI) and RR intervals by treatment with regression line and a 
linear mixed-effects line (90% CI), respectively, will also be given. 
8.3.4. 
Concentration-QTc Analysis (Primary Analysis) 
The relationship between LOXO-305 plasma concentrations and change from baseline QTc 
(ΔQTcF or ΔQTc corrected with the HR correction method chosen as primary if a substantial 
HR effect is observed) will be quantified using a linear mixed-effects modeling approach. 
The model will include ΔQTc as the dependent variable, LOXO-305 plasma concentrations 
as the explanatory variate (0 for placebo), centered baseline QTc (ie, baseline QTcF for 
individual subject minus the population mean baseline QTc for all subjects in the same 
treatment period) as an additional covariate, treatment (active = 1 or placebo = 0) and time (ie, 
nominal postdose timepoint) as fixed effects, and random effects on the intercept and slope 
per subject.18 In addition, if there are significant concentrations of LOXO-305 metabolites, 
their concentrations/QTc relationship may be explored (exploratory metabolite profiling has 
shown that unchanged LOXO-305 is the major drug-related component in human plasma). 
The degrees of freedom of estimates will be determined by the Kenward-Roger method. 
From the model, the slope (ie, the regression parameter for LOXO-305 concentrations) and 
the treatment effect-specific intercept (defined as the difference between active and placebo) 


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will be estimated together with the 2-sided 90% CI. The estimates for the time effect will be 
reported with degrees of freedom and SE.  
The geometric mean of the individual Cmax values for subjects in the active dose group will 
be determined. The predicted effect and its 2-sided 90% CI for ΔΔQTc (ie, slope estimate × 
concentration + treatment effect-specific intercept) at this geometric mean Cmax of 
LOXO-305 will be obtained. If the upper bound of the 2-sided 90% CI of the predicted effect 
of ΔΔQTc at clinically relevant plasma levels of LOXO-305 is below 10 msec, it will be 
concluded that LOXO-305 does not cause clinically relevant QTc prolongation within the 
observed plasma concentration ranges. 
To evaluate the adequacy of model fit with respect to the assumption of linearity, the 
observed ΔQTc values adjusted by population time effect estimated from the model will be 
used. These individual placebo-adjusted ΔQTci,k (ΔΔQTci,k) values equal the observed 
individual ΔQTci,k for subject ‘i’ administered with active drug or placebo at timepoint ‘k’ 
minus the estimated population mean placebo effect at timepoint k (ie, time effect). A 
quantile plot, ie, plot of the quantiles (deciles) of observed drug concentrations and the mean 
placebo-adjusted ΔQTc (ΔΔQTc) and 90% CI at the median concentration within each decile, 
will be given. The regression line presenting the model-predicted ΔΔQTc (as described by 
Tornøe et al17) will be added to evaluate the fit of a linear model and visualize the 
concentration-response relationship. Additional exploratory analysis (via graphical displays 
and/or model fitting) will include assessing for a delayed effect (hysteresis) and the 
justification for the choice of the pharmacodynamic model (linear versus nonlinear). 
8.3.4.1. 
Investigation of Hysteresis 
Hysteresis will be assessed based on joint graphical displays of the least squares (LS) mean 
ΔΔQTc at each postdose timepoint from the by-timepoint analysis and the mean 
concentrations of LOXO-305 at the same timepoints. In addition, hysteresis plots will be 
given for LS mean ΔΔQTc from the by-timepoint analysis and the mean concentrations. If a 
QT effect > 10 msec (ie, the largest LS mean ΔΔQTc > 10 msec) cannot be excluded in the 
by-timepoint analysis, and if the difference (delay) between the time to reach the peak QTc 
effect (∆ΔQTc) and peak plasma concentrations (tmax) is larger than 1 hour, other 
concentration-QTc models, such as a model with an effect compartment, may be explored. 
With the provision stated above, hysteresis will be assumed if the curve of the hysteresis plot 
shows a counterclockwise loop. A significant treatment effect-specific intercept may also be 
indicative of hysteresis or model misspecification, if it cannot be explained by a nonlinear 
relationship. 
8.3.4.2. 
Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal quantile-quantile (Q-Q) plots for the 
standardized residuals and the random effects; scatter plots of standardized residuals versus 
concentration, fitted values, and centered baseline QTc; and box plots of standardized 
residuals versus nominal time and active treatment will be produced, in addition to the 
quantile plot described above. Among these plots, the scatter plots of standardized residuals 
versus concentration and versus centered baseline QTc will also include the locally weighted 
scatter plot smoothing19 lines with optimal smoothing parameters selected by the Akaike 
information criterion with a correction20. A scatter plot of observed concentration and ΔQTc 


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with a locally weighted scatterplot smoothing (LOWESS) line with 90% CI and a linear 
regression line will also be provided to check the assumption of a linear concentration-QTc 
relationship. If there is an indication that a linear model is inappropriate, additional models 
may be fitted, specifically an Emax model. The concentration-QTc analysis will then be 
repeated for the model found to best accommodate the nonlinearity detected.  
8.3.5. 
Assay Sensitivity 
Assay sensitivity will be demonstrated by similar concentration-QTc analysis of 
moxifloxacin data. If the slope of the concentration-QTc (∆QTc) for moxifloxacin is 
statistically significant at 10% level for 2-sided test and the lower bound of the 2-sided 90% 
CI of the predicted effect of ΔΔQTc is above 5 msec at the geometric mean Cmax for 
moxifloxacin, assay sensitivity will be deemed to have been demonstrated. 
8.3.6. 
By-timepoint Analysis (Secondary Analysis) 
The analysis for QTc will be based on a linear mixed-effects model with ΔQTc (ΔQTcF, or 
ΔQTc corrected per the HR correction method chosen as primary if a substantial HR effect is 
observed) as the dependent variable, period, sequence, time (ie, nominal postdose timepoint), 
treatment (LOXO-305, moxifloxacin and placebo), and time-by-treatment interaction as fixed 
effects, and baseline QTc as a covariate. An unstructured covariance matrix will be specified 
for the repeated measures at postdose timepoints for subject within treatment period. If the 
model with unstructured covariance matrix fails to converge, other covariance matrix such as 
compound symmetry and autoregressive will be considered. The model will also include a 
subject-specific random effect. If the fixed effects for period and/or sequence should prove to 
be nonsignificant (that is, if the p-value > 0.1), these effects may be removed from the model 
and the analysis will be repeated without those covariates. From this analysis, the LS mean, 
SE, and 2-sided 90% CI will be calculated for the contrast “LOXO-305 versus placebo” at 
each postdose timepoint, separately. 
For HR, PR, QRS, and QTc intervals with the methods not selected as primary, the analysis 
will be based on the change from baseline post-dosing values (ΔHR, ΔPR, ΔQRS, and 
ΔQTc). The same (by-timepoint analysis) model will be used as described above for QTc. 
The LS mean, SE, and 2-sided 90% CI from the statistical modeling for both change from 
baseline and placebo-corrected change from baseline values will be listed in the tables and 
graphically displayed. 
8.3.7. 
Categorical Analysis 
The analysis results for categorical outliers will be based on treatment-emergent events (ie, 
new findings compared to baseline); T-wave morphology and presence of U-waves will be 
summarized in frequency tables with counts percentages for both number of subjects and 
number of timepoints. For categorical outliers, the number (percentage) of subjects as well as 
time points who had increases in absolute treatment-emergent QTc (QTcF, and QTcS and 
QTcI if derived) values > 450 and ≤ 480 msec, > 480 and ≤ 500 msec, or > 500 msec, and 
changes from predose baseline of > 30 and ≤ 60 msec, or > 60 msec; increase in PR from 
predose baseline > 25% to a PR> 200 msec; increase in QRS from predose baseline > 25% to 
a QRS > 120 msec; decrease in HR from predose baseline > 25% to a HR < 50 bpm; and 
increase in HR from predose baseline > 25% to a HR > 100 bpm will be determined. For 
T-wave morphology and U-wave presence, treatment-emergent changes will be assessed, ie, 


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changes not present at baseline. For each category of T-wave morphology and of U-waves, 
the category will be deemed as present if observed in any replicates at the timepoint.  
8.4. 
Pharmacokinetic Analysis 
Blood samples for the analysis of concentrations of LOXO-305 in plasma will be collected 
for 96 hours after administration of LOXO-305 (Treatment A) and LOXO-305 matched 
placebo (Treatment B). Blood samples for the analysis of concentrations of moxifloxacin in 
plasma will be collected for 
 (Treatment C). 
Blood samples from Treatment A will be analyzed for concentrations of LOXO-305 in 
plasma through 96 hours after administration of LOXO-305. Blood samples from Treatment 
B will be analyzed for concentrations of LOXO-305 in plasma only at the single timepoint 
taken 2 hours after administration of LOXO-305 matched placebo. Blood samples from 
Treatment C will be analyzed for concentrations of moxifloxacin in plasma through 
 
.  
Whenever possible, the following PK parameters will be calculated for each subject, based on 
the plasma concentrations of LOXO-305 (as appropriate): 
• area under the concentration-time curve (AUC) from hour 0 to 24 hours postdose 
(AUC0-24) 
• AUC from hour 0 to the last measurable concentration (AUC0-t) 
• AUC from hour 0 extrapolated to infinity (AUC0-inf) 
• percentage extrapolation for AUC0-inf (%AUCextrap) 
• apparent systemic clearance (CL/F) 
• Cmax 
• mean residence time (MRT) 
• apparent plasma terminal elimination half-life (t½) wherever possible, where t1/2 = 
natural log (2)/λZ 
• time to maximum observed plasma concentration (tmax) 
• apparent terminal elimination rate constant (λZ) 
• apparent volume of distribution at terminal phase (Vz/F) 
Pharmacokinetic calculations will be performed using commercial software such as Phoenix™ 
WinNonlin® Version 8.1 or higher (Certara USA Inc.).  
Other parameters may be added as appropriate. Final PK parameters reported will be detailed 
in the Statistical Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. All statistical 
analyses will be performed using SAS Version 9.4 or greater. More details on the analyses 
will be included in the SAP. 
CCI
CCI


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8.4.1. 
Descriptive Analysis 
Plasma concentrations and PK parameters will be summarized with descriptive statistics 
(number, arithmetic mean, SD, coefficient of variation [CV%], geometric mean, geometric 
CV%, median, minimum, and maximum). 
Individual and mean plasma concentration-time curves (both linear and log linear) will be 
included in the final report. No formal statistical analysis is planned other than previously 
mentioned.  
8.5. 
Safety Analysis 
All safety assessments, including AEs, SAEs, vital sign measurements, clinical laboratory 
results, physical examination results, concomitant medications, and standard safety 12-lead 
ECGs, will be tabulated and summarized where possible, using descriptive methodology, as 
needed, by treatment and timepoint. Unless otherwise specified, baseline value is defined as 
the last non-missing measurement before administration of study drug on Days 1, 12, and 23. 
No formal statistical analyses are planned for the safety data. All safety data will be listed by 
subject. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO Drug Global B3, September 2019). Adverse events will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) Version 22.1 (or higher). The 
incidence of AEs will be presented by severity and by relationship to study drug as 
determined by the Investigator or designee (Appendix 1 for AE reporting). All TEAEs will be 
summarized by system organ class and preferred term. 
8.6. 
Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a CRU staff member authorized to make 
the change. Changes will be made by striking a single line through erroneous data and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
CRU staff member. 
The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the CRU and verified by the Study Monitor. Data 
will then be reviewed by the data management group to resolve any outstanding issues. 
Listings will be generated after the database is cleaned by data management and will be 
reviewed by the Covance scientific team. The eCRF and ancillary data will be converted into 
final SAS® datasets following Study Data Tabulation Model or Sponsor-provided 
specifications. The final datasets structure will be verified using Web Submission Data 
Manager®, while the dataset content will be peer reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs will 
be peer reviewed by an independent programmer. In addition, draft TFLs will be reviewed by 
the Covance scientific team during the dry run and data review meetings. 


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The peer review will be performed by independent programmers following the quality control 
process and programming checklists. 
8.7. 
Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance SOPs or per 
Sponsor request, and as applicable, according to the contract between Covance and the 
Sponsor. 
 
 


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9. ADMINISTRATIVE ASPECTS 
9.1. 
Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator (or designee). 
There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator (or designee), and the IRB (see Form 
FDA 1572). 
9.2. 
Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor and/or Sponsor will 
meet with the Investigator (or designee) and appropriate CRU staff to familiarize the 
Investigator (or designee) and CRU staff with the materials necessary for conducting the 
clinical study. 
9.3. 
Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator (or 
designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
Any publication of the results, in part or in total (eg, articles in journals or newspapers, oral 
presentations, abstracts) by the Investigator (or designee) or their representative(s), shall 
require prior notification and review, within a reasonable timeframe, by the Sponsor, and 
cannot be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of 
the Sponsor’s intellectual property rights. 
9.4. 
Monitoring 
The Sponsor will designate a Study Monitor who will be responsible for monitoring this 
clinical trial. The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF and 
source documentation completion and retention, and accurate study drug accountability. To 
this end, the Sponsor’s Study Monitor will visit the CRU at suitable intervals (or may 
perform activities remotely as per the Monitoring Plan for this study) and be in frequent 
contact through verbal and written communication. It is essential that the Sponsor’s Study 
Monitor has access to all documents (related to the study and the individual participants) at 
any time these are requested. In turn, the Sponsor’s Study Monitor will adhere to all 
requirements for subject confidentiality as outlined in the ICF. The Investigator (or designee) 
and Investigator’s staff will be expected to cooperate with the Sponsor’s Study Monitor, to be 
available during a portion of the monitoring visit to answer questions, and to provide any 
missing information. 
9.5. 
Institutional Review Board 
In accordance with US Title 21 Code of Federal Regulations (CFR) 56, the protocol, 
advertisement, ICF, and other information provided to subjects will be reviewed and 


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approved by the IRB. The Sponsor will supply relevant material for the Investigator (or 
designee) to submit to the IRB for the protocol’s review and approval. Verification of the 
IRB unconditional approval of the protocol and the written ICF statement will be transmitted 
to the Investigator (or designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will be 
transmitted in writing to the Investigator (or designee). If requested, the Investigator (or 
designee) will permit audits by the IRB and regulatory inspections by providing direct access 
to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s (or designee’s) participation in the study. 
9.6. 
Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the test 
product. The subjects will be informed that participation is voluntary and that they can 
withdraw from the study at any time. In accordance with 21 CFR 50, the informed consent 
process shall be documented by the use of a written ICF approved by the IRB and signed by 
the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
9.7. 
Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each eCRF 
will be retained by the Investigator (or designee). All source documents, records, and reports 
will be retained by the CRU in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the CRU archives. 
9.8. 
Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the US 
CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), IRBs (21 CFR 56), and Investigational New Drug Application 
(21 CFR 312), as appropriate. As such, these sections of US Title 21 CFR, along with the 


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applicable ICH Guidelines, are commonly known as Good Clinical Practices, which are 
consistent with the Declaration of Helsinki. 
9.9. 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
 
 


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10. REFERENCES 
1.  Loxo Oncology, Inc. LOXO-305 - Investigator’s Brochure (Version 4.0). 29 October 
2020.  
2.  Brandhuber B, Gomez E, Smith S, Eary T, Spencer S, Rothenberg SM, et al. A next 
generation reversible BTK Inhibitor, for overcoming acquired resistance to irreversible 
BTK inhibitors. Clin Lymphoma Myeloma Leuk. 2018;18; S216.  
3.  Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK 
with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 
4;369(1):32–42.  
4.  Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, et al. 
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin 
Oncol. 2017 May 1;35(13):1437–43.  
5.  Woyach J, Huang Y, Rogers K, Bhat SA, Grever MR, Lozanski A, et al. Resistance to 
acalabrutinib in CLL is mediated primarily by BTK mutations. Blood. 
2019;134(Supplement_1).  
6.  Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle 
reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation 
revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 
2014 Sep;4(9):1022–35.  
7.  Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, et al. Acquired mutations 
associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017 
04;129(18):2519–25.  
8.  Toyoshima S, Kanno A, Kitayama T, Sekiya K, Nakai K, Haruna M, et al. QT 
PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT 
Interval Prolongation by Human Pharmaceuticals [Internet]. Journal of pharmacological 
sciences. 2005 [cited 2020 Jun 10]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/16493187/ 
9.  Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic 
Drugs. Food and Drug Administration; 2005.  
10.  International Conference on Harmonisation. Harmonised Tripartite Guideline: The 
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for 
Non-Antiarrhythmic Drugs. E14 - Questions & Answers (R3). 2015.  
11.  Stass H, A D, Kubitza D, Schühly U. Pharmacokinetics, safety, and tolerability of 
ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to 
healthy subjects [Internet]. Antimicrobial agents and chemotherapy. 1998 [cited 2020 Sep 
1]. Available from: https://pubmed.ncbi.nlm.nih.gov/9687407/ 


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12.  Bloomfield D, Kost J, Ghosh K, Hreniuk D, Hickey L, Guitierrez M, et al. The Effect of 
Moxifloxacin on QTc and Implications for the Design of Thorough QT Studies. Clinical 
Pharmacology & Therapeutics. 2008 Oct 1;84(4):475–80.  
13.  Taubel J, Ferber G, Batchvarov V, Savelieva I, Camm A. Thorough QT study of the 
effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese 
and Caucasian subjects. Br J Clin Pharmacol. 77(1):170–9.  
14.  Darpo B, Benson C, Dota C, Ferber F, Garnett C, Green C, et al. Results from the 
IQ-CSRC prospective study support replacement of the thorough QT study by QT 
assessment in the early clinical phase [Internet]. Clinical pharmacology and therapeutics. 
2015 [cited 2020 Sep 24]. Available from: https://pubmed.ncbi.nlm.nih.gov/25670536/ 
15.  Ferber G, Zhou M, Darpo B. Detection of QTc effects in small studies--implications for 
replacing the thorough QT study. Ann Noninvasive Electrocardiol. 2015 Jul;20(4):368–
77.  
16.  Huang D, Chen J, Dang Q, Tsong Y. Assay sensitivity in “Hybrid thorough QT/QTc 
(TQT)” study [Internet]. Journal of biopharmaceutical statistics. 2019 [cited 2020 Sep 
24]. Available from: https://pubmed.ncbi.nlm.nih.gov/30346877/ 
17.  Garnett C, Bonate P, Dang Q, Ferber G, Huang D, Liu J, et al. Correction to: Scientific 
white paper on concentration-QTc modeling [Internet]. Journal of pharmacokinetics and 
pharmacodynamics. 2018 [cited 2020 Sep 11]. Available from: 
https://pubmed.ncbi.nlm.nih.gov/29330761/ 
18.  Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011 Jul;51(7):1035–42.  
19.  Cleveland W. Robust Locally Weighted Regression and Smoothing Scatterplots: Journal 
of the American Statistical Association: Vol 74, No 368. J Am Stat Assoc. 
1979;74(368):829–36.  
20.  Hurvich CM, Simonoff JS, Tsai C-L. Smoothing Parameter Selection in Nonparametric 
Regression Using an Improved Akaike Information Criterion. Journal of the Royal 
Statistical Society Series B (Statistical Methodology). 1998;60(2):271–93.  
 


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11. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Adverse Events 
Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical occurrence 
experienced by a patient or healthy adult subject, whether or not considered drug-related by 
the Investigator (or designee). A treatment-emergent adverse event (TEAE) is an AE that 
starts on or after the first administration of study drug. 
The following are all AEs: 
• 
unfavorable changes in general condition 
• 
subjective or objective signs/symptoms 
• 
concomitant diseases or accidents 
• 
clinically significant adverse changes in laboratory parameters observed in a subject 
during a clinical study 
Adverse events comprise all disturbances of general health status, subjective and objective 
disease symptoms (including laboratory abnormalities that are deemed clinically significant 
by the Investigator [or designee]), and accidents observed in the context of a clinical trial, 
irrespective of a possible causal relationship with the administration of the trial substance. 
Categorization of Adverse Events 
The severity of AEs will be categorized based on the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as follows: 
• 
Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• 
Grade 2 Moderate: Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)* 
• 
Grade 3 Severe or medically significant but not immediately life-threatening: 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL** 
• 
Grade 4 Life-threatening consequences: An event that puts the subject at 
immediate risk of death 
• 
Grade 5: Death related to AE 
Note: Not all grades are appropriate for all AEs. Therefore, some AEs are listed within the CTCAE with fewer than 
5 options for grade selection. Grade 5 (death) is not appropriate for some AEs and therefore is not an option. 
* Instrumental ADL refer to preparing meals, shopping for groceries, or clothes, using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 


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The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 2-category system according to the following guidelines: 
• 
NOT RELATED = The time course between the administration of investigational 
product and the occurrence or worsening of the AE rules out a causal relationship 
and another cause (eg, concomitant drugs, therapies, complications, comorbidities) 
is suspected 
• 
RELATED = The time course between administration of investigational product 
and the occurrence or worsening of the AE is consistent with a causal relationship 
and no other cause (eg, concomitant drugs, therapies, complications, comorbidities) 
can be identified 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
Pregnancy 
As information is available, a pregnancy (including pregnancy in female partners of male 
subjects) diagnosed through End of Study (EOS) or Early Termination (ET; if the subject 
discontinues from the study and does not complete a follow-up phone call) and for up to 
90 days after study drug administration on Day 23 (or last administration of study drug if 
subject terminates from the study early) should be reported by the Investigator (or designee) 
via email to Covance or the Sponsor’s Clinical Safety Representative within 24 hours of 
being notified. Covance or the Sponsor’s Clinical Safety Representative will then forward the 
Pregnancy Form to the Investigator (or designee) for completion. 
email: SAEIntake@Covance.com 
A subject becoming pregnant while on study drug will immediately be withdrawn from the 
study and ET study procedures will be performed. The subject or partner should be followed 
by the Investigator (or designee) until completion of the pregnancy. If the pregnancy ends for 
any reason before the anticipated date, the Investigator (or designee) should notify Covance 
or the Sponsor’s Clinical Safety Representative. At the completion of the pregnancy, the 
Investigator (or designee) will document the outcome of the pregnancy. If the outcome of the 
pregnancy meets the criteria for immediate classification as a serious adverse event (SAE; ie, 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator (or designee) should follow the procedures for reporting an SAE. 
Male subjects will be instructed to notify the Investigator (or designee) immediately if they 
discover their sexual partner is pregnant. In this instance, the partner must provide written 
consent before pregnancy information can be collected. When a Clinical Research Unit 
(CRU) becomes aware that the female partner of a male subject is pregnant, they are to 
contact the Investigator (or designee) immediately (within 24 hours of the CRU staff 
becoming aware of the event) in addition to notifying Covance or the Sponsor’s Clinical 
Safety Representative via email. 
All pregnancies should be recorded on the AE electronic Case Report Form (eCRF; as 
appropriate), in addition to completion of the required pregnancy forms. If the Investigator 
(or designee) suspects that a pregnancy was the result of an interaction between the study 


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treatment and the contraceptive method, in addition to the pregnancy the drug interaction 
should also be captured as a separate AE. 
Definition of Serious Adverse Events 
An SAE by the Food and Drug Administration (FDA) definition is any adverse drug 
experience occurring at any dose that results in any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse drug experience (ie, one that places the subject, in the 
view of the Investigator [or designee], at immediate risk of death) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
An important medical event that may require medical or surgical intervention to 
prevent 1 of the above outcomes 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent 1 of the outcomes listed in this definition. 
Unexpected Adverse Drug Reaction 
An AE or suspected adverse drug reaction is considered ‘unexpected’ if the event is not listed 
in the Reference Safety Information section of the Investigator’s Brochure (IB) or if it is not 
listed at the specificity or severity that has been observed for an unapproved investigational 
medicinal product (IMP). 
Reporting 
The FDA-reportable AEs are AEs that are associated with the use of the drug and represent 
events that are assessed as serious, related, and unexpected. The FDA-reportable AEs will be 
reported by the CRU to the Sponsor and the responsible Institutional Review Board (IRB). 
Final determination of whether an event represents a suspected unexpected serious adverse 
reaction (SUSAR) will be the responsibility of the Sponsor. 
Within 24 hours of when an AE that is potentially FDA-reportable is first recognized or 
reported, and within 24 hours of any SAE (regardless of whether the event is assessed as 
related or unrelated to study drug) being first recognized or reported, Covance or the 
Sponsor’s Clinical Safety Representative will be notified by the Investigator (or designee) in 
writing using the following email address: 
email: SAEIntake@Covance.com 
To report the SAE, the completed report form should be sent by email to Covance or the 
Sponsor’s Clinical Safety Representative within 24 hours of awareness. Incoming reports are 


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reviewed during normal business hours. Additional reporting instructions and the SAE Report 
Form are provided in the Study Manual. 
The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical Chemistry Panel 
(Fasted): 
Hematology Panel: 
Other Tests: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase 
(AST) 
Bilirubin (direct and total) 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatine kinase  
Creatinine 
Glucose 
Iron 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (percent and 
absolute): 
    Basophils 
    Eosinophils 
    Lymphocytes 
    Monocytes 
    Neutrophils 
Hemoglobin A1c (HbA1c)b 
Thyroid-stimulating hormone 
(TSH)b 
Estimated glomerular filtration 
ratea,d 
SARS-CoV-2 (COVID-19) test 
Coagulation Parameters: 
Partial thromboplastin time 
Prothrombin time 
International normalized ratio 
Serology:b 
Hepatitis B surface antigen 
(HBsAg) 
Hepatitis B virus (HBV) 
immunoglobulin M (IgM) core 
antibody 
Hepatitis C virus (HCV) 
antibody 
Human immunodeficiency virus 
(HIV) antibody 
For Female Subjects Only: 
Pregnancy test (serum 
qualitative, serum quantitative 
may be used for confirmation if 
needed)c 
Follicle-stimulating hormone 
(post-menopausal female 
subjects only)b 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity  
Protein 
Urobilinogen 
Microscopic examination 
including bacteria, casts, 
crystals, epithelial cells, RBCs, 
and WBCs (if protein, leukocyte 
esterase, nitrite, or occult blood 
is positive) 
Urine Drug Screen:a 
Including, but not limited to, the 
following: 
Alcohol (ethanol)e  
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine (metabolite)  
Methadone 
Opiates 
Phencyclidine 
Cotinine 
a. Performed at Screening and Check-in (Day -1) only. 
b. Performed at Screening only. 
c. Performed at Screening, Check-in (Day -1), and Day 32 for End of Treatment (EOT) or Early Termination (ET) only. 
d. Calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 
e. Urine or breath test. 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject: 
a Thyroid stimulating hormone (TSH) and estimated glomerular filtration rate (eGFR) will be assessed as part of the clinical 
chemistry sample. 
b Blood samples collected for analysis of study drug in plasma for Treatments A and B and blood samples for future potential 
and/or exploratory analysis for Treatments A and B may be collected from the same blood collection vial. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 500 mL. 
 
Assessment 
Approximate Blood 
Volume per Sample 
(mL) 
Maximum 
Number of Blood 
Samples 
Approximate 
Total Volume 
(mL) 
Serology 
8.0 
1 
8.0 
Hemoglobin A1c (HbA1c) 
4.0 
1 
4.0 
Pharmacokinetic and/or future exploratory 
and/or exploratory analysis sampling 
6.0 (Treatments A 
and B)b 
34 
204.0 
4.0 (Treatment C) 
14 
56.0 
Clinical laboratory evaluations: 
    Hematology  
    Clinical chemistrya 
    Coagulation  
 
4.0 
4.0 
3.0 
11 
121.0 
Serum pregnancy test (female subjects 
only) 
4.0 
3 
12.0 
Serum follicle-stimulating hormone (FSH; 
post-menopausal female subjects only)  
4.0 
1 
4.0 
Total: 
409.0 mL 


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Appendix 4: Schedule of Assessments


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Study 
Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Conduct 
Clinic 
Discharge/ 
EOT/ETu 
Follow-up 
Phone 
Call 
(EOS) 
Treatment Period 1  
Treatment Period 2 
Treatment Period 3 
Study Day 
1 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 
33 
7 (± 2) 
days post 
EOT/ ETv 
Confined to the 
CRU 
 
X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X 
X 
 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/
BMI 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Standard Safety 
12-lead ECGe 
X 
X 
X 
X X X X 
 
 
 
 
 
X 
X 
X X X X 
 
 
 
 
 
X 
X 
X X X X 
 
 
 
 
 
X 
 
Vital Signsf,g,h 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
HDYF? Inquiryi 
X 
X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X 
X 
X 
AEs/SAEsj 
X 
X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X 
X 
X 
Study Drug 
Administration 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Study 
Proceduresa 
Screening 
(Days -29 
to -2) 
Check-in 
(Day -1) 
Study Conduct 
Clinic 
Discharge/ 
EOT/ETu 
Follow-up 
Phone 
Call 
(EOS) 
Treatment Period 1  
Treatment Period 2 
Treatment Period 3 
Study Day 
1 
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 
33 
7 (± 2) 
days post 
EOT/ ETv 
Cardiodynamic 
Sampling 
(Holter 
Monitoring)m, n 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Clinical 
Laboratory 
Evaluationso 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
eGFR 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and 
HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 
Testingp 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screenq 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medicationsr 
X 
X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X X 
X 
X X X X X X X X X 
X 
X 
Serum 
Pregnancy Tests 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
FSH Testt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; BP = blood pressure; COVID-19 = SARS-CoV-2; CRF = Case Report Form; CRU = Clinical Research Unit; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOS = End of Study; EOT = End of Treatment; ET = Early Termination; FSH = follicle-stimulating hormone; HbA1c = 
hemoglobin A1c; HDYF? = How Do You Feel?; HIV = human immunodeficiency virus; ICF = Informed Consent Form; PK = pharmacokinetic; SAE = serious adverse event; 
TSH = thyroid-stimulating hormone; UA = urinalysis. 
a. For details on study procedures, see Section 7. 
b. Interim medical history only. 
CCI


Protocol 
CONFIDENTIAL 
Covance Study: 8419690  
Protocol Reference: LOXO-BTK-20011 
Protocol Version 1.0, 30 November 2020 
Page 78 of 79 
 
c. Height collected at Screening only; BMI calculated based on Screening height. 
d. A complete physical examination will be performed at Check-in (Day -1). An abbreviated physical examination will be performed at EOT (Day 33) or at ET. 
e. Standard safety 12-lead ECGs will be obtained at Screening and Check-in (Day -1), and at the following times related to administration of each treatment on Days 1, 12, and 23: predose, and 
1, 2, 4, 6, 24, 48, 72, 96, and 240 hours postdose (for Treatment Period 3, 240 hours postdose is EOT [Day 33] or ET). Standard safety 12-lead ECGs will be collected after the subject has 
rested in the supine position for at least 10 minutes. When scheduled at the same time as PK blood draws, standard safety 12-lead ECGs will be obtained prior to and as close as possible to 
having blood drawn. The allowed sampling window for standard safety 12-lead ECGs is ± 30 minutes from the nominal timepoint for all postdose standard safety 12-lead ECGs and no less 
than 10 minutes prior to dosing for predose standard safety 12-lead ECGs. 
f. Vital sign measurements (supine BP and pulse rate) will be obtained at Screening, Check-in (Day -1), and at the following times related to administration of each treatment on Days 1, 12, 
and 23: predose, and 1, 4, 8, 12, 24, 96, and 240 hours postdose (for Treatment Period 3, 240 hours postdose is EOT [Day 33] or ET). Blood pressure and pulse rate will be measured using 
the same arm for each reading after the subject has been supine for at least 5 minutes. When scheduled at the same time as PK blood draws, vital sign measurements should be carried out 
prior to and as close as possible to having blood drawn. The allowed sampling window for vital sign measurements is ± 30 minutes from the nominal timepoint for all postdose vital sign 
measurements and no less than 10 minutes prior to dosing for predose vital sign measurements. 
g. Respiratory rate and body temperature will be obtained at Screening, Check-in (Day -1), predose on Days 1, 12, and 23, and at EOT (Day 33) or ET. 
h. Oxygen saturation will be measured via pulse oximetry at Screening, Check-in (Day -1), predose on Days 1, 12, and 23, and at EOT (Day 33, 240 hours postdose on Day 23) or ET. The 
allowed sampling window for oxygen saturation measurements is ± 30 minutes from the nominal timepoint for all postdose oxygen saturation measurements and no less than 10 minutes 
prior to dosing for predose oxygen saturation measurements. 
i. A HDYF? inquiry will be performed at Screening (after the ICF is signed), at Check-in (Day -1), at each postdose vital sign measurement, and at an appropriate time for all other days. 
j. Adverse events and SAEs will be collected beginning at informed consent. Adverse events will be recorded throughout the study (ie, from signing of the ICF until EOS, or until ET if the 
subject discontinues from the study and does not complete a follow-up phone call), either as subject medical history (if the event is reported as beginning prior to signing of the ICF or if the 
event occurs prior to study drug administration on Day 1 and is assessed as not related to study procedures by the Investigator [or designee]) or as AEs (if the event occurs after signing of the 
ICF but prior to study drug administration on Day 1 and is assessed by the Investigator [or designee]) as related to study procedures, or if the event occurs after study drug administration on 
Day 1 through EOT or ET regardless of relationship to study drug). From EOT or ET through EOS, only AEs assessed as related to study drug are to be recorded. All SAEs that develop from 
the time of ICF signing until EOS (or ET if the subject discontinues from the study and does not complete a follow-up phone call) are to be reported. 
k. Treatment A (900 mg LOXO-305), Treatment B (placebo to match 900 mg LOXO-305), and Treatment C (400 mg moxifloxacin) will be administered in accordance with the randomization 
scheme assigned to each subject, with each treatment administered on either Days 1, 12, or 23. 
l. 
m. Subjects will be required to lie quietly in a supine position with minimal movement and minimal exposure to noise and other environmental stimuli (ie, TV, loud radio, interactions with other 
subjects, etc.) for at least 10 minutes before and 5 minutes during the cardiodynamic ECG extraction. Subjects will remain lying down or sitting and awake for the first 7 hours of the 24-hour 
postdose cardiodynamic ECG monitoring period. Holter monitors will be placed on subjects approximately 1.5 hours prior to dosing.  
n. Cardiodynamic sampling (Holter monitor ECG extraction) will be collected at the following times related to dosing: 45, 30, and 15 minutes predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 
8.5, 12, and 24 hours postdose. A light meal will be provided immediately following completion of the cardiodynamic ECG recording at the 6-hour timepoint and a full meal will be provided 
immediately after the 12-hour postdose timepoints. A snack can also be given just after the 8.5-hour postdose timepoint. Meals and snacks must be scheduled to be completed at least 
CCI


Protocol 
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Covance Study: 8419690  
Protocol Reference: LOXO-BTK-20011 
Protocol Version 1.0, 30 November 2020 
Page 79 of 79 
 
90 minutes prior to any scheduled ECG (ie, standard safety 12-lead ECG, or cardiodynamic ECG). The allowed sampling window for cardiodynamic ECGs will be the following: within 
30 minutes prior to dosing for the predose sample timepoint; ± 5 minutes for sampling timepoints within the first 24 hours postdose. 
o. Clinical chemistry panel (fasted for at least 8 hours), coagulation parameters, hematology panel, and UA will be performed at Screening, Check-in (Day -1), Day 2 (24 hours postdose on Day 
1), Day 6 (120 hours postdose on Day 1), Day 10 (216 hours postdose on Day 1), Day 13 (24 hours postdose on Day 12), Day 17 (120 hours postdose on Day 12), Day 21 (216 hours 
postdose on Day 12), Day 24 (24 hours postdose on Day 23), Day 28 (120 hours postdose on Day 23), and Day 32 (216 hours postdose on Day 23), if the subject completes the study (EOT) 
or on the day of ET. At ET or the day before EOT (Day 32), subjects are not required to be fasted prior to clinical laboratory evaluations. 
p. Testing for COVID-19 will be conducted at a minimum at Screening and Check-in (Day -1). Testing for COVID-19 may also be conducted periodically during the subject’s CRU 
confinement, at the discretion of the Investigator (or designee). Tests will be performed by rapid polymerase chain reaction or equivalent. 
q. Urine drug screen for drugs of abuse (including cotinine) and alcohol screen (urine or breath).  
r. Prior and concomitant medication administration will be recorded beginning at informed consent. In addition, all Investigator-approved prescription and over-the-counter medications taken 
by a subject within 14 days or 5 half-lives (if known), whichever is longer, prior to Day 1 will be recorded on the subject’s electronic CRF. 
s. Female subjects only. Performed at Screening, Check-in (Day -1), and Day 32 (216 hours postdose on Day 23), if the subject completes the study (EOT) or on the day of ET.  
t. Post-menopausal female subjects only. 
u. End of Treatment is defined as when the subject is released from the CRU following completion of all assessments through EOT (Day 33). Early Termination is defined as when the subject 
is released from the CRU if the subject terminates the study early. Vital sign measurements, standard safety ECG, and abbreviated physical examination results are to be available for review 
by the Investigator (or designee) prior to subject release from the CRU on Day 33 (EOT) or ET. Clinical laboratory results (for clinical chemistry, hematology, coagulation, and UA) and 
serum pregnancy test results (female subjects only) are to be available for review by the Investigator (or designee) prior to subject release from the CRU at the EOT visit and prior to subject 
release from the CRU at the ET visit, if available.  
v. To be conducted 7 days (± 2 days) following EOT (Day 33) or ET. End of Study is defined as when the subject is contacted by the CRU for a follow-up phone call 7 days (± 2 days) after the 
EOT visit or ET visit to determine if any SAE or study drug-related AE has occurred since the EOT or ET visit. All subjects who received study drug (including subjects who are terminated 
early) will receive a follow-up phone call. 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan LOXO-BTK-20011
A Phase I, Single-Dose, Randomized, Partially Double-Blind, Placebo- and Positive-Controlled, 
3-Way Crossover Study to Evaluate the Effect of LOXO-305 on QTc Interval in Healthy
Subjects
NCT06215521  
Approval date: 22-Feb-2021


Statistical Analysis Plan for Loxo Oncology, Inc. Study LOXO-BTK-20011 
Page 1 of 25 
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CONFIDENTIAL
Statistical Analysis Plan 
A Phase I, Randomized, Partially Double-Blind, Placebo- and Positive-
Controlled, 3-Way Crossover Study to Evaluate the Effect of LOXO-305 
on the QTc Interval in Healthy Adult Subjects 
Protocol: LOXO-BTK-20011 
Sponsor: Loxo Oncology, Inc. 
Version: 
Final 1.0 
Authors:  
 
Date: 
22 February 2021 
PPD


 
 
 
 
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Revision History 
Version 
Issue Date 
Author(s) 
Description 
Draft 0.1 
19 January 2021 
Initial version for review.  
Draft 0.2 
27 January 2021 
Revised version.  
Draft 0.3 
09 February 2021 
Revised version.  
Draft 0.4 
17 February 2021 
Revised version.  
Final 1.0 
22 February 2021 
Final version. 
 
 
 
 
 
PPD


 
 
 
 
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Table of Contents 
1 Abbreviations .............................................................................................................................4 
2 Introduction ................................................................................................................................5 
3 Study Design ..............................................................................................................................5 
4 Cardiodynamic ECG Assessment ..............................................................................................5 
4.1 
ECG and Pharmacokinetic Sample Collection ...................................................................5 
4.2 
Study Objectives .................................................................................................................6 
4.2.1 Primary Objective ........................................................................................................6 
4.2.2 Secondary Objectives ...................................................................................................6 
4.3 
Cardiodynamic ECG Endpoints .........................................................................................7 
4.3.1 Primary Endpoint .........................................................................................................7 
4.3.2 Secondary Endpoints ....................................................................................................7 
5 Statistical Methods .....................................................................................................................7 
5.1 
General Methodology .........................................................................................................7 
5.2 
Analysis Populations (Subject-Level) and Record-Level Analysis Sets ............................8 
5.3 
Baseline ...............................................................................................................................9 
5.4 
QT Correction Methods ......................................................................................................9 
6 Analyses ...................................................................................................................................10 
6.1 
Evaluation of QT/RR Correction Methods .......................................................................10 
6.2 
Concentration-QTc Analysis (Primary Analysis) .............................................................11 
6.2.1 Investigation of Hysteresis .........................................................................................12 
6.2.2 Appropriateness of a Linear Model ............................................................................12 
6.3 
Assay Sensitivity...............................................................................................................13 
6.4 
By-Time Point Analysis ...................................................................................................13 
6.5 
Categorical Analysis .........................................................................................................14 
6.6 
Morphological analysis for T wave and U wave ..............................................................15 
6.7 
Terminology and Definitions: Placebo-corrected ΔQTcF and Placebo-adjusted ΔQTcF 
(ΔΔQTcF) ..................................................................................................................................15 
6.8 
Determination of Sample Size ..........................................................................................16 
6.8.1 Determination of Sample Size for Assay Sensitivity .................................................16 
7 References ................................................................................................................................18 
8 Tables, Figures, and Listings ...................................................................................................18 
8.1 
Tables ................................................................................................................................18 
8.2 
Figures ..............................................................................................................................20 
8.3 
Listings .............................................................................................................................23 
9 Approvals .................................................................................................................................24 
 
 


 
 
 
 
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1 Abbreviations 
Abbreviation 
Term/Description 
bpm 
Beats per minute 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
∆ 
Change-from-baseline 
ΔΔ 
Placebo-corrected and placebo-adjusted change-from-baseline 
ECG 
Electrocardiogram 
HR 
Heart rate 
LOESS 
Locally weighted scatter plot smoothing 
LS 
Least squares 
ms 
Millisecond 
PK 
Pharmacokinetic(s) 
PR 
PR interval of the ECG 
Q-Q 
Quantile-quantile 
QRS 
QRS interval of the ECG 
QT 
QT interval of the ECG 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia’s formula 
QTcI 
Optimized HR-corrected QT interval 
QTcS 
Individualized heart rate-corrected QT interval 
RR 
RR interval of the ECG 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
tmax 
Time to reach Cmax 
TQT 
Thorough QT 
 
 


 
 
 
 
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2 Introduction 
This statistical analysis plan (SAP) was developed after review of the protocol LOXO-BTK-
20011 (Protocol version 1.0 dated 30 November 2020) for the study “A Phase I, Single-Dose, 
Randomized, Partially Double-Blind, Placebo- and Positive-Controlled, 3-Way Crossover Study 
to Evaluate the Effect of LOXO-305 on QTc Interval in Healthy Adult Subjects” and the ERT 
contract/proposal. This document defines the populations to be analyzed and provides full details 
of the statistical analyses, data displays, and algorithms to be used for data derivations to aid in 
the production of the statistical output and the statistical section of the cardiac safety report in 
regard to electrocardiogram (ECG) and concentration-QTc analyses. Relevant subject 
characteristics as well as the electrocardiographic parameters that will be evaluated are described 
along with the specific statistical methods.  
3 Study Design 
This is a single-dose, randomized, partially double-blind (for LOXO-305 and placebo), placebo 
and positive-controlled, 3-way crossover design study. 
All subjects will participate in 3 treatment periods (Treatment Periods 1, 2, and 3); in each 
treatment period, subjects will receive either a single oral dose of 900 mg LOXO-305 
(Treatment A), a single oral dose of 900 mg LOXO-305 matched placebo (Treatment B), or a 
single oral dose of 400 mg moxifloxacin (Treatment C). Assignment to Treatment A or B will be 
blinded but Treatment C will be open label. All subjects will receive Treatments A, B, and C on 1 
occasion during the study. There will be a washout period of at least 10 days between dosing in 
each period. 
Subjects will be randomly assigned to 1 of 6 treatment sequences (e.g, ABC, BCA, CAB, ACB, 
CBA, and BAC), according to the randomization scheme issued by Covance. A total of 30 
subjects will be randomized, such that 5 subjects will be assigned to each treatment sequence. 
Each treatment (A, B, and C) will be administered orally in the mornings of Day 1, Day 12, and 
Day 23 following a fast of at least 8 hours prior to and 6 hours after dosing. 
4 Cardiodynamic ECG Assessment 
4.1 ECG and Pharmacokinetic Sample Collection 
Holter monitors will be used to collect continuous 12-lead ECG data for the purpose of 
collecting cardiodynamic ECGs for approximately 25.5 hours, starting at approximately 
1.5 hours prior to dosing and at least 24 hours post-dose. Recording will be started and stopped 
at logistically optimal times to ensure that all scheduled time points are collected. Up to 10 
replicate 12-lead ECG recordings will be extracted from the continuous Holter recording at the 
scheduled time points, prior to the collection of blood samples for PK analysis. 


 
 
 
 
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The time points for ECG extraction in each period are 0.75, 0.5, and 0.25 hours prior to dosing 
on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, and 24 hours post-dose (the 24 hours 
post-dose time point will occur on Day 2, at the end of the Day 1 Holter recording). 
Timing and recording technique for ECGs will be standardized for all subjects. Subjects must be 
awakened at least 1 hour prior to the start of the cardiodynamic ECGs on the day of dosing and 
before the ECG recording scheduled at the 24-hour post-dose time point.  
Following dosing on days where cardiodynamic ECG assessments are performed, subjects will 
remain lying down or sitting and awake for the first 7 hours of the 24-hour post-dose 
cardiodynamic ECG monitoring period, as the QT-RR relationship is different during sleep. 
Subjects will be required to lie quietly in a supine position with minimal movement and minimal 
exposure to noise and other environmental stimuli (i.e., TV, loud radio, interactions with other 
subjects, etc.) for at least 10 minutes before and 5 minutes during the ECG extraction to allow 
for quality ECG extraction. In the event that an AE(s) occurs at any time during cardiodynamic 
ECG recordings, subjects may be placed in an appropriate position or will be permitted to lie 
down on their right side. 
All ECG extraction should occur in a 5-minute time window around the scheduled/nominal time 
and always precede the PK draw. If targeted ECG time points are artefactual or of poor quality, 
analyzable 10-second ECGs will be extracted as close as possible to the targeted time points. 
Blood samples for PK analysis of plasma concentrations of LOXO-305 or moxifloxacin plasma 
levels, and for future potential and/or exploratory analysis will be collected at the time points 
immediately after the ECG extractions. 
All Holter/ECG data will be collected using M12R continuous 12-lead digital recorders and the 
M12A Enterprise Holter System Client (Global Instrumentation, LLC, Manlius, New York, 
USA). The equipment will be supplied and supported by ERT. 
ECG intervals will be measured by the core laboratory in a blinded manner using the Early 
Precision QT technique (see Appendix A for more details). The ECG database will be locked 
before any statistical analysis is undertaken. 
4.2 Study Objectives 
4.2.1 Primary Objective 
The primary ECG objective is to evaluate the effects of a supratherapeutic exposure of LOXO-
305 on the QTc interval corrected for heart rate (HR) compared with placebo in healthy subjects. 
4.2.2 Secondary Objectives 
• To assess the effect of a single supratherapeutic dose exposure of LOXO-305 on other ECG 
parameters (HR, PR, and QRS interval) and on T-wave morphology changes compared with 
placebo in healthy subjects. 


 
 
 
 
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• To demonstrate sensitivity of the study to detect a small QTc effect using 400 mg oral 
moxifloxacin as a positive control in healthy subjects. 
• To evaluate the PK of a single supratherapeutic dose of LOXO-305 in healthy subjects. 
• To evaluate the safety and tolerability of a single supratherapeutic dose of LOXO-305 in 
healthy subjects. 
4.3 Cardiodynamic ECG Endpoints 
4.3.1 Primary Endpoint 
The primary endpoint is the placebo-corrected change from baseline (Δ∆) QTc interval 
(Δ∆QTc). The default will be Δ∆QTcF with QTc interval corrected for HR using the Fridericia 
method (QTcF). 
If a substantial HR effect is observed (i.e., the largest least squares [LS] mean Δ∆HR is greater 
than 10 bpm in the by-time point analysis), other correction methods such as optimized HR-
corrected QT interval (QTcI), and individual HR-corrected QT interval (QTcS) will be explored 
and compared. The method that removes the HR dependence of the QT interval most efficiently 
will be chosen as the primary correction method for this primary endpoint. 
4.3.2 Secondary Endpoints 
The secondary endpoints are:  
• Change from baseline (Δ) QTcF, HR, PR, QRS intervals (ΔQTcF, ΔHR, ΔPR, and ΔQRS). 
• If a substantial HR effect is observed: Change-from-baseline QTcS, and QTcI (ΔQTcS, and 
ΔQTcI). 
• Placebo-corrected change from baseline HR, PR, and QRS (Δ∆HR, Δ∆PR, Δ∆QRS). 
• If a substantial HR effect is observed: Change-from-baseline QTcS, and QTcI (ΔQTcS, and 
ΔQTcI). 
• If a substantial HR effect is observed: Placebo-corrected ΔQTcF, and/or ΔQTcS, and/or 
ΔQTcI (Δ∆QTcF, Δ∆QTcS, Δ∆QTcI) if not selected as the primary endpoint. 
• Categorical outliers for QTcF (and QTcS, and QTcI if a substantial HR effect is observed), 
HR, PR, and QRS. 
• Frequency of treatment-emergent changes of T-wave morphology and U-wave presence. 
5 Statistical Methods 
5.1 General Methodology 
All statistical analyses will be performed using the statistical software SAS for Windows Version 
9.4 or higher (SAS Institute, Inc., Cary, NC). Data collected from all randomized subjects will be 


 
 
 
 
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presented in data listings. Both absolute values and change-from-baseline values for each subject 
will be given where applicable. All continuous data will be listed with the same precision as will 
be presented in the database. Data listings will be sorted by treatment, subject ID, and time point. 
Missing values will be represented by an empty cell and no imputation will be made. 
For all descriptive statistics of continuous ECG parameters (i.e., HR, PR, QRS, and QTcF), data 
will be summarized including number of subjects (n), mean, median, standard deviation (SD), 
standard error (SE), 90% confidence interval (CI), minimum, and maximum by treatment and 
time point. For all modeling results of the by-time-point analysis of change-from-baseline values 
of continuous ECG parameters, n, least squares (LS) mean, SE, and 90% CI will be included. 
Modeling results of the by-time point analysis of placebo-corrected change-from-baseline will 
also include LS mean, SE, and 90% CI. Mean and median values will be rounded to the nearest 
tenth. SD, SE, and CI will be rounded to the nearest hundredth. For the concentration-QTc 
analysis, 2 decimal places will be shown for all effect estimates for all results which have an 
absolute value greater than 0.05. Each effect estimate with an absolute value ≤ 0.05 will be 
displayed with 2 significant figures. The CI of the effect estimate will display 1 more decimal 
place than the effect estimate. SE and P values will be reported with 4 digits and 
P values < 0.0001 will be reported as < 0.0001. Degrees of freedom (df), and t-value will be 
reported to the nearest tenth and nearest hundredth, respectively. Percentages will be rounded to 
the nearest tenths decimal place. 
5.2 Analysis Populations (Subject-Level) and Record-Level Analysis Sets 
The analysis populations (subject-level) for cardiodynamic ECG assessment are defined as 
follows (Table 1).  
Table 1 
Analysis populations (subject-level) for cardiodynamic ECG assessment 
Population 
Subjects 
QT/QTc population 
All subjects who have received 1 dose of study drug (LOXO-305, 
moxifloxacin, or placebo) with measurements at baseline as well as on-
treatment with at least 1 post-dose time point with a valid ΔQTc value. The 
QT/QTc population will be used for the by-time point and categorical 
analyses of the cardiodynamic ECG parameters. 
PK Population 
All subjects who received 1 dose of LOXO-305 or moxifloxacin, and have 
at least 1 qauntifiable plasma concentration of LOXO-305 or moxifloxacin 
and have evaluable pharmacokinetic (PK) data. A subject may be 
excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median 
tmax. The impact of protocol deviations on the PK population will be 
evaluated on a case-by-case basis.  
PK/QTc population 
All subjects who are in both the PK and QT/QTc populations with at least 1 
pair of post-dose PK and ΔQTc data from the same time point in at least 1 
period as well as subjects in the QT/QTc population who received placebo. 


 
 
 
 
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Population 
Subjects 
The PK/QT population will be used for the concentration-QTc analysis and 
assay sensitivity. The PK/QTc population will be defined for LOXO-305 
and moxifloxacin. 
Table 2 defines the observations that will be included at a record/time point level in the statistical 
analyses described in this SAP. 
Table 2 
Record-level analysis sets for cardiodynamic ECG assessment 
Analysis set 
Definition 
By-time point 
analysis set 
For all continuous ECG parameters, all post-baseline time points that 
have a nonmissing change-from-baseline observation. Defined for 
subjects in the QT/QTc analysis set. 
Categorical 
analysis set 
For all categorical ECG parameters, all post-baseline time points that 
have an evaluable record at baseline, i.e., treatment-emergent changes 
can be assessed. Defined for all subjects in the QT/QTc analysis set. 
Concentration-QTc 
analysis set 
All time points in the by-time point analysis set that have a 
corresponding planned PK collection at the same time point. Time 
points at which no PK data are available for nonplacebo subjects will 
not be retained. Defined for QTc for subjects in the PK/QTc analysis 
set. 
5.3 Baseline 
For all continuous ECG parameters, baseline will be the average of the derived ECG intervals 
from the 3 time points (0.75, 0.5, and 0.25 hours) prior to treatment administration for each 
period on Day 1, Day 12, and Day 23, respectively. For T-wave morphology and U-wave 
presence, baseline includes findings observed in any of the replicates from the 3 time points prior 
to dosing for each period on Day 1, Day 12, and Day 23, respectively. 
5.4 QT Correction Methods 
The QT and RR value for each beat will be used for HR correction.  
The Fridericia's correction (QTcF) is defined as QTcF (ms) = QT (ms)/[RR(ms)/1000]1/3. 
In case a substantial HR effect is observed on-treatment with LOXO-305 (i.e., if the largest least 
squares [LS] mean ΔΔHR > 10 bpm in the by-time point analysis), additional QT correction 
methods may be explored. Since Holter recordings are not collected on Day -1, prior to 
treatment, additional QT correction methods will be derived from Day 1 of placebo period during 


 
 
 
 
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both the time points of supine rest (QTcS) and from all evaluable QT/RR pairs in the 24-hour 
recording (QTcI). These data will be used to obtain the RR interval (HR) and QT data to enable 
derivations of QTcS and QTcI, as follows.  
• An individualized HR-corrected QT interval (QTcS) will be calculated from QT/RR data 
obtained at supine resting time points on Day 1 of the placebo period. Based on QT/RR 
pairs from all subjects, the QTcS correction coefficient will be derived from a linear 
mixed-effects model: log(QTij) = log(ai) + b1i × log(RRij) + b2i× genderi + b3i× log(RRij) 
× genderi with gender included as a fixed effect, and subject included as a random effect. 
The coefficient of log(RR) for each subject, bi =b1i+ b3i × gender, will then be used to 
calculate QTcS for that subject as follows: QTcS = QT/RRbi. 
• An optimized HR-corrected QT interval (QTcI) will be derived from a broader range of 
HRs by using all QT/RR data from the full 24-hour recording (all acceptable beats) on 
Day 1 of the placebo period. The QT/RR pairs from each subject will be used for that 
subject’s individual correction coefficient, which will be derived from a linear regression 
model: log(QTi) = log(ai) + bi × log(RR′i). The coefficient of log(RR′) for each subject, bi, 
will then be used to calculate QTcI for that subject as follows: QTcI = QT/RR′bi. 
RR′ will be derived using the unadjusted RR, 1-minute average RR, 3-minutes average RR, 1-
minute weighted average RR and 3-minutes weighted average RR, respectively. Hysteresis 
adjustment will also be applied to the extracted ECGs with the same duration of averaging, and 
weighted averaging.  
For QTcS and QTcI, the individual correction coefficients, bi, will be listed and also summarized 
in a table using arithmetic mean, SE, number of subjects, and 90% CI (based on a t-distribution). 
The method that removes the HR dependence of the QT interval most efficiently will be chosen 
as the primary correction method.  
6 Analyses 
6.1 Evaluation of QT/RR Correction Methods  
In case a substantial HR effect is observed, defined as the largest LS mean ΔΔHR greater than 10 
bpm, the relationship between QTc (QTcF and, if derived, QTcS [individual], QTcI [optimized] 
using unadjusted RR, 1-minute average RR, 3-minutes average RR, 1-minute weighted average 
RR and 3-minutes weighted average RR) and RR interval will be investigated using on-treatment 
data (LOXO-305, and moxifloxacin) by a linear regression model: QTc = c + d × RR. Mean QTc 
and RR values from all nominal time points (including pre-dose) will be used. The RR 
coefficient for each subject, di, will then be used to calculate the average sum of squared slopes 
(SSS) for each of the different QT/RR correction methods. In addition, a scatter plot and quantile 
plot of QTc (QTcF, QTcS, QTcI) and RR intervals by treatment with a regression line and a 
linear mixed-effects line (90% CI), respectively, will also be given. QTcI based on a 3-minute 
weighted average will be used as the primary endpoint, with other corrections as supporting 
evidence.   


 
 
 
 
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6.2 Concentration-QTc Analysis (Primary Analysis) 
The relationship between LOXO-305 plasma concentrations and change-from-baseline QTc 
(ΔQTcF, or ΔQTc corrected with the HR correction method chosen as primary if a substantial 
HR effect is observed) be quantified using a linear mixed-effects modeling approach. The model 
will include ΔQTc as the dependent variable, LOXO-305 plasma concentrations as the 
explanatory variate (0 for placebo), centered baseline QTc (i.e., baseline QTc for individual 
subject minus the population mean baseline QTc for all subjects in the same treatment period) as 
an additional covariate, treatment (active = 1 or placebo = 0), time (i.e., nominal post-dose time 
point) as fixed effects, and random effects on the intercept and slope per subject1. In addition, if 
there are significant concentrations of LOXO-305 metabolites, their concentrations/QTc 
relationship may be explored (exploratory metabolite profiling has shown that unchanged 
LOXO-305 is the major drug-related component in human plasma). In all calculations, zero will 
be substituted for concentrations below the quantification limit of the assay and for 
concentrations from subjects who received placebo.  
An unstructured covariance matrix will be specified for the random effects. If convergence 
cannot be achieved even after appropriate rescaling of the concentrations, the random effect on 
the slope and intercept will be dropped, in this order, until convergence is achieved. The degrees 
of freedom of estimates will be determined by the Kenward-Roger method. From the model, the 
slope (i.e., the regression parameter for LOXO-305 concentrations) and the treatment effect-
specific intercept (defined as the difference between active and placebo) will be estimated 
together with the 2-sided 90% CI. The estimates for the time effect will be reported with degrees 
of freedom and SE.  
The geometric mean of the individual Cmax values for subjects in the active dose group will be 
determined. The predicted effect and its 2-sided 90% CI for ΔΔQTc (i.e., slope estimate × 
concentration + treatment effect-specific intercept) at this geometric mean Cmax of LOXO-305 
will be obtained. If the upper bound of the 2-sided 90% CI of the predicted effect of ΔΔQTc at 
clinically relevant plasma levels of LOXO-305 is below 10 ms, it will be concluded that LOXO-
305 does not cause clinically relevant QTc prolongation within the observed plasma 
concentration ranges. 
To evaluate the adequacy of model fit with respect to the assumption of linearity, the observed 
ΔQTc values adjusted by population time effect estimated from the model will be used. These 
individual placebo-adjusted ΔQTci,k (ΔΔQTci,k) values equal the observed individual ΔQTci,k for 
subject i administered with active drug or placebo at time point k minus the estimated population 
mean placebo effect at time point k (i.e., time effect). A quantile plot, i.e. plot of the quantiles 
(deciles) of observed drug concentrations and the mean placebo-adjusted ΔQTc (ΔΔQTc) and 
90% CI at the median concentration within each decile will be given. The regression line 
presenting the model-predicted ΔΔQTc (as described by Tornøe et al2) will be added to evaluate 
the fit of a linear model and visualize the concentration-response relationship. Additional 
exploratory analyses (via graphical displays and/or model fitting) will include assessing for a 
delayed effect (hysteresis, Section 6.2.1) and the justification for the choice of the 
pharmacodynamic model (linear versus nonlinear, Section 6.2.2) as follows. 


 
 
 
 
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The SAS code for the concentration-QTc analysis using the full model is as follows. 
PROC MIXED DATA=PKPD method=reml; 
CLASS SUBJID TIME; 
MODEL DQTc=TRT CONC TIME CBASE/ solution cl noint alpha=0.1 alphap=0.1 COVB DDFM=KR;  
RANDOM INT CONC /type=UN SUBJECT=SUBJID s; 
RUN; 
Where PKPD = PK/QTc population, SUBJID = subject number, TRT = treatment (active = 1 or placebo = 0), 
TIME = nominal post-dose time point, CONC= time-matched plasma concentration of LOXO-305 (0 for placebo), 
CBASE = centered baseline QTcF, and DQTc = ΔQTcF.  
Note: ESTIMATE statements will be included for the prediction of the effect in the active dose group. 
6.2.1 Investigation of Hysteresis 
Hysteresis will be assessed based on joint graphical displays of the least squares (LS) mean 
ΔΔQTc at each post-dose time point from the by-time point analysis and the mean concentrations 
of LOXO-305 at the same time points. In addition, hysteresis plots will be given for LS mean 
ΔΔQTc from the by-time point analysis and the mean concentrations. Other concentration-QTc 
models may be explored if both of the following conditions are met. 
• A QT effect > 10 ms (i.e., LS mean ΔΔQTc  > 10 ms) cannot be excluded in the by-time 
point analysis  
• The difference (delay) between the time to reach the peak QTc effect (ΔΔQTc) and tmax is 
larger than 1 hour.  
With the provision stated above, hysteresis will be assumed if the curve of the hysteresis plot 
shows a counterclockwise loop. A significant treatment effect-specific intercept may also be 
indicative of hysteresis or model misspecification, if it cannot be explained by a nonlinear 
relationship. 
6.2.2 Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal quantile-quantile (Q-Q) plots for the 
standardized residuals and the random effects; scatter plots of standardized residuals versus 
concentration, fitted values, and centered baseline QTc; and box plots of standardized residuals 
versus nominal time, and active treatment will be produced, in addition to the quantile plot 
described above. Among these plots, the scatter plots of standardized residuals versus 
concentration and versus centered baseline QTc will also include the locally weighted scatter 
plot smoothing (LOESS) lines with optimal smoothing parameters selected by the Akaike 
information criterion with a correction (AICC)3,4. A scatter plot of observed concentration and 
ΔQTcF with a LOESS smooth line with 90% CI and a linear regression line will also be provided 
to check the assumption of a linear concentration-QTc relationship. If there is an indication that a 
linear model is inappropriate, additional models may be fitted, specifically an Emax model. The 
concentration-QTc analysis will then be repeated for the model found to best accommodate the 
nonlinearity detected. 


 
 
 
 
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6.3 Assay Sensitivity 
The analysis to show assay sensitivity will be based on the concentration-QTc analysis of the 
effect on ∆QTc of 400 mg oral moxifloxacin using a similar model as for the primary analysis. 
That is, the relationship between moxifloxacin plasma concentration and ∆QTc will be 
investigated by linear mixed-effects modeling. The model will include ΔQTc as the dependent 
variable, moxifloxacin plasma concentration as the explanatory variable (0 for placebo), centered 
baseline QTc (i.e., baseline QTc for individual subject minus the population mean baseline QTc 
for all subjects in the same treatment period) as an additional covariate, study treatment 
(moxifloxacin = 1 or placebo = 0) and time (i.e., post-dose time point) as fixed effects, and a 
random intercept and slope per subject (Garnett et al1). The geometric mean of the individual 
Cmax values for subjects receiving the single dose of 400 mg moxifloxacin will be determined. 
The predicted effect and its 2-sided 90% CI for ΔΔQTc (i.e., slope estimate × concentration + 
treatment effect-specific intercept) at this geometric mean Cmax will be obtained.  
If the slope of the moxifloxacin plasma concentration/∆QTc relationship is statistically 
significant at the 10% level in a 2-sided test and the lower bound of the 2-sided 90% CI of the 
predicted QT effect at the observed geometric Cmax of the 400 mg dose is above 5 ms, assay 
sensitivity will be deemed to have been demonstrated. 
6.4 By-Time Point Analysis 
The analysis for QTc will be based on a linear mixed-effects model with ΔQTc (ΔQTcF, or 
ΔQTc corrected per the HR correction method chosen as primary if a substantial HR effect is 
observed) as the dependent variable, period, sequence, time (i.e., nominal post-dose time point), 
treatment (LOXO-305, moxifloxacin and placebo), and time-by-treatment interaction as fixed 
effects, and baseline QTc as a covariate. An unstructured covariance matrix will be specified for 
the repeated measures at post-dose time points for subject within treatment period. If the model 
with unstructured covariance matrix fails to converge, other covariance matrix such as 
compound symmetry and autoregressive will be considered. The model will also include a 
subject-specific random effect. If the fixed effects for period and/or sequence should prove to be 
nonsignificant (that is, if the P value > 0.1), these effects may be removed from the model and 
the analysis will be repeated without those covariates. From this analysis, the LS mean, SE, and 
2-sided 90 % CI will be calculated for the contrast “LOXO-305 versus placebo” at each post-
dose time point, separately. 
For HR, PR, QRS intervals, and QTc with the methods not selected as primary, the analysis will 
be based on the change-from-baseline post-dosing values (ΔHR, ΔPR, ΔQRS, and ΔQTc). The 
same (by-time point analysis) model will be used as described above for QTc. The LS mean, SE, 
and 2-sided 90% CI from the statistical modeling for both change-from-baseline and placebo-
corrected change-from-baseline values will be listed in the tables and graphically displayed. 
The SAS code for the by-time point analysis for QTc is as follows. 
PROC MIXED DATA=ECG; 
CLASS SUBJID TREAT TIME PERIOD SEQUENCE; 


 
 
 
 
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MODEL DQTc=BASE TREAT TIME TREAT*TIME PERIOD SEQUENCE/DDFM=KR;  
RANDOM INTERCEPT / SUBJECT =SUBJID TYPE=UN; 
REPEATED TIME / SUBJECT = PERIOD*SUBJID TYPE = UN; 
LSMEANS TREAT*TIME/CL DIFF ALPHA=0.1;  
RUN; 
Where ECG = QT/QTc population, SUBJID = subject number, TREAT = treatment (LOXO-305, moxifloxacin and 
placebo), TIME = nominal post-dose time point, BASE = baseline QTc, PERIOD = period, SEQUENCE = sequence, 
and DQTc = ΔQTc. 
6.5 Categorical Analysis 
Results for categorical outliers will be summarized in frequency tables with counts and 
percentages for both number of subjects and number of time points. Subject data will be 
summarized using the count of distinct subjects that fall into the category and the percentage of 
the total number of subjects. Time point data will be summarized using the count of time points 
at which the assessments fall into the category and the percentage of the total number of time 
points at which assessments are performed. Counts (either number of subjects or number of time 
points) for each treatment group will be used as the denominator in the calculation of 
percentages unless otherwise specified. 
A subject or time point will be determined as an outlier if the following criteria (which are 
assessed separately) are met for the ECG intervals (Table 3). 
Table 3 
Criteria for determining a subject or time point outlier 
ECG 
interval 
Categorical outlier criteria 
QTc 
(QTcF, 
QTcS,  
QTcI) 
Treatment-emergent value of > 450 and ≤ 480 ms when not present at baseline (new 
onset) 
Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline (new 
onset) 
Treatment-emergent value of > 500 ms when not present at baseline (new onset) 
Increase of QTc from baseline of > 30 and ≤ 60 ms 
Increase of QTc from baseline > 60 ms 
PR 
Increase of PR from baseline > 25% resulting in PR > 200 ms 
QRS 
Increase of QRS from baseline > 25% resulting in QRS > 120 ms 
HR 
Decrease of HR from baseline >25% resulting in HR < 50 bpm 
Increase of HR from baseline >25% resulting in HR > 100 bpm 
All outliers will be summarized for each treatment on the basis of incidence rates. A subject will 
be counted only once for a particular outlier event if the subject experiences more than 1 episode 


 
 
 
 
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of that event. The total number of time points will be based on the number of observed time 
points across all subjects within a treatment group. 
6.6 Morphological analysis for T wave and U wave 
Morphological analyses will be performed with a focus on detecting changes in T-wave 
morphology and appearance of abnormal U waves. The analyses will evaluate change-from-
baseline (i.e., treatment-emergent changes). 
The analysis results for T-wave morphology and U-wave presence will be summarized in 
frequency tables with counts and percentages for both number of subjects and number of time 
points. The number and percentage of subjects in each treatment group having changes from 
baseline that represent the appearance of the morphological abnormality will be summarized. 
The total number of time points having a particular change event will be summarized in terms of 
number and percentage based on the number of observed time points across all subjects within a 
treatment group. 
6.7 Terminology and Definitions: Placebo-corrected ΔQTcF and Placebo-
adjusted ΔQTcF (ΔΔQTcF) 
Change-from-baseline QTcF (∆QTcF) will be used as the dependent variable in the 
concentration-QTc analysis and in the by-time point analysis.  
By-time Point Analysis 
Placebo-corrected ΔQTcF (ΔΔQTcF) 
• In the by-time point analysis on the QTcF interval, LS mean, SE, and 2-sided 90% CI of 
∆QTcF and ∆∆QTcF will be calculated for active dose group and moxifloxacin group as 
well as on placebo group for ΔQTcF at each post-dose time point. 
 
Concentration-QTc Analysis 
Placebo-corrected ΔQTcF (ΔΔQTcF) 
• In the concentration-QTc analysis, the term placebo-corrected ΔQTcF (ΔΔQTcF) will be 
used for the model-predicted effect across concentrations on a population level. 
• Definition for the estimated placebo-corrected ΔQTcF (ΔΔQTcF): Model-predicted mean 
ΔQTcF in active dose group or moxifloxacin group minus model-predicted mean ΔQTcF 
in the placebo group, which equals slope estimate × concentration + treatment effect-
specific intercept.  
o The term placebo-corrected ΔQTcF (∆∆QTcF) will be used for the model-
predicted effect on the QTcF interval in the concentration-QTc prediction table 
and the scatter plots for concentration-QTc model(s), quantile plots, and 
prediction plots, as described in Section 8. 
 


 
 
 
 
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Placebo-adjusted ΔQTcF (ΔΔQTcF) 
• In the concentration-QTc analysis, the term placebo-adjusted ΔQTcF (ΔΔQTcF) will be 
used to illustrate the underlying data on both subject and population levels. 
• Definition for the estimated placebo-adjusted ΔQTcF on a subject level: observed ΔQTcF 
for each subject (on active dose group or moxifloxacin group or placebo group) minus the 
estimated time effect (i.e., the model-predicted mean ΔQTcF in the placebo group).  
o This term will be used to illustrate the underlying data on a subject level in the 
scatter plot(s) for concentration-QTc model(s), as described in Section 8.  
• Definition for the estimated placebo-adjusted ΔQTcF term on a population level: the 
average of individually estimated placebo-adjusted ΔQTcF values at the associated 
median plasma concentration within each concentration decile.  
o This term will be used to illustrate the underlying data on a population level in the 
quantile plot(s), as described in Section 8.  
6.8 Determination of Sample Size 
A total of up to 30 subjects (5 subjects per treatment sequence) will be enrolled to ensure at least 
24 evaluable subjects completed all three treatment periods of the study. A sample size of 24 
evaluable subjects will provide at least 90% power to exclude that LOXO-305 causes more than 
a 10-ms QTc effect at clinically relevant plasma levels, as shown by the upper bound of the 2-
sided 90% CI of the model-predicted QTc effect (ΔΔQTc) at the observed geometric mean Cmax 
of LOXO-305 in the study. This power is estimated approximately using a paired t-test. The 
calculation assumes a 1-sided 5% significance level, a small underlying effect of LOXO-305 of 
3 ms, and a standard deviation (SD) of the ΔQTc of 8 ms for both LOXO-305 and placebo. The 
concentration-QTc analysis method is supported by Darpo et al5 and Ferber et al6, and is 
consistent with the experiences from 25 recent TQT studies. 
6.8.1 Determination of Sample Size for Assay Sensitivity 
To demonstrate assay sensitivity with concentration-QTc analysis, it has to be shown that the 
ΔΔQTc of a single dose of 400 mg moxifloxacin exceeds 5 ms (ie, the lower bound of the 2-
sided 90% CI of the predicted QTc effect [ΔΔQTc] should exceed 5 ms). In a similarly designed, 
recent crossover study with 24 healthy subjects (on-file data, ERT), the standard error (SE) for 
the prediction of the QT effect of moxifloxacin based on the concentration-QTc analysis was 
1.24 ms. The within-subject SD of ΔQTcF in the referred study was 5.4 ms based on the by-
timepoint analysis. If the effect of moxifloxacin is assumed to be 10 ms, the SE of 1.24 ms 
corresponds to an effect size of (10-5)/(1.24 ×sqrt[24])= 0.82, where the effect size is the effect 
assumed under the alternative hypothesis divided by the SD of the test variable. This value 
should be compared to the effect size of 0.62 required to guarantee a power of at least 90% in a 
paired t-test situation with a sample size of 24 evaluable subjects. In other words, based on this 
calculation, a power of at least 90% for 24 evaluable subjects will be obtained as long as the 
variability of the ΔQTc, as measured by its within-subject SD, does not exceed 7.1 ms (ie, 132% 
[= 0.82/0.62] of the 5.4 ms observed in the referred study assuming the ratio of effective sizes is 


 
 
 
 
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consistent with inverse ratio of within-subject SD). The number also agrees with recent 
recommendations of the FDA, which propose at least 20 subjects7.  
 
 


 
 
 
 
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7 References 
1. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. [Published correction appears in J Pharmacokinet 
Pharmacodyn. 2018;45(3):399]. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
2. Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011;51(7):1035-1042. 
3. Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat 
Assoc. 1979;74(368):829-836. 
4. Hurvich CM, Simonoff JS, and Tsai CL. Smoothing parameter selection in nonparametric 
regression using an improved Akaike Information Criterion. J R Stat Soc Series B Stat 
Methodol. 1998;60(2):271-293. 
5. Darpo B, Benson C, Dota C, et al. Results From the IQ-CSRC Prospective Study Support 
Replacement of the Thorough QT Study by QT Assessment in the Early Clinical Phase. Clin 
Pharmacol Ther. 2015;97(4):326-335. 
6. Ferber G, Zhou M, and Darpo B. Detection of QTc Effects in Small Studies--Implications for 
Replacing the Thorough QT Study. Ann Noninvasive Electrocardiol. 2015;20(4):368-377. 
7. Huang DP, Chen J, Dang Q, and Tsong Y: Assay sensitivity in “Hybrid thorough QT/QTc 
(TQT)” study, Journal of Biopharmaceutical Statistics, 2019; 29(2), 378-384. 
8 Tables, Figures, and Listings 
8.1 Tables 
Number 
Title 
Comments 
14.1.1 
QTcS and QTcI individual 
correction coefficients with 
descriptive statistics 
Number of subjects (n), mean, SD, SE, 90% CI, 
median, minimum, and maximum will be given 
(Section 5.4). 
14.1.2 
Average SSS for different QT-RR 
correction methods 
SSS for LOXO-305, moxifloxacin, and placebo 
will be given (Section 6.1). 
14.1.3 
Baseline values of ECG 
parameters with descriptive 
statistics  
Number of subjects (n), mean, SD, SE, 90% CI, 
median, minimum, and maximum from 
descriptive analysis will be given by treatment for 
each ECG parameter (Section 6.4). 
14.1.4 
Observed values of QTc (primary 
correction method) with 
descriptive statistics 
n, mean, SD, SE, 90% CI, median, minimum, and 
maximum from descriptive statistics will be 
given by treatment and post-dose time point 
(Section 6.4).  


 
 
 
 
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Number 
Title 
Comments 
14.1.5.1-
14.1.5.10 
Change-from-baseline QTcF (and 
QTcI in 5 ways and QTcS if 
calculated), HR, PR, and QRS 
(ΔQTcF, ΔQTcI, ΔQTcS, ΔHR, 
ΔPR, and ΔQRS) at each time 
point 
n, LS mean, SE, and 90% CI from the statistical 
modeling will be given by treatment and time 
point (Section 6.4). 
14.1.6.1-
14.1.6.10 
Placebo-corrected change-from-
baseline QTcF (and QTcI in 5 
ways and QTcS if calculated), HR, 
PR, and QRS (ΔΔQTcF, ΔΔQTcI, 
ΔΔQTcS, ΔΔHR, ΔΔPR, and 
ΔΔQRS) at each time point  
LS mean, SE, and 90% CI from the statistical 
modeling will be given by treatment and time 
point (Section 6.4). 
14.1.7 
QTc outliers per absolute category 
Number (%) of subjects and time points with 
QTc > 450 and ≤ 480 ms, > 480 and ≤ 500 ms, or 
> 500 ms by treatment (Section 6.5).  
14.1.8 
QTc outliers per change-from-
baseline category 
Number (%) of subjects and time points with 
∆QTc > 30 and ≤ 60 ms, or > 60 ms by treatment 
(Section 6.5).  
14.1.9 
Categorical analyses for HR, PR, 
and QRS 
Number (%) of subjects and time points with 
∆PR > 25% and PR > 200 ms at post-dose; ∆QRS 
> 25% and QRS > 120 ms at post-dose; HR 
decrease from baseline > 25% and HR < 50 bpm 
at post-dose; and HR increase from baseline > 
25% and HR > 100 bpm at post-dose 
(Section 6.5). 
14.1.10 
T-wave morphology and U-wave 
presence across treatment groups: 
treatment-emergent changes  
Number (%) of subjects and time points falling 
into each of the T-wave and U-wave categories 
will be given by treatment (Section 6.6). 
14.1.11.1 
Concentration-QTc analysis of 
LOXO-305 and associated ΔQTc 
prolongation  
Fixed-effect estimations and corresponding 
P values will be given (Section 6.2). 
14.1.11.2 
Assay sensitivity analysis of 
moxifloxacin and associated ΔQTc 
prolongation 
Fixed effect estimations and corresponding 
P values will be given (Section 6.3). 
14.1.12.1 
Predicted ΔΔQTc interval at 
geometric mean peak LOXO-305 
concentration  
Section 6.2. Referred to above as a 
“Concentration-QTc prediction table” 
14.1.12.2 
Predicted ΔΔQTc interval at 
geometric mean peak 
moxifloxacin concentration 
Section 6.3. Referred to above as a 
“Concentration-QTc prediction table” 


 
 
 
 
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8.2 Figures 
Number 
Title 
Comments 
14.2.1.1 
Scatter plots of QTc and RR by 
treatment 
Scatter plots of QTc (QTcF, QTcIS, and QTcIS) 
and RR intervals by treatment with regression 
lines will be given (Section 6.1).  
14.2.1.2 
QTc-RR quantile plot by treatment QTc-RR quantile plots (with quantiles) with 
linear mixed-effects line and 90% CI will be 
given (Section 6.1).  
14.2.2 
Observed QTcF (primary 
correction method) across time 
points  
Mean and 90% CI from descriptive analysis will 
be given by treatment (Section 6.4).  
14.2.3.1-
14.2.3.10 
Change-from-baseline QTcF (and 
QTcI in 5 ways and QTcS if 
calculated), HR, PR, and QRS 
(ΔQTcF, ΔQTcI, ΔQTcS, ΔHR, 
ΔPR, and ΔQRS) across time 
point 
LS mean and 90% CI from the statistical 
modeling will be shown by treatment 
(Section 6.4). 
14.2.4.1-
14.2.4.10 
Placebo-corrected change-from-
baseline QTcF (and QTcI in 5 
ways and QTcS), HR, PR, and 
QRS (ΔΔQTcF, ΔΔQTcI, 
ΔΔQTcS, ΔΔHR, ΔΔPR, and 
ΔΔQRS) across time point 
LS mean and 90% CI from the statistical 
modeling will be shown by treatment 
(Section 6.4). 
14.2.5.1 
Mean LOXO-305 plasma 
concentrations over time  
Section 6.2. 
14.2.5.2 
Mean moxifloxacin plasma 
concentration over time 
Section 6.3. 
14.2.6 
LOXO-305 plasma concentrations 
and ΔΔQTc over time 
Section 6.2.1.  
14.2.7 
Hysteresis plot of LOXO-305 
plasma concentration and ΔΔQTc 
connected in temporal order  
Section 6.2.1.  
14.2.8.1 
Scatter plot of observed LOXO-
305 plasma concentrations and 
ΔQTc with simple linear 
regression line and LOESS 
regression  
Scatter plot of ∆QTc versus concentration with 
LOESS line and 90% CI and simple regression 
line (Section 6.2.2). 


 
 
 
 
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Number 
Title 
Comments 
14.2.8.2 
Scatter plot of observed 
moxifloxacin plasma 
concentrations and ΔQTc with 
simple linear regression line and 
LOESS regression 
Scatter plot of ∆QTc versus concentration with 
LOESS line and 90% CI and simple regression 
line (Section 6.3). 
14.2.9.1 
Scatter plot of observed LOXO-
305 plasma concentrations and 
estimated placebo-adjusted ΔQTc  
Scatter plot of placebo-adjusted ∆QTc versus 
concentration with linear mixed-effects 
regression line and 90% CI of ΔΔQTc 
(Section 6.2). Referred to above as “Scatter plot 
for concentration-QTc model(s).” 
14.2.9.2 
Scatter plot of observed plasma 
concentrations of moxifloxacin 
and estimated placebo-adjusted 
ΔQTc 
Scatter plot of placebo-adjusted ∆QTc versus 
concentration with linear mixed-effects 
regression line and 90% CI of ΔΔQTc 
(Section 6.3). Referred to above as “Scatter plot 
for concentration-QTc model(s).” 
14.2.10.1 
Model-predicted ΔΔQTc (mean 
and 90% CI) and estimated 
placebo-adjusted ΔQTc (mean and 
90% CI) across deciles of LOXO-
305 plasma concentrations 
Section 6.2. Referred to above as “Quantile 
plots.” 
14.2.10.2 
Model-predicted ΔΔQTc (mean 
and 90% CI) and estimated 
placebo-adjusted ΔQTc (mean and 
90% CI) across deciles of 
moxifloxacin plasma 
concentrations  
Section 6.3. Referred to above as “Quantile 
plots.” 
14.2.11.1 
Model-predicted ΔΔQTc interval 
at geometric mean peak LOXO-
305 concentrations 
Section 6.2. Referred to above as “Prediction 
plots.” 
14.2.11.2 
Model-predicted ΔΔQTc interval 
(mean and 90% CI) at geometric 
mean peak moxifloxacin 
concentrations  
Section 6.3. Referred to above as “Prediction 
plots.” 
14.2.12.1 
Scatter plot of standardized 
residuals versus fitted values for 
LOXO-305 
Section 6.2.2.  
14.2.12.2 
Scatter plot of standardized 
residuals versus fitted values for 
moxifloxacin 
Section 6.3. 


 
 
 
 
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Number 
Title 
Comments 
14.2.13.1 
Scatter plot of standardized 
residuals versus concentrations 
with LOESS for LOXO-305 
Section 6.2.2.  
14.2.13.2 
Scatter plot of standardized 
residuals versus concentrations 
with LOESS for moxifloxacin 
Section 6.3. 
14.2.14.1 
Scatter plot of standardized 
residuals versus centered baseline 
QTc with LOESS for  LOXO-305 
Section 6.2.2.  
14.2.14.2 
Scatter plot of standardized 
residuals versus centered baseline 
QTc with LOESS for 
moxifloxacin 
Section 6.3. 
14.2.15.1 
Box plot of standardized residuals 
versus nominal time for LOXO-
305 
Section 6.2.2.  
14.2.15.2 
Box plot of standardized residuals 
versus nominal time for 
moxifloxacin 
Section 6.3. 
14.2.16.1 
Box plot of standardized residuals 
versus treatment for LOXO-305 
Section 6.2.2.  
14.2.16.2 
Box plot of standardized residuals 
versus treatment for moxifloxacin 
Section 6.3. 
14.2.17.1 
Normal Q-Q plot of standardized 
residuals for LOXO-305 
Section 6.2.2.  
14.2.17.2 
Normal Q-Q plot of standardized 
residuals for moxifloxacin 
Section 6.3. 
14.2.18.1 
Normal Q-Q plots of the estimated 
random effects for LOXO-305 
Section 6.2.2.  
14.2.18.2 
Normal Q-Q plots of the estimated 
random effects for moxifloxacin 
Section 6.3. 


 
 
 
 
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8.3 Listings 
Number 
Title 
Comments 
16.2.1.1-
16.2.1.10 
QTcF (and QTcI in 5 ways and QTcS 
if calculated), HR, PR, and QRS 
intervals - observed and change-from-
baseline values as well as categorical 
outliers 
Sections 6.4 and 6.5. 
16.2.2 
T-wave morphology and U-wave 
presence  
Section 6.6. 
16.2.3 
ΔQTc and time-matched LOXO-305 
and moxifloxacin concentrations for 
each subject  
Data for concentration-QTc analysis 
(Section 6.2) and assay sensitivity (Section 6.3). 
 
 
 


 
 
 
 
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9 Approvals 
ERT 
Date 
Date 
Date 
 
 
 
 
 
02-Mar-21 | 07:50:25 GMT
01-Mar-21 | 22:26:47 GMT
01-Mar-21 | 14:59:28 PST
PPD
PPD
PPD


 
 
 
 
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Appendix A: Early Precision QT Analysis 
Twelve-lead ECGs will be extracted in up to 10 replicates from each nominal time point pre-
specified in the protocol. The median value of each parameter from the set of evaluable beats in 
each extracted replicate will be calculated, and then the mean of all available medians (minimum 
3 medians) from the nominal time point will be used as the subject’s reportable value at that time 
point. 
Early Precision QT analysis (formerly High Precision QT analysis) will be performed on all 
analyzable (non-artifact) beats in the 10 ECG replicates (1 replicate consists of one 14 second 
ECG). Statistical quality control procedures will be used to review and assess all beats and 
identify “high” and “low” confidence beats using several criteria including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
• RR values exceeding or below certain thresholds (biologically unlikely) 
• Rapid changes in QT, QTc, or RR from beat to beat 
Placement of fiducials and measurements of all primary ECG parameters (QT, QTc, RR) in all 
recorded beats of all replicates will be performed using the iCOMPAS software. All beats that 
are deemed “high confidence” will not be reviewed by an ERT ECG analyst. All low confidence 
beats will be reviewed manually by an ERT ECG analyst and adjudicated using pass-fail criteria. 
The beats found acceptable by manual review will be included in the analysis. The beats 
confirmed to meet fail criteria will not be included in the analysis. 
For the purpose of measuring PR and QRS intervals and to assess T-wave morphology and 
presence of U-waves, the TQT Plus algorithm will select the 3 ECG replicates with the highest 
quality score from the ECG extraction window. These 3 ECGs will be analyzed using a semi-
automated process to determine these parameters. If 3 consecutive usable beats cannot be 
identified in at least 2 of the 3 replicates, then all beats in all replicates will be reviewed for that 
time point using a manual analysis. 
If manual analysis is required, then all beats in a minimum of 3 replicates will be reviewed using 
the iCOMPAS software. The ERT ECG analyst will review all usable beats in Lead II (or an 
alternate lead) for each replicate and will review and/or adjust the fiducial placements (onset of 
P, onset of Q, offset of S, and offset of T-wave that were electronically marked) of each 
waveform and also document the T-wave morphology and the presence of U-waves for each 
beat. A replicate will only be reported if it has 3 approved, usable beats.