Clinical trial NCT05906732
Conditions: Long QT Syndrome
Keywords: LQT-1213 Congenital Long QT Syndrome LQTS Serum glucocorticoid regulated kinase-1 SGK-1 inhibitor Drug induced long QT
Sponsor: Thryv Therapeutics, Inc.
Start date: 2023-03-12; Completion date: 2024-05-31
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Part 1: This is a Phase 1b, randomized, double-blind, crossover, dose escalation, placebo-controlled study to evaluate the effect of oral LQT-1213 on dofetilide-induced QTc prolongation in healthy adult subjects. This is a 2-treatment, 2-period crossover study with approximately up to 28 healthy subjects, with screening procedures within 28 days of enrolment.

Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to evaluate the safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT2 or LQT3. Up to 12 participants with LQT2 and up to 12 participants with LQT3 will be recruited.

Detailed description:
Part 1: This is a 2-treatment, 2-period crossover study. Approximately 28 healthy subjects, with the attempt to balance for sexes, will be enrolled to complete approximately up to 20 subjects in the study. In both treatment periods, all subjects will receive dofetilide on Days 1 and 2 of each period. Randomization will take place before Day 3 of Period 1. Subjects will be randomly assigned to 1 of 2 treatment sequences (AB or BA).

Part 2: Up to 12 participants with LQT2 and up to 12 participants with LQT3 will be enrolled. After initial screening, which may be conducted remotely by the CRU, individual participants with LQT2 or LQT3 will undergo a 1-day, single-blind placebo run-in period followed by 3 dosing days of LQT-1213 administered TID (the last dosing day will have a single dose). Participants will be discharged from the CRU on Day 5. Approximately 7 days after discharge from the CRU, the Follow-up Visit will be conducted remotely via telephone call.

Arms: arm 1: Sequence A :Dofetilide 500 μg BID (Days 1-8) and LQT-1213 TID 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8. After adequate washout, Dofetilide 500 μg BID (Days 1-8) and placebo (Days 3-8). arm 2: Sequence B : Dofetilide 500 μg BID, orally (Days 1-8) and placebo TID (Days 3-8). After adequate washout, Dofetilide 500 μg BID, orally (Days 1-8) and LQT-1213 3 times a day (TID) 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8. arm 3: LQT-1213 16 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo. arm 4: LQT-1213 7 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.
Interventions: intervention 1: LQT-1213 intervention 2: Placebo intervention 3: Dofetilide 250 μg Cap
Intervention descriptions: intervention 1: LQT-1213 is a serum glucocorticoid regulated kinase 1 (SGK-1) inhibitor intervention 2: Matching Placebo intervention 3: Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
NCT Number: NCT05906732 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Title: A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, 
Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 
Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in 
Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study 
to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in 
Patients Diagnosed With Type 2 or 3 Long QT Syndrome 
 
 
 
 
 
Study Number: LQT-1213 061  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, 
Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc 
Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, 
Multiple-Dose, Safety Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed 
With Type 2 or 3 Long QT Syndrome 
PROTOCOL NO. LQT-1213-0061 
 
Name of Drug: 
LQT-1213 
Sponsor: 
Thryv Therapeutics Inc. 
999 Blvd. De Maisonneuve West 
Suite 1250 
Montreal, Québec 
 
Medical Monitor: 
Pirouz Shamszad, MD 
Thryv Therapeutics Inc. 
Telephone: 732-354-1563  
Email: pirouz@thryvtrx.com 
Version: 
7.0 
Date: 
05 December 2023 
 
Good Clinical Practice Statement 
This study will be conducted in compliance with the protocol, the International Council for 
Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice, and the applicable 
regulatory requirement(s). 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the express written 
consent of Thryv Therapeutics Inc. 


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Sponsor Signature Page 
 
Protocol Title: 
A Phase 1b/2a, 2-Part Study; Part 1: Randomized, 
Double-Blind, Crossover, Dose-Escalation, 
Placebo-Controlled Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase 
Inhibition by LQT-1213 on Dofetilide-Induced QTc 
Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, 
Multiple-Dose, Safety Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LQT-1213 in Patients 
Diagnosed With Type 2 or 3 Long QT Syndrome 
Protocol Number: 
LQT-1213-0061 
 
The undersigned have reviewed the format and content of this protocol and approve 
issuance of the document. 
 
 
 
 
 
(signed) 
 
 
 
Douglas WightXX 
Vice President of Drug Development 
Thryv Therapeutics Inc. 
 
Date 
08-Dec-2023 
 
 
 
 
 
 
(signed) 
 
 
 
Philip Sager, MD, FACC, FAHA, FHRS 
Chief Medical Officer 
Thryv Therapeutics Inc. 
 
Date 
08-Dec-2023 


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Investigator Signature Page 
I agree to conduct the study as outlined in the protocol entitled “A Phase 1b/2a, 2-Part 
Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, 
Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced 
QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, 
Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 
in Patients Diagnosed With Type 2 or 3 Long QT Syndrome” in accordance with the 
guidelines and all applicable government regulations including United States Title 21 
of the Code of Federal Regulations Part 54. I have read and understand all sections of 
the protocol. 
 
 
 
(signed) 
 
 
Jan Matousek, DO 
Principal Investigator 
 
Date 
08-Dec-2023 


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Table of Contents 
1. 
Protocol Synopsis .......................................................................................................... 16 
2. 
List of Abbreviations ..................................................................................................... 35 
3. 
Introduction ................................................................................................................... 38 
3.1. 
Background ....................................................................................................... 38 
3.2. 
Summary of LQT-1213 Nonclinical Development .......................................... 39 
3.3. 
Summary of LQT-1213 Preclinical Cardiovascular Safety ............................... 41 
3.4. 
Dose Rationale .................................................................................................. 42 
3.4.1. Part 1 ..................................................................................................... 42 
3.4.2. Part 2 ..................................................................................................... 42 
3.5. 
Dofetilide ........................................................................................................... 42 
3.6. 
Study Rationale ................................................................................................. 43 
3.6.1. Part 1 ..................................................................................................... 43 
3.6.2. Part 2 ..................................................................................................... 43 
4. 
Study Objectives ............................................................................................................ 44 
4.1. 
Part 1 ................................................................................................................. 44 
4.2. 
Part 2 ................................................................................................................. 44 
5. 
Investigational Plan ....................................................................................................... 45 
5.1. 
Study Design ..................................................................................................... 45 
5.1.1. Part 1 ..................................................................................................... 45 
5.1.2. Part 2 ..................................................................................................... 48 
5.1.3. Safety Review Committee .................................................................... 50 
5.2. 
Selection of Study Population ........................................................................... 51 
5.2.1. Inclusion Criteria .................................................................................. 51 
5.2.2. Exclusion Criteria ................................................................................. 54 
5.3. 
Withdrawal of Subjects from the Study ............................................................ 59 
5.3.1. Reasons for Withdrawal ........................................................................ 59 
5.3.2. Handling of Withdrawals ...................................................................... 60 
5.3.3. Stopping Criteria for Individual Subjects ............................................. 60 
5.3.4. Stopping Criteria for the Study ............................................................. 63 
5.3.5. Replacement Subjects. .......................................................................... 63 
5.4. 
Study Procedures. .............................................................................................. 63 
5.4.1. Pharmacodynamic Assessments ........................................................... 64 
5.4.2. Pharmacokinetic Assessments .............................................................. 64 
5.4.3. Safety Assessments ............................................................................... 65 
5.4.4. Demographics, Medical History, and Other Baseline Assessments ..... 79 
5.4.5. Documentation of Concomitant Medications ....................................... 79 
5.4.6. Total Blood Volume ............................................................................. 80 
5.5. 
Study Treatments ............................................................................................... 80 


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5.5.1. Method of Assigning Subjects to Treatment Groups ........................... 80 
5.5.2. Treatments Administered ...................................................................... 81 
5.5.3. Identity of Study Drug .......................................................................... 82 
5.5.4. Management of Clinical Supplies ......................................................... 83 
5.5.5. Blinding ................................................................................................ 84 
5.5.6. Treatment Compliance .......................................................................... 85 
5.5.7. Prior and Concomitant Medications ..................................................... 85 
5.5.8. Diet, Fluid, Activity Control, and Subject Housing ............................. 87 
5.6. 
Statistical Analysis Plan .................................................................................... 88 
5.6.1. Sample Size Considerations.................................................................. 90 
5.6.2. Analysis Populations ............................................................................. 90 
5.7. 
Statistical Analyses ........................................................................................... 91 
5.7.1. Pharmacodynamic Analyses ................................................................. 91 
5.7.2. Pharmacokinetic Analyses .................................................................... 93 
5.7.3. Safety Analyses .................................................................................... 94 
5.7.4. Pharmacodynamic Biomarker Analyses ............................................... 96 
5.7.5. Pharmacokinetic/Pharmacodynamic Analyses ..................................... 96 
5.8. 
Data Quality Assurance ..................................................................................... 96 
6. 
Investigator’s Obligations .............................................................................................. 96 
6.1. 
Confidentiality ................................................................................................... 97 
6.2. 
Institutional Review .......................................................................................... 97 
6.3. 
Subject Consent ................................................................................................. 98 
6.4. 
Study Reporting Requirements .......................................................................... 99 
6.5. 
Financial Disclosure and Obligations ................................................................ 99 
6.6. 
Investigator Documentation .............................................................................. 99 
6.7. 
Study Conduct ................................................................................................. 100 
6.8. 
Data Management ........................................................................................... 100 
6.8.1. Case Report Forms and Source Documents ....................................... 100 
6.9. 
Adherence to the Protocol ............................................................................... 100 
6.10. Reporting Adverse Events ............................................................................... 100 
6.11. Investigator’s Final Report .............................................................................. 101 
6.12. Records Retention ........................................................................................... 101 
6.13. Publications ..................................................................................................... 101 
7. 
Study Management ...................................................................................................... 101 
7.1. 
Monitoring ....................................................................................................... 101 
7.1.1. Monitoring of the Study ..................................................................... 102 
7.1.2. Inspection of Records ......................................................................... 102 
7.2. 
Management of Protocol Amendments and Deviations .................................. 102 
7.2.1. Modification of the Protocol ............................................................... 102 
7.2.2. Protocol Deviations ............................................................................ 102 


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7.3. 
Study Termination ........................................................................................... 103 
7.4. 
Final Report ..................................................................................................... 103 
8. 
Appendices .................................................................................................................. 104 
8.1. 
Appendix A: Schedule of Events – Part 1 ....................................................... 104 
8.2. 
Appendix B: Schedule of Events – Part 2 ....................................................... 107 
8.3. 
Appendix C: Pharmacokinetic and Pharmacodynamic Time Points - Part 1 . 109 
8.4. 
Appendix D: Pharmacokinetic and Pharmacodynamic Time Points – Part 2. 112 
8.5. 
Appendix E: Responsibilities of the Investigator ............................................ 115 
9. 
Reference List ............................................................................................................. 116 
 
List of Tables 
Table 5-1 Clinical Laboratory Tests – Part 1 .................................................................... 74 
Table 5-2 Clinical Laboratory Tests – Part 2 .................................................................... 76 
 
List of Figures 
Figure 5-1 Study Schematic - Part 1 ................................................................................... 48 
Figure 5-2 Study Schematic - Part 2 ................................................................................... 50 


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Protocol Amendment Summary of Changes Tables 
Note: Only major changes to the protocol are presented in this summary of changes. 
Administrative changes have been made throughout the document to reflect changes in 
version number and date of issue. Corrections of minor typographical errors and 
inconsistencies, grammar, or formatting changes are not listed here. 
 
DOCUMENT HISTORY 
Document 
Date 
Original 
14 February 2023 
Amendment 1, Version 2.0 
02 March 2023 
Amendment 2, Version 3.0 
10 March 2023 
Amendment 3, Version 4.0 
17 March 2023 
Amendment 4, Version 5.0 
20 June 2023 
Amendment 5, Version 6.0 
29 September 2023 
Amendment 6, Version 7.0 
05 December 2023 
Amendment 1, Version 2.0 (02 March 2023): 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 (Synopsis), Section 3.4 
(Dose Rationale), Section 5.1 
(Study Design), Section 5.5.1 
(Method of Assigning Subjects to 
Treatments), Section 5.5.2 
(Treatments Administered), 
Section 5.5.3 (Identity of Study 
Drug), Section 5.5.4 
(Management of Clinical 
Supplies) 
Updated the wording in the body 
of the protocol for the 
low/mid/high dosing to match the 
details in Section 8.1 
(Appendix A: Schedule of Events, 
footnote m) 
To address 
inconsistencies in the 
original protocol 
Section 1 (Synopsis), Section 3.6 
(Study Rationale) 
Revised the washout between 
doses to 5 times the half-life, 
which was shortened to at least 
4 days 
To clarify and take 
into account the 
half-life of 
LQT-1213 
Section 1 (Synopsis), Section 5.1 
(Study Design), Section 5.5.1 
(Method of Assigning Subjects to 
Treatment Groups), Section 8.1 
(Appendix A: Schedule of 
Events) 
Revised randomization to take 
place before Day 3 of Period 1 
To provide flexibility 
in the randomization 
language to clarify 
that randomization 
will take place before 
Day 3 of Period 1 


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Section 1 (Synopsis), Section 2 
Added the collection of samples 
To provide an 
(List of Abbreviations), 
for assessment of human 
exploratory endpoint 
Section 4.3 (Exploratory 
peripheral blood mononuclear 
of cell activation by 
Objectives), Section 5.1 (Study 
cells 
LQT-1213 
Design), Section 5.4.1.3 
 
 
(Human Peripheral Blood 
 
 
Mononuclear Cell Collection), 
 
 
Section 5.7.4 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
(Pharmacokinetic/ 
Pharmacodynamic Analyses), 
Section 8.1 (Appendix A: 
Schedule of Events), Section 
8.2 (Appendix B: 
Pharmacokinetic and 
Pharmacodynamic Time 
Points) 
 
 
Section 8.1 (Appendix A: 
Schedule of Events) 
Updated footnote f to change 
Hour 6 to Hour 15 
For consistency with 
changes made in 
Section 8.2 
Section 8.2 (Appendix B: 
Pharmacokinetic and 
Pharmacodynamic Time 
Points) 
• Day 1: Added 
electrocardiogram (ECG) 
extraction at 5 and 6 hours, 
removed the 6-hour safety ECG, 
and added a safety ECG at 
15 hours 
• Day 2: Added safety ECGs at 3 
and 15 hours and removed the 
8.5-hour time point row 
• Day 3: Separated from Days 4-8 
and added 15- and 24-hour time 
points for safety ECGs and ECG 
extractions 
• Days 4-8: Added 4- and 24-hour 
PK time points and removed the 
6-hour pharmacokinetic time 
point 
Updated footnote c to change 
Hour 6 to Hour 15 
To ensure subject 
safety and provide 
clarity 
Amendment 2, Version 3.0 (10 March 2023): 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 (Synopsis), 
Section 5.2.2. (Exclusion Criteria) 
Revised Exclusion Criterion #8 
for 12-lead ECGs to occur at 
Screening and on Day –2, updated 
time from the onset of the P wave 
to the start of the QRS complex 
(PR) interval to >240 ms and QT 
interval corrected for heart rate by 
Fridericia’s formula (QTcF) 
interval to <400 ms, and added if 
heart rate <50 or >85 bpm, then 
2 more ECGs will be recorded and 
the mean values will be used 
To clarify 12-lead 
ECG exclusion 
criterion 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1 (Synopsis), Section 
5.1 (Study Design), Section 
5.2.2 (Exclusion Criteria), Table 
5-1 (Clinical Laboratory Tests), 
Section 8.1 (Appendix A: 
Schedule of Events -footnote i) 
Added that electrolyte 
supplementation is allowed at any 
time as long as it is >4 hours 
before dosing but preferred, 
especially on Days 1, 4, 6, and 8, 
that this be done in the evening 
(after the 12-hour time point) 
To clarify the timing 
for when electrolyte 
supplementation is 
allowed 
Section 1 (Synopsis), Section 
5.1 (Study Design), Section 
5.5.2 (Treatments Administered) 
Clarified that the high dose should 
not exceed 0.747 mg/kg 3 times a 
day (TID) 
To clarify the high 
dose frequency 
Section 1 (Synopsis), Section 5.1 
(Study Design), Figure 5-1 
(Study Schematic – Part 1), 
Section 5.2.2 (Exclusion 
Criteria), Section 5.3.2 (Stopping 
Criteria or Dose Adjustment for 
Individual Subjects), Section 8.2 
(Appendix B: Pharmacokinetic 
and Pharmacodynamic Time 
Points -footnote b) 
Clarified that on Day 1 at 3 hours 
postdose the QTcF will be 
measured in the 3 ECGs and the 
mean value calculated in Period 1 
only 
To clarify QTcF will 
be measured on 
Day 1 at 3 hours 
postdose in Period 1 
only 
Section 1 (Synopsis), Section 5.1 
(Study Design), Figure 5-1 
(Study Schematic – Part 1), 
Section 5.2.2 (Exclusion 
Criteria), Section 5.3.1 (Reasons 
for Withdrawal), Section 5.3.2 
(Stopping Criteria or Dose 
Adjustment for Individual 
Subjects), Section 5.3.3 (Stopping 
Criteria for the Study), 
Section 5.4.3.5 (Safety 12-Lead 
Electrocardiograms), Section 
5.5.2 (Treatments Administered), 
Section 8.2 (Appendix B: 
Pharmacokinetic and 
Pharmacodynamic Time Points) 
Revised ECG criteria, stopping 
criteria, and dose adjustments to 
remove semiautomatic 
measurements at baseline and on 
Day 1 at 3 hours and to further 
clarify these criteria in Period 1 
To clarify ECG 
criteria in Period 1 
Section 1 (Synopsis), 
Section 5.1 (Study Design) 
Added that LQT-1213 or placebo 
matched to LQT-1213 dosing time 
points may be adjusted based upon 
emerging data 
To allow for 
adjustment to dosing 
based on emerging 
data 
Section 1 (Synopsis), 
Section 5.1 (Study Design) 
Removed that dofetilide dosing 
will be consistent, including 
dose-down titration, with the 
label 
To be consistent with 
revised stopping 
rules 
Section 5.3.3 (Stopping Criteria 
for the Study) 
Revised stopping criteria to 
include documented Torsade de 
Pointes 
To provide additional 
detail for this 
criterion 
Section 5.4.3.2.1 (Reporting of 
Serious Adverse Events) 
Updated sponsor study physician 
contact information 
To provide sponsor 
study physician text 


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Section # and Name 
Description of Change 
Brief Rationale 
 
 
number 
Section 5.5.2 (Treatments 
Administered) 
Added time points for first and 
second doses 
To provide additional 
details for dosing 
Section 5.7.1.1 (Categorical 
Analyses) 
Added a categorical analysis 
criterion for change from 
baseline in QTc (ΔQTc) from 
dofetilide/placebo reduction and 
updated the ΔQTc categorical 
analysis criterion from ΔQTc to 
ΔQTc from baseline 
To clarify the ΔQTc 
categorical analyses 
criteria 
Section 8.1 (Appendix A: 
Schedule of Events) 
Added continuous telemetry with 
corresponding footnote p and 
updated footnote e to change 
Hour 6 to Hour 15 
For consistency with 
changes made in 
Section 8.2 
Amendment 3, Version 4.0 (17 March 2023): 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 (Synopsis), Section 5.1 
(Study Design), Section 5.3.2 
(Stopping Criteria or Dose 
Adjustment for Individual 
Subjects), Section 8.2 (Appendix 
B: Pharmacokinetic and 
Pharmacodynamic Time Points- 
footnote b), Section 5.3.1 
(Reasons for Withdrawal – Note) 
Clarified that the 6 ECGs 
measurements on Day 1 at 3 hours 
postdose the QTcF will be 
captured as 3 (triplicate) repeated 
ECGs and the mean value 
calculated in Period 1 
To clarify that 3 
(triplicate) repeated 
ECG measurements 
will be taken 
Section 1 (Synopsis), Section 5.1 
(Study Design) 
Removed the light meal start and 
stop times 
To ensure consistent 
fasting times across 
subjects 
Section 5.5.1 (Method of 
Assigning Subjects to Treatment 
Groups), Section 5.5.3 (Identity 
of Study Drug) 
Specified that placebo will consist 
of the sugar-free Gatorade™ and 
cornstarch 
Update the placebo 
treatment to align 
with the 
investigative product 
Amendment 4, Version 5.0 (20 June 2023): 
Section # and Name 
Description of Change 
Brief Rationale 
All applicable sections 
Global change to add Part 2, 
specify what was applicable for 
Part 1 only, and what was 
applicable for both Parts 1 and 
2 
Part 2 is a safety and 
PK study in subjects 
with Long QT 
Syndrome 2 or 3 
Section 1 (Synopsis), Section 4 
(Study Objectives), 
Section 5.4.1.3 (Human 
Peripheral Blood Mononuclear 
Cell Collection), Section 8.1 
(Appendix A: Schedule of 
Events – Part 1), and 
Section 8.2 (Appendix B: 
Schedule of Events – Part 2) 
Removed exploratory objective 
from Part 1 and moved it to Part 2 
Samples were not 
collected in Part 1 
and deemed more 
feasible for Part 2 


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All applicable sections 
Global update of title and text to 
update multiple-dose escalation to 
multiple dose and patients 
diagnosed with LQT-2 
To align with 
change in study 
design 
Section 3.1 (Background) 
Added preclinical data 
Updated 
background 
information 
Section 3.2 (Summary of LQT- 
1213 Nonclinical Development) 
Revised cellular assay data; added 
blood pressure data 
Updated 
nonclinical 
information 
Section 5.3.5 (Replacement 
Subjects) 
Specified that participants 
discontinued form the study due 
to drug-related hepatic AESIs will 
not be replaced 
To provide clarity 
Section 1 (Synopsis), 
Section 5.4.3 (Safety 
Assessments), Section 5.4.3.3 
(Clinical Laboratory Tests- 
Part 2) 
Coagulation added as a safety 
endpoint for Part 2 
To ensure subject 
safety and provide 
clarity 
Section 5.4.3 (Safety 
Assessments) 
Added Continuous telemetry 
ECG monitoring for Part 2 
To provide more 
stringent safety 
requirement 
Section 5.4.3.1.3 (Adverse 
Events of Special Interest) 
Added Adverse Events of Special 
Interest Section 
To include Hepatic 
AEs as AEs of 
special interest for 
Part 2 
Section 6.3 (Subject Consent) 
Added that ICFs may be in paper 
or electronic forms and that 
original paper ICFs will be 
retained if used 
To clarify ICF 
formats and 
handling of paper 
ICFs 
Section 6.6 (Investigator 
Documentation) 
Investigator documentation text 
added 
Omitted from 
previous amendment 
in error 
Amendment 5, Version 6.0 (29 September 2023): 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 (Synopsis), 
Section 5.4.1.2 (Pharmacodynamic 
Assessments -Part 2), 
Section 5.6.2.2 (Analysis 
Populations), Section 5.7.1.2 
(Pharmacodynamic Analyses - 
Part 2) 
Text relevant to pharmacodynamic 
ECG endpoint, assessments and 
analyses, and population were 
removed and sections updated text 
relative to human PBMCs and 
SGK-1 protein target was added 
SGK-1 data is more 
relevant to the target 
population 
Section 1 (Synopsis), 
Section 5.2.1.2 (Inclusion Criteria 
– Part 2) 
Removed upper age limit in 
Inclusion Criteria #1 
To reflect the target 
population 
Section 1 (Synopsis), 
Section 5.2.1.2 (Inclusion Criteria 
– Part 2) 
Removed Criteria #2 that 
participant must not have 
previously been enrolled in the 
clinical study with LQT-1213 
Requirement is more 
relevant to first-in- 
human studies 


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Section 1 (Synopsis), 
Section 5.2.1.2 (Inclusion Criteria 
– Part 2) 
Removed BMI requirement in 
new Inclusion Criteria #2 
Minimum weight of 
45 kg is sufficient for 
this target population 
Section 1 (Synopsis), 
Section 5.2.1.2 (Inclusion Criteria 
– Part 2) 
Revised new Inclusion 
Criterion #7 to update QTcF 
values to have “or equal to” 
symbols (ie, QTcF interval 
≥480 and ≤560 ms) 
Correction from 
previous protocol 
versions 
Section 1 (Synopsis), 
Section 5.2.1.2 (Inclusion Criteria 
– Part 2) 
Revised new Inclusion 
Criterion #6 to stipulate that in 
addition to screening, historical 
documentation, if available 
may be used for consideration 
of LQTS2 or LQTS 3 
pathology or likely pathology 
To allow additional 
data for pathology or 
likely pathology 
consideration 
Section 1 (Synopsis), 
Section 5.2.1.2 (Inclusion 
Criteria – Part 2) 
Revised new Inclusion Criterion 
#8 to note that this stipulation 
may be altered upon agreement 
between the principal investigator 
and Sponsor based on emerging 
data 
To allow 
flexibility based 
emerging data 
All applicable sections in 
Part 2 
Global change from BID (time 
points 0 and 11.5 hour) dosing to 
TID (0, 8, and 16 hour) dosing. 
Change in study 
design 
All applicable sections in 
Part 2 
Global change to remove all ECG 
analysis until possibly after 
database lock 
 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Updated Exclusion Criterion #7 
to note blood volume donation 
greater than 300 mL should not 
occur within 30 days before 
dosing rather than before 
Screening 
Correction from 
previous protocol 
versions 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Updated Exclusion Criterion #9 
heart rate limits to <45 bpm and 
>95 bpm 
Updated limits 
sufficient for 
study design and 
target population 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Updated Exclusion Criterion #9 
to clarify that ‘2 or more ECGs’ 
text should be updated to describe 
a second set of triplicate ECGs 
Text updated for 
clarity 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Combined Exclusion Criteria #12 
and 18 and renumbered list 
accordingly 
Simplification 
purposes 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Added ECG electrodes to new 
Exclusion Criteria #18 
To reflect 
adhesive items 
planned for use in 
the study 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Updated new Exclusion 
Criteria #21 to remove 
Applicable to 
Part 1 objectives 


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Criteria – Part 2) 
cruciferous vegetables and 
charbroiled meats restriction 
not Part 2 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Updated new Exclusion 
Criteria #21 to restrict oranges, 
grapefruit and/or grapefruit juice 
consumption from within 14 days 
to 7 days before Check-in 
Sufficient given 
the objectives for 
Part 2 
Section 1 (Synopsis) and 
Section 5.2.2.2 (Exclusion 
Criteria – Part 2) 
Removed Exclusion Criteria #27 
to all smokers to be included in 
the study. The principal 
investigator will retain discretion 
to exclude based on judgement 
To reflect 
LQT-1213 
limited drug-drug 
interaction 
potential. 
Section 1 (Synopsis), 
Section 5.5.2.2 (Treatments 
Administered – Part 2), and 
Section 5.5.8.2 (Diet, Fluid, 
Activity Control, and Subject 
Housing – Part 2) 
Updated meal and fasting 
requirements and present 
requirements only in 
Section 5.5.8.2 
To align with 
updated study 
design and 
correct 
duplicative text 
Section 1 (Synopsis – ECG 
and QT/QTc Analyses), 
Section 5.1.2 (Study Design – 
Part 2), Section 5.4.3.5.2 
(Safety 12-Lead ECG – 
Part 2), and Section 5.7.1.2 
(Pharmacodynamic Analyses – 
Part 2) 
Removed text specifying ECG 
analysis to be done by Clario at 
study conclusion and replaced 
with text specifying that all ECG 
data will be stored for potential 
future analysis by Clario and 
specify that all Thryv staff will be 
fully blinded to all Part 2 
postdose ECG data until database 
lock 
To allow 
flexibility on 
timing of Clario 
ECG analysis and 
reduce study bias. 
Section 3.2 (Summary of 
LQT-1213 Nonclinical 
Development 
Nonclinical text was updated 
To reflect 
updated 
nonclinical data 
Section 5.1.3 (Safety Review 
Committee) 
Added chief medical officer to 
the individuals comprising the 
SRC at a minimum and updated 
text to specify data to include any 
available PK, PD, or safety data. 
To ensure 
relevant 
stakeholders 
included in 
discussion 
Table 5-2 Clinical Laboratory 
Tests – Part 2 
Text updated to specify that 
serum pregnancy tests are to be 
conducted for females of 
childbearing potential instead of 
all female participants. 
Serum pregnancy 
tests not 
necessary for 
postmenopausal 
female 
participants 
Section 5.4.1.2 
(Pharmacodynamic 
Assessments – Part 2) 
Continuous 12-Lead ECG 
Acquisition heading was removed 
To reflect that 
safety is the 
primary objective 
Section 5.4.3.6.2 (Physical 
Examinations – Part 2) 
Day −1 was removed for height 
measurement. 
Not needed as 
height will be 
captured at 
Screening 


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Section 5.7.1.3.2 (Categorical 
Analyses – Part 2) 
Removed categorical analysis 
To align with 
updated study 
design 
Appendix B (Schedule of 
Schedule of events, PK, PD, and 
To align with 
Events – Part 2) and 
meal assessments updated 
updated study 
Appendix D (PK, PD, and 
 
design 
Meal Time Points – Part 2) 
 
 
 
 
 
Amendment 6, Version 7.0 (05 December 2023): 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1 (Synopsis), Study 
Design Part 2, Section 5.4.3.5 Part 
2, and Section 5.5.5.2 Part 2 
Removed sentence requiring 
the study blind 
Thryv staff will not be
blinded 
to 
Part 
2
postdose ECG data
prior to database lock,
which aligns with the
single-blind 
study
design. 
Section 1 (Synopsis), Part 2 
Exclusion criteria #9 and 
Section 5.2.2.2. Part 2 
Exclusion criteria #9 
Adding allowance for sponsor 
and investigator approval for PR 
interval in participants on beta 
blockade 
Given beta 
blockade can 
confound PR 
interpretation, 
allowance made 
for sponsor and 
investigator to 
review PR. 
Section 8.4: Appendix D: 
Pharmacokinetic and 
Pharmacodynamic, and Meal 
Time Points – Part 2: 
For Part 2; updated start of 
mealtime and updated ECG and 
ECG extraction times 
The start time of 
the mealtime 
period on Day 1 
Part 2 was 
updated to begin 
after all ECG 
collections are 
complete. 
Timepoints for 
collection of 12- 
lead ECGs and 
ECG extractions 
in Part 2 were 
updated, 
primarily to 
capture ECG 
information 
during the 
placebo period on 
Day 1. 


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1. 
Protocol Synopsis 
 
Title: 
A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, 
Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 
Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation 
in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
LQT-1213 in Patients Diagnosed With Type 2 or 3 Long QT Syndrome 
Phase of development: 
1b/2a 
Investigator: 
Jan Matousek, DO 
Study site: 
Spaulding Clinical Research, LLC, 525 South Silverbrook Drive, West 
Bend, WI 53095  
Objectives: 
Part 1 is a randomized, double-blind, crossover, dose-escalation, 
placebo-controlled study in 28 healthy adult subjects with the following 
objectives:  
• 
Primary: To evaluate the effect of oral LQT-1213 on 
dofetilide-induced QT interval corrected for heart rate (HR; QTc) 
prolongation in healthy adult subjects 
• 
Secondary: To evaluate the safety and tolerability of a combination 
of oral dofetilide and oral LQT-1213 in healthy adults 
• 
Secondary: To determine the pharmacokinetics (PK) of oral 
LQT-1213 and oral dofetilide in healthy adults 
Part 2 is a single-blind, multiple-dose study in up to 12 adult 
participants with Long QT Syndrome Type 2 (LQT/LQTS 2) and in up 
to 12 adult participants with Long QT Syndrome Type 3 
(LQT/LQTS 3) with the following objectives: 
• 
Primary: To evaluate the safety and tolerability of oral LQT-1213 in 
participants with LQT2 or LQT3 
• 
Secondary: To determine the PK of oral LQT-1213 in participants 
with LQT2 or LQT3 
• 
Exploratory: To evaluate the correlation between the PK of 
LQT-1213 and candidate serum- and glucocorticoid-regulated 
kinase-1 (SGK-1) protein targets in participant peripheral 
blood mononuclear cells (PBMCs) in order to derive 
PK/pharmacodynamic (PD) relationships between drug 
exposure and target engagement; additional exploratory PD 
endpoints may be assessed 
Endpoints: 
Part 1: 
Pharmacodynamic: The primary analysis will be the time-based 
comparison in the change from baseline (baseline defined as the Day 1 of 
Period 1 and Day 1 of Period 2 mean predose QTc) QTc by Fridericia’s 
formula (QTcF) during approximate peak dofetilide exposure as detailed 
in the statistical analysis plan (SAP) between dofetilide and placebo 
treatment, and the dofetilide and LQT-1213 treatment on Day 8 of each 
period with secondary endpoints on Days 4 and 6 of each period. If a 
substantial HR effect is observed, other correction methods such as QTc 
with individual correction (QTcI) and QTc with population correction 


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(QTcP) will be explored and compared, as will be detailed in the SAP. 
The primary correction method will be the one that removes the HR 
dependence of the QT interval most efficiently. 
Primary pharmacodynamic endpoints: 
• 
Dofetilide/placebo-corrected ΔQTcF (ΔΔQTcF) 
• 
Dofetilide/placebo-corrected ΔQTcI or ΔQTcP (ΔΔQTcI, ΔΔQTcP) 
if used as the primary correction method if a substantial HR effect is 
observed 
Secondary pharmacodynamic endpoints: 
• 
Change from baseline QTcF, HR, time from the onset of the P wave 
to the start of the QRS complex (PR), ventricular depolarization 
(QRS) intervals (ΔQTcF, ∆HR, ∆PR, and ∆QRS) 
• 
Dofetilide/placebo-corrected ΔHR, ΔPR, and ΔQRS (ΔΔHR, ΔΔPR, 
ΔΔQRS) 
• 
Exposure-response QTc analysis 
• 
Categorical outliers for QTcF (QTcI and QTcP if a substantial HR 
effect is observed), HR, PR, and QRS 
• 
Frequency of treatment-emergent changes of T-wave morphology 
and U-waves presence 
Pharmacokinetic: Plasma LQT-1213 and dofetilide PK endpoints will 
include the following: 
• 
AUC0-t: Area under the concentration-time curve (AUC) from time 0 
to the time of the last measurable concentration 
• 
AUCtau: AUC from time 0 to the end of the dosing interval 
• 
Cmax: Maximum observed plasma drug concentration 
• 
Tmax: Time to the maximum observed plasma concentration 
• 
t1/2: Terminal half-life 
• 
CLss/F: Apparent clearance at steady state 
• 
Vd/F: Apparent volume of distribution 
• 
λz: Apparent terminal rate constant 
Other PK parameters, as identified, agreed, and documented in the SAP. 
Safety: The safety and tolerability endpoints include: 
• 
Adverse events (AEs) monitoring, including clinically significant 
ECG abnormalities as determined by the investigator, recorded as 
AEs 
• 
Clinical laboratory tests results (hematology, serum chemistry, and 
urinalysis) 
• 
Vital sign measurements (including systolic and diastolic blood 
pressure, HR, respiratory rate, and oral temperature) 
• 
Physical examination findings 
Part 2: 
Safety: The safety and tolerability endpoints include: 
• 
Adverse events monitoring, including clinically significant ECG 
abnormalities as determined by the investigator, recorded as AEs 
• 
Clinical laboratory tests results (hematology, serum chemistry, 
coagulation, and urinalysis) 
• 
Vital sign measurements (including systolic and diastolic blood 
pressure, HR, respiratory rate, and oral temperature) 
• 
Physical examination findings 


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Pharmacokinetic: Plasma LQT-1213 PK endpoints will include the 
following: 
• 
AUC0-t, AUCtau, Cmax, Ctrough, Tmax, t1/2, CLss/F, Vd/F, λz 
Other PK parameters as identified and documented in the SAP. 
Pharmacodynamic: The exploratory PD (SGK-1 protein targets) 
endpoints and analyses will be detailed in a separate analysis 
document. 
Pharmacokinetic/Pharmacodynamic: The exploratory PK 
(LQT-1213)/PD (SGK-1 protein targets) endpoints and analyses to derive 
PK/PD relationships between drug exposure and target engagement will 
be detailed in a separate analysis plan. 
Number of subjects planned: 
Part 1: Approximately 28 healthy subjects, with the attempt to balance 
for sexes, will be enrolled to complete approximately up to 20 subjects in 
Part 1. Additional subjects may be enrolled in Part 1 to compensate for 
subjects that do not complete both treatment periods, at the discretion of 
the sponsor. The exact number will be determined during the conduct of 
the study. 
Part 2: Up to 12 participants with LQT2 and up to 12 participants 
with LQT3 will be recruited. 
Inclusion criteria: 
Part 1: All subjects considered for study participation must meet the 
following criteria: 
1. Male and female subjects between 18 and 60 years of age (inclusive) 
at Screening. 
2. 
Not previously enrolled in a clinical study with LQT-1213. 
3. 
Normal general health. 
4. 
Body mass index within 18.0 to 32.0 kg/m2, inclusively at Screening. 
5. Female subjects of nonchildbearing potential must be either 
surgically sterile (hysterectomy, bilateral tubal ligation, 
salpingectomy, and/or bilateral oophorectomy at least 26 weeks 
before Screening) or postmenopausal, defined as spontaneous 
amenorrhea for at least 2 years, with follicle-stimulating hormone in 
the postmenopausal range at Screening, based on the central 
laboratory’s ranges. 
6. Female subjects of childbearing potential (ie, ovulating, 
premenopausal, and not surgically sterile) must use a highly effective 
contraceptive regimen during their participation in the study and for 
30 days after the last administration of study drug. Highly effective 
contraceptive methods are defined as those with <1% failure rate per 
year. Acceptable methods of contraception for female subjects 
enrolled in the study include the following: 
• 
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, transdermal 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation: oral, injectable, implantable 
• 
Intrauterine device 


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• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Heterosexual abstinence 
7. Male subjects and their partners must use highly effective methods 
of contraception (ie, condom and spermicide) for the entire duration 
of the study. Male subjects must continue to use contraception and 
refrain from fathering a child and sperm donation for 90 days after 
the last administration of study drug. Acceptable methods of 
contraception for male subjects enrolled in the study include the 
following: 
• 
Condoms and spermicide 
• 
Surgical sterilization (vasectomy) of the subject at least 
26 weeks before Screening 
• 
Heterosexual abstinence (subject must agree to use condom and 
spermicide if they become sexually active) 
8. Understand the requirements of the study and voluntarily consent to 
participate in the study. 
Part 2: All participants with LQT2 or LQT3 considered for 
study participation must meet the following criteria: 
1. Male and female participants 18 years of age or older at Screening. 
2. 
Body weight of at least 45 kg at Screening. 
3. Female participants of nonchildbearing potential must be either 
surgically sterile (hysterectomy, bilateral tubal ligation, 
salpingectomy, and/or bilateral oophorectomy at least 26 weeks 
before Screening) or postmenopausal, defined as spontaneous 
amenorrhea for at least 2 years, with follicle-stimulating hormone in 
the postmenopausal range (>40 mlU/mL) at Screening, based on the 
central laboratory’s ranges. 
4. Female participants of childbearing potential (ie, ovulating, 
premenopausal, and not surgically sterile) must use a highly effective 
contraceptive regimen during their participation in the study and for 
30 days after the last administration of study drug. Highly effective 
contraceptive methods are defined as those with <1% failure rate per 
year. Acceptable methods of contraception for female participants 
enrolled in the study include the following: 
• 
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, transdermal 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation: oral, injectable, implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Heterosexual abstinence 
5. Male participants and their partners must use highly effective 
methods of contraception (ie, condom and spermicide) for the 
entire duration of the study. 


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Male participants must continue to use contraception and refrain 
from fathering a child and sperm donation for 90 days after the last 
administration of study drug. Acceptable methods of contraception 
for male participants enrolled in the study include the following: 
• 
Condoms and spermicide 
• 
Surgical sterilization (vasectomy) of the participant at 
least 26 weeks before Screening 
• 
Heterosexual abstinence (participant must agree to use condom 
and spermicide if they become sexually active) 
6. LQT2 or LQT3 mutation: 
• 
LQTS 2: Participants with potassium voltage-gated channel 
subfamily H member 2 (KCNH2) mutations that are dominant 
negative and considered to be pathologic or likely pathologic by 
the screening laboratory (or historical documentation, if 
available) can be included after approval from the sponsor. 
Participants with haploinsufficiency will not be eligible for this 
study. 
• 
LQTS 3: LQTS 3: Participants with a sodium 
voltage-gated channel alpha subunit 5 (SCN5A) gene 
chromosome 3 mutations that are considered to be pathologic or 
likely pathologic by the screening laboratory (or historical 
documentation, if available) can be included after approval 
from the sponsor. Participants with mutations associated with 
Brugada syndrome, overlap syndromes or where the effect of 
the mutations on the window current is the major effect without 
a substantial increase in the persistent ‘late’ Na current. 
7. QTcF interval ≥480 and ≤560 ms determined at Screening and on 
Day −1 triplicate ECGS as assessed by a physician trained in complex 
ECG interpretation. 
8. The first 2 participants with LQT2 require having an implantable 
cardioverter defibrillator (ICD) before further participants with 
LQT2 are enrolled and the first 2 participants with LQT3 require 
having an ICD before further participants with LQT3 are enrolled. 
This stipulation may be altered based on agreement between the 
principal investigator and Sponsor based on emerging data. The ICD 
implantation must have been at least 2 months before Screening. 
Note: Subsequent participants may or may not have had an ICD. The 
results of the ICD interrogation within the last 6 months should be 
available for review unless waived by the investigator and sponsor. 
9. Understand the requirements of the study and voluntarily consent to 
participate in the study. 


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Exclusion criteria: 
Part 1: Subjects will be excluded from the study if they meet any of the 
following criteria: 
1. On Day 1 at 3 hours postdose in Period 1 only, of the first cycle of 
dofetilide, the QTcF on the triplicate ECGs will be manually 
confirmed by cardiologist experienced in ECG interval 
measurements. The ECG measurements at baseline and at the 3-hour 
time points will be performed by the same technician and 
cardiologist. If the mean QTcF increase from baseline is <25 ms on 
triplicate safety ECGs compared to the mean from baseline (all ECG 
QTcF measurements averaged), the subject will be disqualified from 
further study participation. 
2. Clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, 
psychiatric, or cardiovascular disease or any other condition, which, 
in the opinion of the investigator, would jeopardize the safety of the 
subject or impact the validity of the study results. No history of 
myocardial infarction or angina or ischemic heart disease, 
nonsustained or sustained ventricular tachycardia, atrial fibrillation, 
stroke, transient ischemic attack, syncope, congestive heart failure, 
family history of LQTS, Torsades de Pointes, or sudden cardiac 
death. 


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3. Female subjects must not be pregnant, lactating, or breastfeeding, 
and must not be planning to become pregnant. 
4. Female subjects of childbearing potential must have a negative result 
for the serum pregnancy test at Screening and Check-in. 
5. Clinically significant abnormal findings on the physical examination 
or medical history during Screening as deemed by the investigator. 
6. Participated in a previous clinical study in the previous 3 months 
before dosing. 
7. Donation of blood volume greater than 300 mL within 30 days 
before Screening and agree to avoid donation from Screening and 
throughout the study. 
8. At Screening and on Day –2, if the 12-lead ECG demonstrates any of 
the following: PR >240 ms; QRS >110 ms, or QTcF <400 ms and 
>440 ms; second- or third-degree atrioventricular block; bundle 
branch block, significant ST-T wave abnormalities or flat T waves 
that could interfere with QT analysis. If HR <50 or >85 bpm, then 
2 more ECGs will be recorded, and the mean values will be used. 
9. 
Known sensitivity to kinase inhibitors. 
10. Abnormal renal function with an estimated glomerular filtration rate 
(eGFR) of <70 mL/min/1.73 m2, with eGFR calculated by the 
Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 
formula at Screening. One retest of the exclusionary eGFR value is 
allowed at the discretion of the investigator. 
11. Subject has abnormal liver function tests (transaminases or total 
bilirubin) greater than 2.5 × the upper limit of normal at Screening or 
baseline. One retest of exclusionary abnormal liver function tests is 
allowed at the discretion of the investigator. 
12. Subject has a positive serology test for HIV antibodies, hepatitis B 
surface antigen, or hepatitis C virus antibody at Screening. 
13. Subject has a hemoglobin <11.0 g/dL, potassium <3.8 mg/dL, 
magnesium <1.9 mg/dL, or calcium <8.5 mg/dL at Screening or 
baseline. One retest of exclusionary hemoglobin, potassium, 
magnesium, and calcium is allowed at the discretion of the 
investigator. Electrolyte supplementation is allowed at any time as 
long as it is >4 hours before dosing. 
14. Subject has a history of hypersensitivity to drugs with a clinically 
significant reaction or any clinically significant hypersensitivities. 
15. Subject has an allergy to band aids, adhesive dressing, or medical 
tape. 
16. Subject has a history within the past 2 months of strenuous exercise 
(eg, marathon running) and is unwilling to refrain from strenuous 
exercise from 7 days before Check-in and until the end of the study. 
Subject has abnormal creatine phosphokinase test greater than 
3 × the upper limit of normal at Screening and baseline. One retest of 
exclusionary abnormal creatine phosphokinase tests is allowed at the 
discretion of the investigator. 
17. Subject is unable to refrain from or anticipates the use of any drug, 
including prescription and nonprescription medications (with the 
exception of hormonal contraception), herbal preparations, or 
vitamin supplements beginning 14 days before the first dose and 
until the end of the study. After dosing, acetaminophen (up to 2 g per 


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24 hours) may be administered at the discretion of the investigator or 
designee. 
a. Hepatic or renal clearance altering agents within 30 days before 
the first dose and until the end of the study. 
b. Avoid vaccinations from Screening until the end of the study. 
c. Has consumed cruciferous vegetables (eg, kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, and 
mustard greens) or charbroiled meats within 7 days before 
Check-in through the Follow-up Visit. 
d. Use of any drugs known to be significant strong inducers of 
cytochrome P450 (CYP) 3A enzymes, including St. John’s 
Wort, for 28 days before Day –1 or 5 half-lives (whichever is 
longer) and through the Follow-up Visit. 
e. Has consumed Seville oranges, grapefruit and/or grapefruit juice 
within 14 days before Check-in and is unwilling to abstain from 
consuming these items until the end of the study. 
18. Subject is considering or scheduled to undergo any surgical 
procedure during the study. 
19. Subject has experienced an acute illness that has resolved in less than 
14 days before the first study drug dose or has had a major illness or 
hospitalization within 1 month before the first study drug dose. 
20. Subject is unwilling to abstain from ingestion of caffeine- or 
xanthine-containing products (eg, tea, coffee, chocolate, cola, etc.) 
beginning 96 hours before Check-in until the final PK sample of the 
study has been collected. 
21. Subject is unwilling to abstain from alcohol beginning 48 hours 
before Check-in and until the final PK sample of the study has been 
collected. 
22. Subject has a history of high alcohol consumption within 9 months 
before Screening, defined as an average weekly intake of >14 units 
for males or >10 units for females. One unit is equivalent to 8 g of 
alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine, or 
1 measure (25 mL) of spirits. 
23. Subject has a history of drug abuse in the 3 years before Screening or 
positive screen for drugs of abuse or alcohol at Screening or 
baseline. Subjects may undergo a repeat urine drug screen at the 
discretion of the investigator. 
24. Subject uses or has used tobacco-or nicotine-containing products (eg, 
cigarettes, cigars, chewing tobacco, snuff, etc.) within 6 months 
before Screening and is unwilling to abstain from tobacco-containing 
products until the end of the study, based on subject self-reporting. 
25. Subject, who, for any reason, is deemed by the investigator to be 
inappropriate for this study or has any condition which would 
confound or interfere with the evaluation of the safety, tolerability, 
or PK of the investigational drug or prevent compliance with the 
study protocol. 


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Part 2: Participants with LQT2 or LQT3 will be excluded from the 
study if they meet any of the following criteria: 
1. Clinically significant gastrointestinal, renal, hepatic, neurologic, 
hematologic, endocrine, oncologic, pulmonary, immunologic, 
psychiatric, or significant structural cardiovascular disease or any 
other condition beyond LQT2 or LQT3, which, in the opinion of the 
investigator or sponsor, would jeopardize the safety of the participant 
or impact the validity of the study results. History of myocardial 
infarction or ongoing angina or active ischemic heart disease, atrial 
fibrillation, stroke, or transient ischemic attack within the past 
12 months, greater than New York Heart Association Class II 
congestive heart failure, bundle branch block, hemodynamically 
significant ventricular tachycardia not due to Torsades de Pointes, or 
Brugada syndrome. 
2. Participant has a history of an aborted cardiac arrest, ICD 
implantation, syncopal episode due to a ventricular arrhythmia or 
where confidence in the etiology cannot be established, or 
appropriate ICD therapy for ventricular tachycardia/ventricular 
fibrillation within 2 months before Screening. Participants with 
LQT2 or LQT3 can be enrolled after the 2-month time period has 
lapsed. 
3. Female participants must not be pregnant, lactating, or 
breastfeeding, and must not be planning to become pregnant. 
4. Female participants of childbearing potential must have a negative 
result for the serum pregnancy test at Screening and Check-in. 
5. Clinically significant abnormal findings on the physical examination 
at Check-in or medical history during Screening as deemed by the 
principal investigator. 
6. Currently participating in another interventional clinical study. 
7. Donation of blood volume greater than 300 mL within 30 days 
before dosing and unwilling to avoid donation from Screening 
and throughout the study. 
8. Screening diastolic blood pressure <45 or >95 mm Hg, systolic 
blood pressure <90 or >150 mm Hg, or with sponsor and investigator 
approval. 
9. At Screening and on Day –1, if the triplicate 12-lead ECG 
demonstrates any of the following: mean PR >250 ms; QRS 
>110 ms, or QTcF >560 ms and <480 ms; bundle branch block or 
significant ST-T wave abnormalities or flat T waves that could 
interfere with QT analysis. Heart rate <45 bpm, unless receiving a 
beta-blocker in which case <40 bpm, or HR >95 bpm. If any of 
these exclusionary criteria are met, then a second set of triplicate 
ECGs may be acquired, and the mean values may be used. For 
participants on beta blockade, the PR interval may be higher than 
250 ms with sponsor and investigator approval. 
10. Atrial pacing rate set to ≥80 bpm in those with atrial pacing. 
11. Participant has a pacemaker or ICD that is actively used for 
ventricular pacing. 
12. Known sensitivity to kinase inhibitors or clinically significant drug 
allergies to any of the components of LQT-1213. 
13. Abnormal renal function with an eGFR of <60 mL/min/1.73 m2, with 
eGFR calculated by the CKD-EPI formula at Screening. One retest 
of the exclusionary eGFR value is allowed at Screening and 
Check-in at the discretion of the investigator. 
14. Participant has abnormal liver function tests (transaminases greater 


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than 2 × the upper limit of normal [ULN]) or total bilirubin > 1.5 × 
ULN. If the participant has documented Gilbert’s Syndrome, 
participation is at the combined principal investigator and Sponsor’s 
discretion after review of historical liver and bilirubin tests. 
15. Participant has a positive serology test for HIV antibodies, 
hepatitis B surface antigen, or hepatitis C virus antibody at 
Screening. 
16. Participant has a hemoglobin <11.0 g/dL, potassium <3.8 mg/dL, 
magnesium <1.8 mg/dL, or calcium <8.5 mg/dL at Screening or 
baseline. One retest of exclusionary hemoglobin, potassium, 
magnesium, and calcium is allowed at the discretion of the 
investigator. 
17. Participant has a history of hypersensitivity to drugs with a 
clinically significant reaction or any clinically significant 
hypersensitivities. 
18. Participant has a clinically significant allergy to band aids, 
adhesive dressing, ECG electrodes, or medical tape. 
19. Participant has abnormal creatine phosphokinase test greater than 
3 × ULN at Screening or baseline. One retest of exclusionary 
abnormal creatine phosphokinase tests is allowed at the discretion of 
the investigator. 
20. Participant is currently taking, within the last 7 days before 
Spaulding admission or 5 half-lives (whichever is longer), or 
anticipates the use of any antiarrhythmic medications (including 
mexilitene except beta-blockers which are allowed,) or drugs known 
to affect the QT interval (including ranolazine; refer to drug lists for 
“Drugs with known, possible, or conditional risk of TdP” that are 
known to prolong the QT interval at https://crediblemeds.org), 
unless approved by the sponsor and principal investigator. 
21. Participant is not permitted to use/consume the following: 
a. 
Any drugs known to be significant strong inducers of CYP 3A 
enzymes, including St. John’s Wort, for 28 days before Day –1 
or 5 half-lives (whichever is longer) and through the Follow-up 
Visit. 
b. 
Seville oranges, grapefruit and/or grapefruit juice within 7 days 
before Check-in and is unwilling to abstain from consuming 
these items until the end of the study. 
22. Participant is considering or scheduled to undergo any 
surgical procedure during the study. 
23. Participant has experienced an acute illness that has resolved in less 
than 14 days before the first study drug dose or has had a major 
illness or hospitalization within 1 month before the first study drug 
dose. 
24. Participant is unwilling to abstain from ingestion of caffeine- or 
xanthine-containing products (eg, tea, coffee, chocolate, cola, etc.) 
beginning 96 hours before Check-in until the final PK sample of the 
study has been collected. 
25. Participant is unwilling to abstain from alcohol beginning 48 hours 
before Check-in and until the final PK sample of the study has been 
collected. 
26. Participant has a history of high alcohol consumption or substance 
abuse that would pose a risk for the participant’s safety and 
compliance with the study protocol. Participant must not have 
positive screen for drugs of abuse at Screening or baseline and 
alcohol at baseline, except with sponsor permission. Participants 
may undergo a repeat urine drug screen at the discretion of the 


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investigator. 
27. Participant, who, for any reason, is deemed by the investigator to be 
inappropriate for this study or has any condition which would 
confound or interfere with the evaluation of the safety, tolerability, 
or PK of the investigational drug or prevent compliance with the 
study protocol. 


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Study design: 
This is a Phase 1b/2a, 2-part study; Part 1: randomized, double-blind, 
crossover, dose-escalation, placebo-controlled study to evaluate the 
safety, tolerability, PK, and PD of SGK-1 kinase inhibition by LQT-1213 
on dofetilide-induced QTc prolongation in healthy adult subjects. Part 2: 
single-blind, multiple-dose safety study to evaluate the safety, 
tolerability, and PK of LQT-1213 in patients diagnosed with LQT2 or 
LQT3. 
Part 1: This is a 2-treatment, 2-period crossover study. Approximately 
28 healthy subjects, with the attempt to balance for sexes, will be enrolled 
to complete approximately up to 20 subjects in the study. Additional 
subjects may be enrolled to compensate for subjects that do not complete 
both treatment periods, at the discretion of the sponsor. The exact number 
will be determined during the conduct of the study. A sentinel group of 
up to 5 subjects may be enrolled first if warranted by the principal 
investigator. 
In both treatment periods, all subjects will receive dofetilide on Days 1 
and 2 of each period. Randomization will take place before Day 3 of 
Period 1. Subjects will be randomly assigned to 1 of 2 treatment 
sequences (AB or BA), with treatment arms as follows: 
• 
Arm A: Dofetilide 500 µg twice daily (BID) (2 × 250 µg capsules), 
orally (Days 1-8) and LQT-1213 3 times a day (TID). LQT-1213 or 
matching placebo dosing: 
o 
Low dose: 3 doses on Day 3 and the first 2 doses on Day 4 
o 
Mid dose: Last dose on Day 4, 3 doses on Day 5, and the first 
2 doses on Day 6 
o 
High dose (not to exceed 0.747 mg/kg TID, daily dose 
2.24 mg/kg/day): Last dose on Day 6, 3 doses on Day 7, and the 
first dose on Day 8. The specific doses will be determined 
before administration of the first dose of LQT-1213. 
• 
Arm B: Dofetilide 500 µg BID (2 × 250 µg capsules), orally 
(Days 1-8) and placebo matched to LQT-1213 TID (Days 3-8) 
Note: Only 1 dose of dofetilide and LQT-1213 (or placebo) will be 
administered on Day 8. 
Screening will occur within 28 days of clinical research unit (CRU) 
admission. In both treatment periods, subjects will be domiciled starting 
2 days before dofetilide dosing until after the last doses of dofetilide and 
LQT-1213 or placebo matched to LQT-1213 (Days –2 through 8). Days 1 
and 2 are to establish near-steady state dofetilide plasma levels and 
observe the QTc response to dofetilide. On Day 1 at 3 hours postdose in 
Period 1 only, the QTcF will be measured in the 3 (triplicate) ECGs and 
the mean value calculated. Measurements will be manually confirmed by 
a cardiologist who is specifically trained and experienced in ECG interval 
measurements. The ECG measurements at baseline and at the 3-hour time 
points will be performed by the same technician and cardiologist. If the 
mean QTcF increase is <25 ms on the triplicate safety ECGs compared 
with the mean from baseline (triplicate –30 min and triplicate –15 min), 
the subject will be discontinued from the study. If on Day 1 at 3 hours 
postdose in Period 1 only, the mean QTcF on the triplicate ECGs, when 
repeated within 30 minutes and manually confirmed by a cardiologist 


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specifically trained and experienced in ECG interval measurements, has a 
mean value on the 3 (triplicate) repeated ECGs >80 ms from the mean 
baseline QTcF, the dose of dofetilide will be reduced to 250 µg BID. If 
the mean QTcF is >500 ms on Day 1 in Period 1 only (repeated in 
triplicate within 30 minutes with a QTcF > 500 ms), the dose of 
dofetilide will be reduced to 250 µg BID. If the safety ECGs (repeated in 
triplicate within 30 minutes) shows a mean value on the 3 (triplicate) 
repeated ECGs of a QTcF of >500 ms on Day 2 or afterwards (or any 
time in Period 2), the subject will be discontinued from the study. All 
ECGs for these safety assessments must be manually confirmed by a 
cardiologist who is specifically trained and experienced in ECG interval 
measurements before actions are taken. If the dose is reduced to 250 µg 
BID, this will be the dose used in Period 2. Note: If the subject has a new 
QRS >110 ms or a new bundle branch block, then an adjusted QTcF will 
be utilized to account for the widened QRS interval (Adjusted 
QTcF = QTcF [ms] – [QRS interval [ms] – 90 [ms]). 
LQT-1213 or placebo matched to LQT-1213 will be administered at 
time 0, immediately after the 7.75-hour ECG extraction time point, and at 
17 hours, though these time points may be adjusted based upon emerging 
data. Subjects will be discharged from the CRU on Day 9 or 10 (safety 
washout) in each period, if the QTcF is <460 ms and the increase from 
baseline is <40 ms. Day 10 evaluations will be performed if the subject is 
not discharged on Day 9. There will be a washout of at least 4 days (or at 
least 5 times the half-life) after the last dose of study drug. Subjects will 
return to the CRU on Day –2 and crossover to receive the alternate 
treatment in Period 2. 
Approximately 7 days after the end of treatment in Period 2, the 
Follow-up Visit will be conducted remotely via telephone call. 
Full PK sampling for dofetilide and LQT-1213 will be conducted on 
Days 4, 6, and 8 of each period. Continuous 12-lead 24-hour Holter data 
will be collected at the approximate 90-minute time point on Day –1 
(corresponding to predose on Day 1) and stored, and on Day 1 starting 
2 hours before dosing through Day 8. On each day, the Holter data card 
will be removed and a new one inserted 90 minutes before dosing. The 
ECGs will be extracted from the Holters on specific days and time points 
for core laboratory analysis, as detailed in the PK and PD time points 
table (Section 8.3, Appendix C). 
Subjects will have an overnight fast on Days –1 through Day 8 and will 
remain fasted until immediately after the 6-hour ECG extraction, when a 
light meal will immediately be provided, followed by a meal immediately 
after the 9.5- and 12-hour ECG extraction time points. 
Subjects will fast after the meals at 6 and 9.5 hours are completed, which 
must be within 20 minutes for these 2 time points. Subjects can eat at will 
after the 12-hour meal, a light meal will be provided, which must be 
completed to ensure the overnight fasting requirement is met (6-hour 
fast), (no food or fluid except water). Serum potassium and magnesium 
will be checked each day on Days –1, 1, and 2 and thereafter, beginning 
on Day 3, potassium and magnesium will be checked every other day. 
Potassium <3.8 mg/dL and magnesium <1.9 mg/dL will result in 
additional electrolyte supplementation. It is preferred, especially on 
Days 1, 4, 6, and 8, that this be done in the evening (after the 12-hour 
time point). Electrolyte supplementation is allowed at any time as long as 
it is >4 hours before dosing. 


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Safety assessments will include AEs, clinical laboratory test results, vital 
signs measurements, and safety 12-lead ECG findings. Bedside safety 
12-lead ECGs will be collected by the CRU staff and reviewed by the 
investigator; 12-lead ECGs will be classified as normal or abnormal not 
clinically significant or abnormal clinically significant. 
The safety ECG data, including all time points, will be recorded on the 
electronic case report form, and be used for evaluating general safety of 
the subjects during study and for evaluation of an AE. The ECGs 
analyzed (the cardiodynamic evaluation) by Clario are the primary ECG 
data for the analysis of the ECG intervals for the study, once completed. 
The dosing, meal timing, and PK and ECG time points and extractions 
may be modified based on emerging data. 
Stopping rules will be predefined and evaluated after each successive 
dosing group. 
Part 2: A Phase 2a, single-blind, multiple-dose, safety study to evaluate 
the safety, tolerability, and PK of LQT-1213 in participants with LQT2 
or LQT3. The study will utilize TID dosing of LQT-1213 for 3 days (the 
last dosing day will be a single dose). The actual dose may be modified 
based upon evolving data. After the second participant completes the 
end of study visit for each LQT subtype (LQT2 or LQT3), a safety 
review committee (SRC) will review all available data before enrolling 
additional participants. All participants with LQT2 or LQT3 will have a 
QTcF ≥480 and ≤560 ms. Up to 12 participants with LQT2 and up to 12 
participants with LQT3 will be enrolled. The first 2 participants with 
LQT2 require having an ICD before further participants with LQT2 are 
enrolled and the first 2 participants with LQT3 require having an ICD 
before further participants with LQT3 are enrolled. The ICD 
implantation must have been performed at least 2 months before 
Screening. After initial screening, which may be conducted remotely by 
the CRU, individual participants with LQT2 or LQT3 will undergo a 1- 
day, single-blind placebo run-in period followed by 3 dosing days of 
LQT-1213 administered TID (the last dosing day will have a single 
dose). 
Screening (remote or in-person) will be conducted within 60 days of 
CRU admission. Participants with LQT2 or LQT3 will be domiciled 
starting on Day –1 until the end of treatment on Day 5. On Days –1 
(CRU admission day) and 1, participants with LQT2 or LQT3 will 
undergo partial (Day –1) and baseline 24-hour 12-lead high fidelity 
Holter monitoring during placebo single-blind administration (Day 1 
only). 
LQT-1213 will be administered TID (at time 0, 8, and 16 hours) on 
Days 2 and 3, with the final dose on Day 4 at time 0, though these time 
points may be adjusted based upon emerging data. Participants with 
LQT2 or LQT3 will be discharged from the CRU on Day 5. 
Approximately 7 days after discharge from the CRU, the Follow-up Visit 
will be conducted remotely via telephone call. 
The intensive PK sampling for LQT-1213 will be conducted on Days 2 
and 4 and the morning of Day 5. Continuous 12-lead 24-hour Holter data 
will be collected on Days -1 through 5, as detailed in the PK and PD time 
points table (Section 8.4, Appendix D). All Holter data starting on Day -1 
will be stored for potential future analysis. On each day, the Holter data 
card will be removed and a new one inserted approximately 90 minutes 
before first dosing on each Days and on Day 5. ECG extraction time 
points for potential future analysis are detailed in the PK and PD time 
points table (Section 8.4, Appendix D). 
On Day −1, there are no fasting requirements with the exception of an 
overnight 6-hour fast for clinical laboratory collections. On Days 1, 2, 


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and 4, participants will begin fasting at midnight and will remain fasted 
until immediately after the 6-hour ECG extraction time point when a light 
low carbohydrate meal will be provided, which should be consumed 
within 30 minutes. Participants will then fast until after the 10-hour 
(Day 1) or 12-hour (Days 2 and 4) ECG extraction when food will be 
provided ad libitum until midnight. On Day 3, participants will begin 
fasting at midnight and will remain fasted until the 2- hour time point 
when food will be provided ad libitum until the 6- hour time point. 
Fasting will resume at the 6-hour time point until the 10- hour time point 
when food will be provided ad libitum until midnight. Food intake must 
be completed prior to the midnight fast to ensure the midnight fasting 
requirement is met (no food or fluid except water). On Day 5, normal 
food intake will begin ad libitum after the 29-hour ECG extraction. 
Serum potassium and magnesium will be checked each day while 
participants are housed (Days −1, 1, 2, 3, 4 and 5). In addition, serum 
potassium and magnesium may be repeated at the investigator’s 
discretion. Potassium <3.8 mg/dL and magnesium <1.8 mg/dL will 
result in additional electrolyte supplementation. Electrolyte 
supplementation can be administered 12-18 hours after the morning 
dose of LQT-1213. 
Safety assessments will include AEs, clinical laboratory test results, vital 
signs measurements, continuous telemetry ECG monitoring, and safety 
12-lead ECG findings. Bedside safety 12-lead ECGs will be collected by 
the CRU staff and reviewed by the investigator. The safety ECG data, 
including all time points, will be recorded on the eCRF, and be used for 
evaluating general safety of the participants with LQT2 or LQT3 during 
study and for evaluation of an AE. All ECG sent to Clario will be stored 
for possible future analysis.  
The dosing, meal timing, and PK and ECG time points and 
extractions may be modified based on emerging data. 


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Study drug, dosage, and 
route of administration: 
Part 1: 
• 
LQT-1213 low, mid, and high (not to exceed 0.747 mg/kg TID, daily 
dose 2.24 mg/kg/day) doses TID (at time 0, immediately after the 
7.75-hour ECG extraction time point, and at 17 hours) for oral 
suspension (Days 3-8; only 1 dose will be administered on Day 8) 
Part 2: 
• 
LQT-1213: TID (at time 0, 8, and 16 hours) on Days 2 and 3 and a 
single morning dose on Day 4 (last dose on Day 4 is the am dose). 
The dose will not exceed daily dose 2.24 mg/kg/day for oral 
suspension 
Reference drug, dosage, and 
route of administration: 
Part 1: 
• 
Dofetilide 500 µg BID for oral administration (for both treatment 
sequences, Days 1-2 alone and Days 3-8 with LQT-1213 or placebo 
matched to LQT-1213; only 1 dose will be administered on Day 8). 
Potential dose-down-titration to 250 µg BID for oral administration 
based on safety parameters. 
• 
Placebo matched to LQT-1213 (Days 3-8; only 1 dose will be 
administered on Day 8) 
Part 2: 
• 
Placebo matched to LQT-1213 (Day 1) TID 
Study duration: 
Part 1: The duration of treatment for each subject in the study will be 
approximately 34 days, from admission on Day –2 to the telephone 
follow-up call. This does not include the 28-day screening period. 
Part 2: The duration of the treatment for each participant with LQT2 or 
LQT3 in the study will be approximately 13 days, from admission on 
Day –1 to the telephone follow-up call. This does not include the 60-day 
screening period. 
Criteria for evaluation: 
Part 1: 
Electrocardiogram and QT/QTc Analyses: Pharmacodynamics will 
be evaluated using extracted ECG data obtained from continuous 12- 
lead Holter monitors placed on all subjects in Periods 1 and 2 at time 
points specified in the PK and PD time points table (Appendix C) and 
will be analyzed consistent with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E14 guidance. 
Pharmacokinetics: Blood samples for dofetilide and LQT-1213 PK 
analysis will be collected in both treatment periods on Days 4, 6, and 8 at 
the following time points: predose (time 0 for dofetilide) and at 1, 2, 2.5, 
3, 3.5, 4, 4.5, 5, 5.5, 6, 7.75, 9.5, 12, and 24 hours postdose. 
Safety: Safety will be determined by monitoring AEs, clinical 
laboratory test results (hematology, serum chemistry, coagulation and 
urinalysis), vital sign measurements (blood pressure, HR, respiratory 
rate, and oral body temperature), 12-lead ECG results, and physical 
examination findings. 


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Part 2: 
Safety: Safety will be determined by monitoring AEs, clinical laboratory 
test results (hematology, serum chemistry, coagulation, and urinalysis), 
vital sign measurements (blood pressure, HR, respiratory rate, and oral 
body temperature), continuous telemetry ECG monitoring, 12-lead ECG 
results, and physical examination findings. 
Pharmacokinetics: Blood samples for LQT-1213 PK analysis will be 
collected as detailed in Appendix D. 
Pharmacodynamics: Pharmacodynamics will be evaluated by analyzing 
SGK-1 targets obtained from Human PBMCs for potential biomarkers. 
Pharmacodynamic Biomarkers: Human PBMC and plasma samples 
will be isolated and stored for potential analysis of for potential PD 
biomarkers, including SGK-1 targets. 
Analysis populations: 
Part 1: 
Five analysis populations are defined, as follows: 
• 
The primary QT/QTc population will be those subjects in the total 
QT/QTc population meeting a threshold effect of dofetilide to 
prolong the QTc interval as will be defined in the SAP. 
• 
The total QT/QTc population will include all subjects in the safety 
population with measurements at baseline as well as on-treatment 
with at least 1 postdose time point with a valid change from baseline 
in QTc (ΔQTc) value. The QT/QTc population will be used for the 
by-time point and categorical analyses of cardiodynamic ECG 
parameters. 
• 
The PK population will include all subjects who received at 
least 1 dose of study drug and provided at least 1 evaluable PK 
concentration for LQT-1213 or dofetilide. 
• 
The primary PK/QTc population will include all subjects who are in 
both the PK and primary QT/QTc populations with at least 1 pair of 
postdose PK and QTc data from the same time point in each period. 
The PK/QTc population will be used for the concentration-QTc 
analysis. 
The safety population will include all subjects who received at least 1 
dose of dofetilide and provide at least 1 postdose safety assessment. 
 
Part 2: 
Three analysis populations are defined, as follows: 
• 
The safety population will include all participants with LQT2 or 
LQT3 who received at least 1 dose of study drug (placebo or 
LQT-1213) and provide at least 1 postdose safety assessment. 
• 
The PK population will include all participants with LQT2 or 
LQT3 who received at least 1 dose of LQT-1213 and provided 
at least 1 evaluable PK concentration for LQT-1213. 
• 
The PD population (SGK-1 protein targets) will include all 
participants who received at least 1 dose of study drug (placebo 
or LQT-1213) and have at least 1 PD measurement. 


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Statistical methods: 
Part 1: 
Electrocardiogram and QT/QTc Analyses: The analysis will be 
described in the SAP. All QTc data will represent the means of the 
extracted QTc intervals, based on ECGs extracted from the Holters at the 
defined time points. Each individual QT and time elapsed between 
2 successive R waves of the QRS signal on the ECG (RR) interval will be 
used to calculate a QTc interval. The individual QTc intervals will then 
be averaged for analysis. Baseline will be defined as the mean of the 
triplicate ECG data collected predose for each period. 
Fridericia’s formula will be the default correction method for QT 
intervals to remove HR dependence. 
If the QTcF is not an adequate correction, other methods will be 
reviewed. For each method tested (including Fridericia’s correction), the 
relationship between the QTc and RR will be evaluated with a 
linear-regression model. Mean QTc and RR values at all nominal time 
points will be used. The model with the slope closest to zero will be 
selected as the primary QTc endpoint. The additional correction methods 
and definition of an adequate correction will be detailed in the SAP. 
A statistical analysis will be performed per ICH E14 guidance using the 
appropriate population and will be detailed in the SAP. The specifics of 
the concentration-QTc and categorical analyses will be detailed in the 
SAP. 
Pharmacokinetics: The analysis will be detailed in the SAP which will 
be finalized before database lock. Data will be listed and summarized, 
where applicable. Plasma concentrations of dofetilide and LQT-1213 will 
be listed and summarized by treatment for each sample time point using 
descriptive statistics. Mean and individual plasma dofetilide and 
LQT-1213 concentration-time profiles will be presented in figures on 
linear and semilogarithmic scales. Assessment of a drug interaction 
between dofetilide and LQT-1213 will be examined. 
Safety: Safety data including reported AEs, clinical laboratory 
assessments, vital signs measurements, and safety 12-lead ECGs will be 
summarized. Physical examination findings will be listed. 
Part 2: 
Safety: Safety data including reported AEs, clinical laboratory 
assessments, vital signs measurements, continuous telemetry ECG 
monitoring, and safety 12-lead ECGs will be summarized. Physical 
examination findings will be listed. 
Pharmacokinetics: The analysis will be detailed in the SAP which will 
be finalized before database lock. Data will be listed and summarized, 
where applicable. Plasma concentrations of LQT-1213 will be listed and 
summarized by LQT subtype for each sample time point using 
descriptive statistics. Mean and individual LQT-1213 concentration-time 
profiles will be presented in figures on linear and semilogarithmic scales. 
Pharmacokinetics/Pharmacodynamics: Details of the potential PD 
(SGK-1 protein targets) analyses to derive PK (LQT-1213)/PD 
relationships between drug exposure and target engagement will be 
provided in a separate analysis plan. 


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Sample size: 
Part 1: Based on the calculation of the sample size for a Thorough QT 
study (Zhang and Machado, 2008), as the test is performed at 5 time 
points separately, a 1 sided 5% significance level (with adjusted 1-sided 
significance levels of 5%, 2.5%, 1.67%, 1.25%, and 1%) is used along 
with a within-subject SD of 8 ms for ΔQTcF for all treatment groups. A 
sample size of 20 evaluable subjects in a crossover design who complete 
the study will provide a power of 90% to detect 7 ms QTc effect, ie, the 
lower bound of all the 2 sided 90% CIs on ΔΔQTcF will exceed 7 ms at 
least 1 of the 5 prespecified time points. Multiplicity will be controlled by 
using a Hochberg procedure (Hochberg 1988). Twenty-eight subjects will 
be enrolled to account for dropouts. 
Part 2: In this exploratory safety study, up to 12 participants with LQT2 
and up to 12 participants with LQT3 will be recruited. The sample size 
was not estimated based on statistical considerations but was considered 
sufficient to achieve the primary safety objectives of the study. 
Date of protocol: 
05 December 2023 


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2. 
List of Abbreviations 
Abbreviation 
Definition 
ΔΔHR 
 time-matched, placebo-adjusted, change from baseline in HR 
ΔΔQRS 
 time-matched, placebo-adjusted, change from baseline in QRS 
ΔΔQTc 
time-matched, placebo-adjusted, change from baseline in QTc 
ΔΔQTcF 
time-matched, placebo-adjusted, change from baseline in QTcF 
ΔΔPR 
time-matched, placebo-adjusted, change from baseline in PR 
ΔHR 
change from baseline in heart rate 
ΔQRS 
change from baseline in QRS 
ΔQTc 
change from baseline in QTc 
ΔQTcF 
change from baseline in QTcF 
ΔQTcI 
change from baseline in QTcI 
ΔQTcP 
change from baseline in QTcP 
ΔPR 
change from baseline in PR interval 
λz 
apparent terminal rate constant 
ACLS 
Advanced Cardiovascular Life Support 
APD 
action potential duration 
AE 
adverse event 
AESI 
adverse events of Special Interest 
AUC 
area under the plasma concentration-time curve5 
AUC0-t 
area under the plasma concentration-time curve from time 0 to the 
time of the last measurable concentration 
AUCtau 
area under the concentration-time curve from time 0 to the end of 
the dosing interval 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CKD-EPI 
 Chronic Kidney Disease Epidemiology Collaboration 
CLss/F 
apparent clearance at steady state 
Cmax 
maximum observed plasma concentration 
CRU 
clinical research unit 
Ctrough 
concentration at the end of the dosing interval 
CV% 
percent coefficient of variation 
CYP 
cytochrome P450 
DHHS 
Department of Health and Human Services 
ECG 
electrocardiogram 
eCRF 
electronic case report form 


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eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
hiPSC-CMs 
human-induced pluripotent stem cell-derived cardiomyocytes 
HR 
heart rate 
IC50 
half-maximal inhibitory concentration 
ICD 
Implantable cardioverter defibrillator 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
Ikr 
inward-rectifier potassium channels 
IRB 
institutional review board 
KCNQ1 
potassium voltage-gated channel subfamily Q member 1 
KCNH2 
potassium voltage-gated channel subfamily H member 2 
LFT 
liver function tests 
LQT/LQTS 
long QT syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect-level 
PBMCs 
peripheral blood mononuclear cells 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PR 
time from the onset of the P wave to the start of the QRS complex 
QRS 
ventricular depolarization 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
QTcI 
QT interval corrected for heart rate with individual correction 
QTcP 
QT interval corrected for heart rate with population correction 
RR 
time elapsed between 2 successive R waves of the QRS signal on 
the ECG 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCN5A 
sodium voltage-gated channel alpha subunit 5 
SGK-1 
serum- and glucocorticoid-regulated kinase 1 
SRC 
Safety Review Committee 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 


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TID 
3 times a day 
Tmax 
time to the maximum observed plasma concentration 
US 
United States 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution 


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3. 
Introduction 
 
3.1. 
Background 
Congenital Long QT syndrome (LQTS) is a rare cardiac disorder most commonly caused 
by mutations in 1 of 3 genes that encode for ion channels involved in ventricular 
repolarization. Changes in the function of these ion channels result in ventricular action 
potential duration (APD) prolongation and prolongation of the QT interval corrected for 
heart rate (HR; QTc) interval, which can precipitate the ventricular arrhythmia Torsades 
de Pointes, which can lead to fainting, seizures, ventricular fibrillation, and sudden death. 
LQTS can also occur as the result of adverse effects of drugs and/or electrolyte 
abnormalities that inhibit the hERG (referred to as acquired LQTS). 
Serum- and glucocorticoid-regulated kinase 1 (SGK-1) is a serine-threonine kinase that is 
under acute transcriptional control by several stimuli, including serum and 
glucocorticoids. SGK-1 is activated both by insulin and growth factor signaling. Baseline 
SGK-1 activity is low in cardiomyocytes but is upregulated in pathological states. SGK-1 
plays a critical role in the regulation of the voltage-gated sodium channel Nav1.5 in 
cardiomyocytes by direct phosphorylation as well as regulation of interacting proteins 
(Bezzerides et al 2017). Activation of SGK-1 in the heart causes an increase in the late 
sodium current leading to prolongation of the APD, while genetic inhibition of the gene 
coding for SGK-1 reduces the increase in APD seen with both cardiac stressors and in 
inherited arrhythmia syndromes in animal models (Das et al 2012, Bapat et al 2021) and 
cell culture models (Bezzerides et al 2017), respectively. SGK-1 inhibition has been 
shown to reduce the APD in human-induced pluripotent stem cell-derived 
cardiomyocytes (hiPSC-CMs) from patients with several types of inherited arrhythmia 
syndromes such as LQT1 (potassium voltage-gated channel subfamily Q member 1 
[KCNQ1] potassium channel locus; loss of function), LQT2 (potassium voltage-gated 
channel subfamily H member 2 [KCNH2] potassium channel locus; loss of function), and 
LQT3 (sodium voltage-gated channel alpha subunit 5 [SCN5A] sodium channel locus; 
gain of function) (Bezzerides et al 2017), as well as acquired LQTS in hiPSC-CMs 
treated with anemonia viridis toxin II or dofetilide and a guinea pig Langendorff model 
treated with dofetilide (Kim et al 2023). 
Beta-blockers are prescribed as first line therapy for congenital LQTS. This approach 
reduces autonomic triggers and the probability of Torsades de Pointes but does not 
address the underlying pathology of prolonged ventricular repolarization, and 
breakthrough episodes are not uncommon. Beta-blockers are prescribed most commonly 
to patients with LQT1 mutations and, less commonly, to patients with LQT2 mutations. 
However, beta-blockers have not been demonstrated to be effective in patients with 
LQT3 mutations (Han et al 2020). Compliance with beta-blocker therapy is limited by 
unpleasant side effects including lethargy, dizziness, weight gain, and nausea, and 
patients often do not comply with dosing recommendations. In certain patients, failure 


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of beta-blocker therapy is followed by the use of an implantable cardiac defibrillator 
(ICD). 
Thryv Therapeutics Inc. is developing LQT-1213, a potent and selective small molecule 
drug that inhibits the activity of SGK-1, for the treatment of individuals with congenital 
or acquired LQTS. In a study of 44,496 Caucasian infants, the prevalence of LQTS was 
estimated to be 1:2,534 (Schwartz et al 2009). Of these patients, it is estimated that 60% 
have LQT1, 32% have LQT2, and 8% have LQT3 (Priori et al 2003). Inhibition of 
SGK-1 inhibition by LQT-1213 likely prevents SGK-1 activity on the late sodium 
channel current, modulating the late sodium current (including the mutant channel seen 
in LQT3) and possibly impacting cardiac calcium handling. Multiple preclinical data in 
hiPSC-CMs bearing LQT2 (KCNH2) and LQT3 (SCN5A) mutations, hiPSC-CMs 
sheets with KCNH2 mutations, a rabbit heart with a KCNH2 mutations, normal hiPSC- 
CMs treated with anemone toxin II (mimicking LQT3) and experiments using dofetilide, 
a hERG blocker, have shown that SGK-1 inhibition shortens or normalizes the 
prolonged APD. Thus, it is reasonable to evaluate the effects of LQT-1213 in patients 
with LQTS 2 or 3. 
 
3.2. 
Summary of LQT-1213 Nonclinical Development 
A comprehensive program of in vitro and in vivo nonclinical studies has been completed 
or is in progress to investigate the primary, secondary, and safety pharmacology, 
pharmacokinetics (PK), general toxicity, and genotoxicity of LQT-1213 in-line with 
current International Council on Harmonisation (ICH) and Good Laboratory Practice 
(GLP) regulatory guidance. Results from these studies are briefly described in this 
section; additional details can be found in the investigator’s brochure. 
In vitro studies were conducted to demonstrate the inhibitory effect of LQT-1213 on 
SGK-1, and the subsequent ability to inhibit APD. LQT-1213 was screened in 
biochemical and whole cell assays, where LQT-1213 inhibited SGK-1 with half-maximal 
inhibitory concentration (IC50) values of 0.25 and 89 Nm, respectively. There was no 
effect of different concentrations of serum protein on LQT-1213 potency against SGK-1. 
In cellular assays in hiPSC-CMs bearing LQT1 (V254M-KCNQ1), LQT2 
(G604S-KCNH2), and LQT3 (P1332L-SCN5A) mutations, LQT-1213 markedly reduced 
the prolonged APD in all hiPSC-CMs cells. LQT-1213 additionally inhibited the 
prolongation of APD induced by treatment with anemonia viridis toxin II (a model for 
LQT3) or dofetilide (a specific hERG blocker and a model for LQT2) in both hiPSC-CMs 
(CRISPR/Cas-9 corrected P1332L isogenic line) and normal induced pluripotent stem cell- 
derived cardiomyocytes (unmodified by CRISPR/Cas-9). The in vivo efficacy of SGK-1 
has not been evaluated in animal models of congenital LQTS (caused by ion channel 
mutations) as the available animal models are either not well-characterized, not translatable 
to human disease, or not accessible. Note that traditional models, such as heterologous 
systems, are considered to be incapable of completely recapitulating genetic and phenotypic 


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features of LQTS, while animal models, particularly in rodents, have electrophysiological 
characteristics that are often species-specific and different from humans (Sala et al 2019). 
This hampers the possibility of promptly translating results obtained in vitro directly to the 
clinics, with significant delays occurring between the discovery of promising treatments 
and their clinical application. However, the sponsor has shown that LQT-1213 reduced 
dofetilide-induced QTc prolongation (a model for LQT 2) in Langendorff-perfused guinea 
pigs and in vivo in dogs. 
In secondary pharmacology studies, at presumed supratherapeutic exposures, LQT-1213 
demonstrated antagonistic activity toward adrenergic receptors α1A, α1B, α1D, and α2B; 
AKT3; the calcium channel L-type; nicotinic acetylcholine receptor α3β4; and serotonin 
receptor 5HT2B, and had agonistic activity toward serotonin receptor 5HT1A. 
Half-maximal inhibitory concentration/half-maximal inhibitory effective concentration 
for these receptors were greater than 400 times the IC50 of free LQT-1213 against its 
target, SGK-1. Clinically significant central tendency effects on blood pressure or 
orthostatic blood pressure were not observed in the healthy volunteer single-ascending 
dose/ multiple-ascending dose study. 
In vitro safety pharmacology findings indicated that LQT-1213 was found to be a weak 
inhibitor of hERG channel (IC50 3.38 µM; given 99% human protein binding the margin 
between the hERG IC50 and the LQT-1213 free fraction at the inhibitory exposure of the 
SGK-1 IC50 (89 nM is >3500 times). No significant inhibitory effects were observed 
against the other cardiac ion channels evaluated (hCav1.2, hKir6.2/SUR2A, hKv1.5, 
hKv4.3/KchiP2.2, and hNav1.5), with the exception of a mild potentiating effect on 
Nav1.5 channel currents at high supratherapeutic exposures. 
In PK studies in mouse, rat, dog, and monkey, LQT-1213 was rapidly absorbed following 
oral administration with the fastest absorption in rodents (mouse and rat) followed by dog 
and monkey (time to the maximum observed plasma concentration [Tmax] <1 h). 
Bioavailability was low to moderate in mouse, rat, and dog (22.2%, 17.9-24.0%, and 
14.0%, respectively) and lower in monkey (2.88 to 3.01%), consistent with findings of 
low permeability in Caco-2 and Madin-Darby canine kidney II cells. Volume of 
distribution at steady state values was slightly greater than total body water 
(0.91-1.57 L/kg), suggesting distribution to tissues. LQT-1213 partitioned primarily into 
plasma (blood:plasma ratio of 0.74). LQT-1213 demonstrated high plasma protein 
binding in human and variable, moderate-to-high binding in nonclinical species. 
LQT-1213 demonstrated very high metabolic stability in hepatocytes, liver and intestinal 
microsomes, S9 liver fractions, plasma, and whole blood. No unique human metabolites 
were identified in studies in liver microsomes or hepatocytes. Based on cytochrome P450 
(CYP) induction and inhibition studies as well as transporter studies, there appears to be 
limited potential for LQT-1213 to be involved in drug-drug interactions. 
Repeat-dose studies were conducted to evaluate the potential toxicity of LQT-1213 in 
Sprague Dawley rats and Beagle dogs in studies of up to 14-day durations. LQT-1213 


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was well tolerated in 7-day studies in rats and dogs at doses up to 300 mg/kg/day and 
100 mg/kg/day, respectively, which were the highest doses administered and considered 
to be the no-observed-adverse-effect levels (NOAELs) for each study. Fourteen-day GLP 
studies in both rats and dogs were conducted using twice daily (BID) administration. 
LQT-1213 was well tolerated over 14 days of BID dosing in both rats and dogs at doses 
up to 300 mg/kg/day and 100 mg/kg/day, respectively. At the high dose of 
100 mg/kg/day in dogs, sporadic emesis was observed in both male and female animals. 
Decreases in body weight and food consumption as well as slight changes in clinical 
pathology parameters (increases in white blood cell parameters [neutrophils, monocytes], 
bilirubin [rat], urea nitrogen and urine volume and decreases in total protein and albumin 
[rat] and urine specific gravity [dog]) were observed in both rats and dogs; however, 
these findings were typically minimal in severity, were reversible following the recovery 
period, and were not considered adverse. 
The 3-month repeat dose GLP toxicology studies in dogs and rats is underway. The total 
daily doses in these studies are 10, 30 and 100mg/kg in dogs (BID) and 30mg, 100mg and 
300mg/kg in rats (BID). The dosing and recovery phases have been completed. Elevations 
in liver enzymes (ALT, AST, ALP and GGT) and total bilirubin were observed at the end 
of the dosing phase (Day 92) in the preliminary and unaudited results for the study in dogs 
at the highest dose of 100mg/kg/day with smaller elevations in ALT at the 30mg/kg/day 
dose in one dog, compared to control animals. These elevations were reversible in the 
recovery phase (Day 119). Preliminary results from the study in rats did not show 
elevations in these enzymes or total bilirubin. 
No evidence of genotoxicity has been observed with LQT-1213 in non-GLP and GLP 
bacterial reverse mutation studies in Salmonella typhimurium or Escherichia coli strains, 
in a non-GLP in vitro micronucleus assay in Chinese hamster ovary cells, or in a GLP in 
vivo rat micronucleus assay. 
 
3.3. 
Summary of LQT-1213 Preclinical Cardiovascular Safety 
The potential for LQT-1213 to adversely affect cardiovascular system function was 
evaluated via in vivo GLP safety pharmacology assessments in male Sprague Dawley rats 
and telemetered male Beagle dogs. Single-doses of LQT-1213 at 0 (vehicle), 30, 100, and 
300 mg/kg by oral gavage showed no adverse effects on the central nervous system, as 
measured by Functional Observational Battery assessments, or respiratory functions in 
Sprague Dawley rats. In telemetered Beagle dogs, single-doses of LQT-1213 
administered at 0 (vehicle), 10, 30, or 100 mg/kg/day (5, 15, and 50 mg/kg/dose BID) by 
oral gavage showed limited to slight-to-moderate material in the cage pan at 
≥30 mg/kg/day, indicative of vomiting. LQT-1213 related cardiovascular effects were 
observed and included dose-dependent and transient decreases in blood pressure (by 
12 and 20 mm Hg, at the 5 mg/kg BID and 50 mg/kg BID doses; the maximal reductions 
[maximum change relative to baseline adjusted controls] were 17 and 27 mm Hg, 


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respectively) and presumed compensatory increases in HR beginning at 0.5 hours 
postdose and continuing until 5 hours postdose. No other meaningful cardiovascular 
effects or changes in temperature were observed. However, clinically meaningful blood 
pressure reductions have not been observed to date in the first-in-human single dose 
study (completed) and the multiple-ascending dose study (completed). No other 
meaningful cardiovascular effects or changes in temperature were observed. 
 
3.4. 
Dose Rationale 
3.4.1. 
Part 1 
The 3 times a day (TID) dosing regimen and dose selection is based on PK modeling 
using data from the ongoing single-ascending dose/multiple-ascending dose study 
LQT-1213-0059 to achieve similar concentration at the end of the dosing interval (Ctrough) 
levels in the general range of 250 to 620 ng/mL while slightly reducing the maximum 
observed plasma concentration (Cmax). These levels were chosen to provide multiples of 
the whole cell SGK-1 IC50 for inhibition of 89 ng/mL. The model is based on the 
single-and multiple-dose study with BID dosing in healthy subjects. The high dose of 
LQT-1213 used in this study will be equal to or lower than the maximum dose that has 
been evaluated in the multiple-ascending dose study (daily dose of 2.24 mg/kg/day). The 
LQT-1213-0059 study is ongoing at the time of finalization of this protocol, so the actual 
low, mid, and high doses of LQT-1213 to be used in this study will be determined before 
dosing with LQT-1213 but will not exceed 2.24 mg/kg/day. 
 
3.4.2. 
Part 2 
The TID dosing regimen and dose selection is based on the PK data obtained from the 
ongoing single-ascending dose/multiple-ascending dose study LQT-1213-0059. 
LQT-1213 dose used in Part 2 will be equal to or lower than the maximum dose that has 
been evaluated in the multiple-ascending dose study (daily dose of 2.24 mg/kg/day). 
The actual dose of LQT-1213 to be used in Part 2 will be determined before dosing with 
LQT-1213 but will not exceed 2.24 mg/kg/day. 
 
3.5. 
Dofetilide 
Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker with current 
indications for the conversion of atrial fibrillation/flutter, and for maintenance of normal 
sinus rhythm in patients with atrial fibrillation/flutter of greater than 1 week duration who 
have been converted to normal sinus rhythm. The PK, pharmacodynamic (PD), and 
safety profile of the commercially available formulation of dofetilide has been well 
characterized in prior studies, making it a good candidate for characterization of the 


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interplay between Ikr and late sodium current in cardiac repolarization. 
The dose selection for dofetilide reflects the maximum dose approved in the United 
States (US) product label. The safety of this dose, in addition to its PK, PD, and safety 
profile, has been demonstrated in several cohorts of healthy subjects (Allen et al 2000; 
Johannesen et al 2014; Le Coz et al 1995; Tham et al 1993). Dofetilide was shown to be 
well absorbed with a systemic bioavailability >90%, to reach mean Cmax in 2.6 hours, 
and to have a terminal elimination half-life of about 8 hours (Allen et al 2000; Tham et 
al 1993). 
 
3.6. 
Study Rationale 
This is a Phase 1b/2a, 2-part study. 
 
3.6.1. 
Part 1 
This is a Phase 1b, randomized, double-blind, crossover, dose-escalation, 
placebo-controlled study to evaluate the safety, tolerability, PK, and PD of SGK-1 kinase 
inhibition by LQT-1213 on dofetilide-induced QTc prolongation in healthy adult 
subjects. To avoid any issues with carryover, a washout period of at least 4 days between 
doses or at least 5 times the half-life of LQT-1213 will be utilized. 
 
3.6.2. 
Part 2 
This will be a Phase 2a, single-blind, multiple-dose safety study to evaluate the safety, 
tolerability, and PK of LQT-1213 in participants diagnosed with LQT2 or LQT3. The 
ability to attenuate QT prolongation in LQT2 and LQT3 is the basis for the anticipated 
effect of LQT-1213 in this proposed study. All participants with LQT2 or LQT3 will 
have a QTc by Fridericia’s formula (QTcF) ≥480 and ≤560 ms. Up to 12 participants 
with LQT2 and up to 12 participants with LQT3 will be enrolled, of which the first 2 
participants for each LQT subtype require having an ICD, which must have had ICD 
implantation at least 2 months before Screening. After initial screening which may be 
conducted remotely by the clinical research unit (CRU), individual participants with 
LQT2 or LQT3 will undergo a 1-day, single-blind placebo run-in period followed by 
LQT-1213 administered TID. 
This study has been designed to minimize potential risk to participants. The short dosing 
duration was chosen to reduce any potential long term exposure risk to participants while 
maintaining the ability to assess the objectives of this study. Given the inpatient setting of 
this study, participants will be closely monitored clinically, electrographically, and by 
laboratory assessments during the treatment period. Furthermore, safety data obtained in 
Part 1 of this protocol did not suggest any safety signals or trend and is considered 


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supportive of this current design. 
4. 
Study Objectives 
 
4.1. 
Part 1 
Part 1 is a randomized, double-blind, crossover, dose-escalation, placebo-controlled study 
in 28 healthy adult subjects with the following objectives: 
• Primary: To evaluate the effect of oral LQT-1213 on dofetilide-induced QTc 
prolongation in healthy adult subjects 
• Secondary: To evaluate the safety and tolerability of a combination of oral dofetilide 
and oral LQT-1213 in healthy adults 
• Secondary: To determine the PK of oral LQT-1213 and oral dofetilide in healthy 
adults 
 
4.2. 
Part 2 
Part 2 is a single-blind, multiple-dose study in up to 12 adult participants with LQT2 
and in up to 12 participants with LQT3 with the following objectives: 
• Primary: To evaluate the safety and tolerability of oral LQT-1213 in participants 
with LQT2 or LQT3 
• Secondary: To determine the PK of oral LQT-1213 in participants with LQT2 or LQT3 
• Exploratory: To evaluate the correlation between the PK of LQT-1213 and candidate 
SGK-1 protein targets in participant peripheral blood mononuclear cells (PBMCs) in 
order to derive PK/PD relationships between drug exposure and target engagement; 
additional exploratory PD endpoints may be assessed 


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5. 
Investigational Plan 
 
5.1. 
Study Design 
This is a Phase 1b/2a, 2-part study; Part 1: randomized, double-blind, crossover, 
dose-escalation, placebo-controlled study to evaluate the safety, tolerability, PK, and PD 
of SGK-1 kinase inhibition by LQT-1213 on dofetilide-induced QTc prolongation in 
healthy adult subjects. Part 2: single-blind, multiple-dose safety study to evaluate the 
safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT2 or LQT3. 
 
5.1.1. 
Part 1 
This is a 2-treatment, 2-period crossover study. Approximately 28 healthy subjects, with 
the attempt to balance for sexes, will be enrolled to complete approximately up to 
20 subjects in the study. Additional subjects may be enrolled to compensate for subjects 
that do not complete both treatment periods, at the discretion of the sponsor. The exact 
number will be determined during the conduct of the study. A sentinel group of up to 
5 subjects may be enrolled first if warranted by the principal investigator. 
In both treatment periods, all subjects will receive dofetilide on Days 1 and 2 of each 
period. Randomization will take place before Day 3 of Period 1. Subjects will be 
randomly assigned to 1 of 2 treatment sequences (AB or BA), with treatment arms as 
follows: 
• Arm A: Dofetilide 500 µg BID (2 × 250 µg capsules), orally (Days 1-8) and 
LQT-1213 3 times a day (TID). LQT-1213 or matching placebo dosing: 
o Low dose: 3 doses on Day 3 and the first 2 doses on Day 4 
o Mid dose: Last dose on Day 4, 3 doses on Day 5, and the first 2 doses on Day 6 
o High dose (not to exceed 0.747 mg/kg TID, daily dose 2.24 mg/kg/day): Last dose 
on Day 6, 3 doses on Day 7, and the first dose on Day 8. The specific doses will 
be determined before administration of the first dose of LQT-1213. 
• Arm B: Dofetilide 500 µg BID (2 × 250 µg capsules), orally (Days 1-8) and placebo 
matched to LQT-1213 TID (Days 3-8) 
Note: Only 1 dose of dofetilide and LQT-1213 (or placebo) will be administered on 
Day 8. 
Screening will occur within 28 days of CRU admission. In both treatment periods, 
subjects will be domiciled starting 2 days before dofetilide dosing until after the last 
doses of dofetilide and LQT-1213 or placebo matched to LQT-1213 
(Days –2 through 8). Days 1 and 2 are to establish near-steady state dofetilide plasma 


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levels and observe the QTc response to dofetilide. On Day 1 at 3 hours postdose in 
Period 1 only, the QTcF will be measured in the 3 (triplicate) ECGs and the mean value 
calculated. Measurements will be manually confirmed by a cardiologist who is 
specifically trained and experienced in ECG interval measurements. The ECG 
measurements at baseline and at the 3-hour time points will be performed by the same 
technician and cardiologist. If the mean QTcF increase is <25 ms on the triplicate safety 
ECGs compared with the mean from baseline (triplicate –30 min and triplicate –15 min), 
the subject will be discontinued from the study. If on Day 1 at 3 hours postdose in 
Period 1 only, the mean QTcF on the triplicate ECGs, when repeated within 30 minutes 
and manually confirmed by a cardiologist specifically trained and experienced in ECG 
interval measurements, has a mean value on the 3 (triplicate) repeated ECGs >80 ms 
from the mean baseline QTcF, the dose of dofetilide will be reduced to 250 µg BID. If 
the mean QTcF is >500 ms on Day 1 in Period 1 only (repeated in triplicate within 
30 minutes with a QTcF > 500 ms), the dose of dofetilide will be reduced to 250 µg BID. 
If the safety ECGs (repeated in triplicate within 30 minutes) shows a mean value on the 
3 (triplicate) repeated ECGs of a QTcF of >500 ms on Day 2 or afterwards (or any time 
in Period 2), the subject will be discontinued from the study. All ECGs for these safety 
assessments must be manually confirmed by a cardiologist who is specifically trained and 
experienced in ECG interval measurements before actions are taken. If the dose is 
reduced to 250 µg BID, this will be the dose used in Period 2. Note: If the subject has a 
new QRS >110 ms or a new bundle branch block, then an adjusted QTcF will be utilized 
to account for the widened QRS interval (Adjusted QTcF = QTcF [ms] – [QRS interval 
[ms] – 90 [ms]). 
LQT-1213 or placebo matched to LQT-1213 will be administered at time 0, immediately 
after the 7.75-hour ECG extraction time point, and at 17 hours, though these time points 
may be adjusted based upon emerging data. Subjects will be discharged from the CRU on 
Day 9 or 10 (safety washout) in each period, if the QTcF is <460 ms and the increase 
from baseline is <40 ms. Day 10 evaluations will be performed if the subject is not 
discharged on Day 9. There will be a washout of at least 4 days (or at least 5 times the 
half-life) after the last dose of study drug. Subjects will return to the CRU on Day –2 and 
crossover to receive the alternate treatment in Period 2. 
Approximately 7 days after the end of treatment in Period 2, the Follow-up Visit will be 
conducted remotely via telephone call. 
Full PK sampling for dofetilide and LQT-1213 will be conducted on Days 4, 6, and 8 of 
each period. Continuous 12-lead 24-hour Holter data will be collected at the approximate 
90-minute time point on Day –1 (corresponding to predose on Day 1) and stored, and on 
Day 1 starting 2 hours before dosing through Day 8. On each day, the Holter data card 
will be removed and a new one inserted 90 minutes before dosing. The ECGs will be 
extracted from the Holters on specific days and time points for core laboratory analysis, 
as detailed in the Part 1 PK and PD time points table (Section 8.3, Appendix C). 


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Subjects will have an overnight fast on Days –1 through Day 8 and will remain fasted 
until immediately after the 6-hour ECG extraction, when a light meal will immediately be 
provided, followed by a meal immediately after the 9.5- and 12-hour ECG extraction 
time points. 
Subjects will fast after the meals at 6 and 9.5 hours are completed, which must be within 
20 minutes for these 2 time points. Subjects can eat at will after the 12-hour meal, a light 
meal will be provided, which must be completed to ensure the overnight fasting 
requirement is met (6-hour fast), (no food or fluid except water). Serum potassium and 
magnesium will be checked each day on Days –1, 1, and 2 and thereafter, beginning on 
Day 3, potassium and magnesium will be checked every other day. Potassium 
<3.8 mg/dL and magnesium <1.9 mg/dL will result in additional electrolyte 
supplementation. It is preferred, especially on Days 1, 4, 6, and 8, that this be done in the 
evening (after the 12-hour time point). Electrolyte supplementation is allowed at any time 
as long as it is >4 hours before dosing. 
Safety assessments will include AEs, clinical laboratory test results, vital signs 
measurements, and safety 12-lead ECG findings. Bedside safety 12-lead ECGs will be 
collected by the CRU staff and reviewed by the investigator; 12-lead ECGs will be 
classified as normal or abnormal not clinically significant or abnormal clinically 
significant. The safety ECG data, including all time points, will be recorded on the 
electronic case report form, and be used for evaluating general safety of the subjects 
during study and for evaluation of an AE. The ECGs extracted from Holters and 
analyzed by Clario are the primary ECG data for the analysis of the ECG intervals of 
the study, once completed.  
The dosing, meal timing, and PK and ECG time points and extractions may be modified 
based on emerging data. 
Stopping rules will be predefined and evaluated after each successive dosing group. 


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Figure 5-1 Study Schematic - Part 1 
 
5.1.2. 
Part 2 
This is a Phase 2a, single-blind, multiple-dose, safety study to evaluate the safety, 
tolerability, and PK of LQT-1213 in participants with LQT2 or LQT3. The study will 
utilize TID dosing of LQT-1213 for 3 days (the last dosing day will be a single dose). 
The actual dose may be modified based upon evolving data. After the second participant 
completes the end of study visit for each LQT subtype (LQT2 or LQT3), a safety review 
committee (SRC) will review all available data before enrolling additional participants. 
All participants with LQT2 or LQT3 will have a QTcF ≥480 and ≤560 ms. Up to 
12 participants with LQT2 and up to 12 participants with LQT3 will be enrolled. The 
first 2 participants with LQT2 require having an ICD before further participants with 
LQT2 are enrolled and the first 2 participants with LQT3 require having an ICD before 
further participants with LQT3 are enrolled. The ICD implantation must have been 


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performed at least 2 months before Screening. After initial screening, which may be 
conducted remotely by the CRU, individual participants with LQT2 or LQT3 will 
undergo a 1-day, single-blind placebo run-in period followed by 3 dosing days of 
LQT-1213 administered TID (the last dosing day will have a single dose). 
Screening (remote or in-person) will be conducted within 60 days of CRU admission. 
Participants with LQT2 or LQT3 will be domiciled starting on Day –1 until the end of 
treatment on Day 5. On Day 1, participants with LQT2 or LQT3 will undergo baseline 
24-hour 12-lead high fidelity Holter monitoring during placebo single-blind 
administration. 
LQT-1213 will be administered TID (at time 0, 8, and 16 hours) on Days 2 and 3, with 
the final dose on Day 4 at time 0, though these time points may be adjusted based upon 
emerging data. Participants with LQT2 or LQT3 will be discharged from the CRU on 
Day 5. Approximately 7 days after discharge from the CRU, the Follow-up Visit will 
be conducted remotely via telephone call. 
The intensive PK sampling for LQT-1213 will be conducted on Days 2 and 4, and the 
morning of Day 5. Continuous 12-lead 24-hour Holter data will be collected on 
Days −1 through 5, as detailed in the PK and PD time points table (Section 8.4 
Appendix D). All Holter data starting on Day -1 will be stored for potential future 
analysis. On each day, the Holter data card will be removed and a new one inserted 
approximately 90 minutes before first dosing on each Days and on Day 5. ECG 
extraction time points for potential future analysis are detailed in the PK and PD time 
points table (Section 8.4, Appendix D). 
Serum potassium and magnesium will be checked daily while participants are housed 
(Days −1, 1, 2, 3, 4, and 5) and may be repeated at any time at the investigator’s 
discretion. Potassium <3.8 mg/dL and magnesium <1.8 mg/dL will result in additional 
electrolyte supplementation. Electrolyte supplementation can be administered 
12-18 hours after the morning dose of LQT-1213. 
Safety assessments will include AEs, clinical laboratory test results, vital signs 
measurements, continuous telemetry ECG monitoring, and safety 12 lead ECG findings. 
Bedside safety 12-lead ECGs will be collected by the CRU staff and reviewed by the 
investigator. The safety ECG data, including all time points, will be recorded on the 
electronic case report form, and be used for evaluating general safety of the participants 
with LQT2 or LQT3 during the study and for evaluation of an AE. 
The dosing, meal timing, and PK and ECG time points and extractions may be modified 
based on emerging data. 


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Figure 5-2 Study Schematic - Part 2 
 
Abbreviations: TID, 3 times a day; CRU, clinical research unit; EOS, end of study; EOT, end of treatment; ET, 
early termination; F/U, Follow-Up; QTcF, QT interval corrected for heart rate by Fridericia’s formula. 
a 
Up to 12 participants with LQT2 and up to 12 participants with LQT3 will be enrolled, of which the first 
2 participants for each LQT subtype require having an implantable cardioverter defibrillator (ICD), which must 
have had ICD implantation at least 2 months before Screening. All participants with LQT2 or LQT3 will have a 
QTcF ≥480 and ≤560 ms. 
b 
On Day 1, participants with LQT2 or LQT3 will undergo baseline 24-hour 12-lead high fidelity Holter 
monitoring during placebo single-blind administration. 
c 
LQT-1213: LQT-1213 will be administered TID (at time 0, 8, and 16 hours) on Day 2 and 3, with the final 
dose on Day 4 at time 0, though these time points may be adjusted based upon emerging data. 
d 
Approximately 7 days after discharge from the CRU, the Follow-up Visit will be conducted remotely via 
telephone call. 
 
 
5.1.3. 
Safety Review Committee 
In Part 2, after the second participant completes the end of study visit for each LQT 
subtype (LQT2 or LQT3), a SRC, will at a minimum, be comprised of the 
investigator and sponsor’s chief medical officer and medical monitor. Other 
consultants may be added to the SRC as needed. The data reviewed will include any 
available PK, PD, and safety data as well as any other findings that the investigator 
or sponsor finds clinically significant. One primary responsibility of the SRC is to 
review accumulated safety and PK (as available) and make recommendations for 
continued participant enrollment. The SRC may recommend changes to the planned 
dosing scheme, adding dose groups, stopping dosing, and potential replacement of 
participants. The final outcome/decision from the SRC will be documented. 
Additional details may be found in the SRC Charter. 


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5.2. 
Selection of Study Population 
The investigator or designee will be responsible for confirming subject eligibility by 
documenting in the electronic case report form (eCRF) that each subject meets all of the 
inclusion criteria in Section 5.2.1 and does not meet any of the exclusion criteria in 
Section 5.2.2. 
 
5.2.1. 
Inclusion Criteria 
 
5.2.1.1. 
Part 1 
All subjects considered for study participation must meet the following criteria: 
1. Male and female subjects between 18 and 60 years of age (inclusive) at Screening. 
2. Not previously enrolled in a clinical study with LQT-1213. 
3. Normal general health. 
4. Body mass index within 18.0 to 32.0 kg/m2, inclusively at Screening. 
5. Female subjects of nonchildbearing potential must be either surgically sterile 
(hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy 
at least 26 weeks before Screening) or postmenopausal, defined as spontaneous 
amenorrhea for at least 2 years, with follicle-stimulating hormone in the 
postmenopausal range at Screening, based on the central laboratory’s ranges. 
6. Female subjects of childbearing potential (ie, ovulating, premenopausal, and not 
surgically sterile) must use a highly effective contraceptive regimen during their 
participation in the study and for 30 days after the last administration of study drug. 
Highly effective contraceptive methods are defined as those with <1% failure rate per 
year. Acceptable methods of contraception for female subjects enrolled in the study 
include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Heterosexual abstinence 


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7. Male subjects and their partners must use highly effective methods of contraception 
(ie, condom and spermicide) for the entire duration of the study. Male subjects must 
continue to use contraception and refrain from fathering a child and sperm donation 
for 90 days after the last administration of study drug. Acceptable methods of 
contraception for male subjects enrolled in the study include the following: 
• Condoms and spermicide 
• Surgical sterilization (vasectomy) of the subject at least 26 weeks before 
Screening 
• Heterosexual abstinence (subject must agree to use condom and spermicide if 
they become sexually active) 
8. Understand the requirements of the study and voluntarily consent to participate in the 
study. 
 
5.2.1.2. 
Part 2 
All participants with LQT2 or LQT3 considered for study participation must meet 
the following criteria: 
1. Male and female participants 18 years of age or older at Screening. 
2. Body weight of at least 45 kg at Screening. 
3. Female participants of nonchildbearing potential must be either surgically sterile 
(hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy 
at least 26 weeks before Screening) or postmenopausal, defined as spontaneous 
amenorrhea for at least 2 years, with follicle-stimulating hormone in the 
postmenopausal range (>40 mlU/mL) at Screening, based on the central laboratory’s 
ranges. 
4. Female participants of childbearing potential (ie, ovulating, premenopausal, and not 
surgically sterile) must use a highly effective contraceptive regimen during their 
participation in the study and for 30 days after the last administration of study drug. 
Highly effective contraceptive methods are defined as those with <1% failure rate per 
year. Acceptable methods of contraception for female participants enrolled in the 
study include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 


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• Bilateral tubal occlusion 
• Vasectomized partner 
• Heterosexual abstinence 
5. Male participants and their partners must use highly effective methods of 
contraception (ie, condom and spermicide) for the entire duration of the study. 
Male participants must continue to use contraception and refrain from fathering a 
child and sperm donation for 90 days after the last administration of study drug. 
Acceptable methods of contraception for male participants enrolled in the study 
include the following: 
• Condoms and spermicide 
• Surgical sterilization (vasectomy) of the participant at least 26 weeks 
before Screening 
• Heterosexual abstinence (participant must agree to use condom and 
spermicide if they become sexually active) 
6. LQT2 or LQT3 mutation: 
• LQTS 2: Participants with potassium voltage-gated channel subfamily H member 
2 (KCNH2) mutations that are dominant negative and considered to be pathologic 
or likely pathologic by the screening laboratory can be included after approval 
from the sponsor. Participants with haploinsufficiency will not be eligible for this 
study. 
• LQTS 3: Participants with a sodium voltage-gated channel alpha subunit 5 
(SCN5A) gene chromosome 3 mutations that are mutations and considered to be 
pathologic or likely pathologic by the screening laboratory can be included after 
approval from the sponsor. Participants with mutations not associated with 
Brugada syndrome or overlap syndromes or where mutations affect the window 
current or the persistent ‘late’ Na current to exert a primary or major role in the 
phenotype, will be eligible for this study. 
7. QTcF interval ≥480 and ≤560 ms determined at Screening and on Day −1 triplicate 
ECGs as assessed by a physician trained in complex ECG interpretation. 
8. The first 2 participants with LQT2 require having an ICD before further 
participants with LQT2 are enrolled and the first 2 participants with LQT3 require 
having an ICD before further participants with LQT3 are enrolled. This stipulation 
may be altered based on agreement between the principal investigator and Sponsor 
based on emerging data. The ICD implantation must have been at least 2 months 
before Screening. 
Note: Subsequent participants may or may not have had an ICD. The results of the 
ICD interrogation within the last 6 months should be available for review unless 


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waived by the investigator and sponsor. 
9. Understand the requirements of the study and voluntarily consent to participate in the 
study. 
 
5.2.2. 
Exclusion Criteria 
 
5.2.2.1. 
Part 1 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. On Day 1 at 3 hours postdose in Period 1 only, of the first cycle of dofetilide, the 
QTcF on the triplicate ECGs will be manually confirmed by cardiologist experienced 
in ECG interval measurements. The ECG measurements at baseline and at the 3-hour 
time points will be performed by the same technician and cardiologist. If the mean 
QTcF increase from baseline is <25 ms on triplicate safety ECGs compared to the 
mean from baseline (all ECG QTcF measurements averaged), the subject will be 
disqualified from further study participation. 
2. Clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, 
endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease 
or any other condition, which, in the opinion of the investigator, would jeopardize the 
safety of the subject or impact the validity of the study results. No history of 
myocardial infarction or angina or ischemic heart disease, nonsustained or sustained 
ventricular tachycardia, atrial fibrillation, stroke, transient ischemic attack, syncope, 
congestive heart failure, family history of LQTS, Torsades de Pointes, or sudden 
cardiac death. 
3. Female subjects must not be pregnant, lactating, or breastfeeding, and must not be 
planning to become pregnant. 
4. Female subjects of childbearing potential must have a negative result for the serum 
pregnancy test at Screening and Check-in. 
5. Clinically significant abnormal findings on the physical examination or medical 
history during Screening as deemed by the investigator. 
6. Participated in a previous clinical study in the previous 3 months before dosing. 
7. Donation of blood volume greater than 300 mL within 30 days before Screening and 
agree to avoid donation from Screening and throughout the study. 
8. At Screening and on Day –2, if the 12-lead ECG demonstrates any of the following: 
PR >240 ms; QRS >110 ms, or QTcF <400 ms and >440 ms; second- or third-degree 
atrioventricular block; bundle branch block, significant ST-T wave abnormalities or 


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flat T waves that could interfere with QT analysis. If HR <50 or >85 bpm, then 
2 more ECGs will be recorded, and the mean values will be used. 
9. Known sensitivity to kinase inhibitors. 
10. Abnormal renal function with an estimated glomerular filtration rate (eGFR) of 
<70 mL/min/1.73 m2, with eGFR calculated by the Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] formula at Screening. One retest of the 
exclusionary eGFR value is allowed at the discretion of the investigator. 
11. Subject has abnormal liver function tests (transaminases or total bilirubin) greater 
than 2.5 × the upper limit of normal at Screening or baseline. One retest of 
exclusionary abnormal liver function tests is allowed at the discretion of the 
investigator. 
12. Subject has a positive serology test for HIV antibodies, hepatitis B surface antigen, or 
hepatitis C virus antibody at Screening. 
13. Subject has a hemoglobin <11.0 g/dL, potassium <3.8 mg/dL, 
magnesium <1.9 mg/dL, or calcium <8.5 mg/dL at Screening or baseline. One retest 
of exclusionary hemoglobin, potassium, magnesium, and calcium is allowed at the 
discretion of the investigator. Electrolyte supplementation is allowed at any time as 
long as it is >4 hours before dosing. 
14. Subject has a history of hypersensitivity to drugs with a clinically significant reaction 
or any clinically significant hypersensitivities. 
15. Subject has an allergy to band aids, adhesive dressing, or medical tape. 
16. Subject has a history within the past 2 months of strenuous exercise (eg, marathon 
running) and is unwilling to refrain from strenuous exercise from 7 days before 
Check-in and until the end of the study. Subject has abnormal creatine phosphokinase 
test greater than 3 × the upper limit of normal at Screening and baseline. One retest of 
exclusionary abnormal creatine phosphokinase tests is allowed at the discretion of the 
investigator. 
17. Subject is unable to refrain from or anticipates the use of any drug, including 
prescription and nonprescription medications (with the exception of hormonal 
contraception), herbal preparations, or vitamin supplements beginning 14 days before 
the first dose and until the end of the study. After dosing, acetaminophen (up to 2 g 
per 24 hours) may be administered at the discretion of the investigator or designee. 
a. Hepatic or renal clearance altering agents within 30 days before the first dose and 
until the end of the study. 
b. Avoid vaccinations from Screening until the end of the study. 


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c. Has consumed cruciferous vegetables (eg, kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts, and mustard greens) or charbroiled meats 
within 7 days before Check-in through the Follow-up Visit. 
d. Use of any drugs known to be significant strong inducers of cytochrome P450 
(CYP) 3A enzymes, including St. John’s Wort, for 28 days before Day –1 or 
5 half-lives (whichever is longer) and through the Follow-up Visit. 
e. Has consumed Seville oranges, grapefruit and/or grapefruit juice within 14 days 
before Check-in and is unwilling to abstain from consuming these items until the 
end of the study. 
18. Subject is considering or scheduled to undergo any surgical procedure during the 
study. 
19. Subject has experienced an acute illness that has resolved in less than 14 days before 
the first study drug dose or has had a major illness or hospitalization within 1 month 
before the first study drug dose. 
20. Subject is unwilling to abstain from ingestion of caffeine- or xanthine-containing 
products (eg, tea, coffee, chocolate, cola, etc.) beginning 96 hours before Check-in 
until the final PK sample of the study has been collected. 
21. Subject is unwilling to abstain from alcohol beginning 48 hours before Check-in and 
until the final PK sample of the study has been collected. 
22. Subject has a history of high alcohol consumption within 9 months before Screening, 
defined as an average weekly intake of >14 units for males or >10 units for females. 
One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass 
(125 mL) of wine, or 1 measure (25 mL) of spirits. 
23. Subject has a history of drug abuse in the 3 years before Screening or positive screen 
for drugs of abuse or alcohol at Screening or baseline. Subjects may undergo a repeat 
urine drug screen at the discretion of the investigator. 
24. Subject uses or has used tobacco-or nicotine-containing products (eg, cigarettes, 
cigars, chewing tobacco, snuff, etc.) within 6 months before Screening and is 
unwilling to abstain from tobacco-containing products until the end of the study, 
based on subject self-reporting. 
25. Subject, who, for any reason, is deemed by the investigator to be inappropriate for 
this study or has any condition which would confound or interfere with the evaluation 
of the safety, tolerability, or PK of the investigational drug or prevent compliance 
with the study protocol. 


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5.2.2.2. 
Part 2 
Participants with LQT2 or LQT3 will be excluded from the study if they meet any of 
the following criteria: 
1. Clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, 
endocrine, oncologic, pulmonary, immunologic, psychiatric, or significant structural 
cardiovascular disease or any other condition beyond LQT2 or LQT3, which, in the 
opinion of the investigator or sponsor, would jeopardize the safety of the participant 
or impact the validity of the study results. History of myocardial infarction or 
ongoing angina or active ischemic heart disease, atrial fibrillation, stroke, or transient 
ischemic attack within the past 12 months, greater than New York Heart Association 
Class II congestive heart failure, bundle branch block, hemodynamically significant 
ventricular tachycardia not due to Torsades de Pointes, or Brugada syndrome. 
2. Participant has a history of an aborted cardiac arrest, ICD implantation, syncopal 
episode due to a ventricular arrhythmia or where confidence in the etiology cannot be 
established, or appropriate ICD therapy for ventricular tachycardia/ventricular 
fibrillation within 2 months before Screening. Participants with LQT2 or LQT3 can 
be enrolled after the 2-month time period has lapsed. 
3. Female participants must not be pregnant, lactating, or breastfeeding, and must 
not be planning to become pregnant. 
4. Female participants of childbearing potential must have a negative result for the 
serum pregnancy test at Screening and Check-in. 
5. Clinically significant abnormal findings on the physical examination at Check-in or 
medical history during Screening as deemed by the principal investigator. 
6. Currently participating in another interventional clinical study. 
7. Donation of blood volume greater than 300 mL within 30 days before dosing and 
unwilling to avoid donation from Screening and throughout the study. 
8. Screening diastolic blood pressure <45 or >95 mm Hg, systolic blood pressure <90 or 
>150 mm Hg, or with sponsor and investigator approval. 
9. At Screening and on Day –1, if the triplicate 12-lead ECG demonstrates any of the 
following: mean PR >250ms; QRS >110 ms, or QTcF >560 ms and <480 ms; bundle 
branch block or significant ST-T wave abnormalities or flat T waves that could 
interfere with QT analysis. Heart rate <45 bpm, unless receiving a beta-blocker in 
which case <40 bpm, or HR >95 bpm. If any of these exclusionary criteria are met, 
then a second set of triplicate ECGs may be acquired, and the mean values may be 
used. For participants on beta blockade, the PR interval may be higher than 250 ms 
with sponsor and investigator approval. 
10. Atrial pacing rate set to ≥80 bpm in those with atrial pacing. 


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11. Participant has a pacemaker or ICD that is actively used for ventricular pacing. 
12. Known sensitivity to kinase inhibitors or clinically significant drug allergies to any of 
the components of LQT-1213. 
13. Abnormal renal function with an eGFR of <60 mL/min/1.73 m2, with eGFR 
calculated by the CKD-EPI formula at Screening. One retest of the exclusionary 
eGFR value is allowed at Screening and Check-in at the discretion of the investigator. 
14. Participant has abnormal liver function tests (transaminases greater than 2 × the 
upper limit of normal [ULN] or total bilirubin > 1.5 × ULN. If the participant has 
documented Gilbert’s Syndrome, participation is at the combined principal 
investigator and Sponsor’s discretion after review of historical liver and bilirubin 
tests. 
15. Participant has a positive serology test for HIV antibodies, hepatitis B surface 
antigen, or hepatitis C virus antibody at Screening. 
16. Participant has a hemoglobin <11.0 g/dL, potassium <3.8 mg/dL, magnesium 
<1.8 mg/dL, or calcium <8.5 mg/dL at Screening or baseline. One retest of 
exclusionary hemoglobin, potassium, magnesium, and calcium is allowed at the 
discretion of the investigator. 
17. Participant has a history of hypersensitivity to drugs with a clinically 
significant reaction or any clinically significant hypersensitivities. 
18. Participant has a clinically significant allergy to band aids, adhesive dressing, ECG 
electrodes, or medical tape. 
19. Participant has abnormal creatine phosphokinase test greater than 3 × the ULN at 
Screening or baseline. One retest of exclusionary abnormal creatine phosphokinase 
tests is allowed at the discretion of the investigator. 
20. Participant is currently taking, within the last 7 days before Spaulding admission or 
5 half-lives (whichever is longer), or anticipates the use of any antiarrhythmic 
medications (including mexilitene except beta-blockers which are allowed,) or drugs 
known to affect the QT interval (including ranolazine; refer to drug lists for “Drugs 
with known, possible, or conditional risk of TdP” that are known to prolong the QT 
interval at https://crediblemeds.org), unless approved by the sponsor and principal 
investigator. 
21. Participant is not permitted to use/consume the following: 
a. Any drugs known to be significant strong inducers of CYP 3A enzymes, 
including St. John’s Wort, for 28 days before Day –1 or 5 half-lives (whichever is 
longer) and through the Follow-up Visit. 
b. Seville oranges, grapefruit and/or grapefruit juice within 7 days before Check-in 
and is unwilling to abstain from consuming these items until the end of the study. 
22. Participant is considering or scheduled to undergo any surgical procedure during 


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the study. 
23. Participant has experienced an acute illness that has resolved in less than 14 days 
before the first study drug dose or has had a major illness or hospitalization within 1 
month before the first study drug dose. 
24. Participant is unwilling to abstain from ingestion of caffeine- or xanthine- 
containing products (eg, tea, coffee, chocolate, cola, etc.) beginning 96 hours 
before Check-in until the final PK sample of the study has been collected. 
25. Participant is unwilling to abstain from alcohol beginning 48 hours before Check-in 
and until the final PK sample of the study has been collected. 
26. Participant has a history of high alcohol consumption or substance abuse that would 
pose a risk for the participant’s safety and compliance with the study protocol. 
Participant must not have positive screen for drugs of abuse at Screening or baseline 
and alcohol at baseline, except with sponsor permission. Participants may undergo a 
repeat urine drug screen at the discretion of the investigator. 
27. Participant, who, for any reason, is deemed by the investigator to be inappropriate for 
this study or has any condition which would confound or interfere with the evaluation 
of the safety, tolerability, or PK of the investigational drug or prevent compliance 
with the study protocol. 
 
5.3. 
Withdrawal of Subjects from the Study 
5.3.1. 
Reasons for Withdrawal 
Parts 1 and 2: The primary reason for treatment discontinuation will be noted using the 
following categories: 
1. Adverse event: The subject experiences an AE that, in the opinion of the 
investigator, requires early termination. If a subject is discontinued from the study 
due to an AE, the investigator or designee will be required to follow-up with the 
subject until the event resolves or becomes stable. If a subject dies during the study, 
the cause of death will be reported as a serious AE (SAE), with an outcome of death 
noted on the eCRF. 
Additionally, refer to Section 5.4.3.5 for safety 12-lead ECG discontinuation criteria. 
2. Stopping criterion: The subject meets one of the stopping criteria for individual 
subjects (Section 5.3.3). 
3. Protocol deviation/violation: The subject fails to meet protocol entry criteria or does 
not adhere to protocol requirements, and continued participation poses an 
unnecessary risk to the subject’s health. 
Note: For Part 1 only, if the safety ECGs (repeated in triplicate within 30 minutes) 


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shows a mean QTcF of >500 ms on the repeated (triplicate) ECGs on Day 2 or 
afterwards, which will be manually confirmed by a cardiologist who is specifically 
trained and experienced in ECG interval measurements, the subject will be 
discontinued from the study. Details for subject discontinuation from the study and 
QTcF adjustment for a new QRS >110 ms or a new bundle branch block are provided 
in Section 5.3.3. 
4. Voluntary withdrawal of consent: The subject wishes to withdraw from the study for 
any reason. 
Note: Withdrawal due to an AE will not be recorded in the voluntary withdrawal 
category. 
5. Study termination: The sponsor, institutional review board (IRB), Food and Drug 
Administration (FDA), or other regulatory agency terminates the study. 
6. Pregnancy: The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject is to be withdrawn 
immediately. The pregnancy will be followed to term, and the outcome, including 
premature termination, will be recorded. A second follow-up will be performed after 
30 calendar days of pregnancy outcome. 
7. Other. 
Note: This category includes withdrawals caused by an accidental or a medical 
emergency, unblinding, or other rare cases. The specific reasons will be recorded on 
the eCRF. 
 
5.3.2. 
Handling of Withdrawals 
Parts 1 and 2: The investigator may terminate a subject’s study participation at any time 
during the study if the subject meets any of the withdrawal criteria described in 
Section 5.3.1. Should a subject’s participation be discontinued, the primary reason for 
termination must be recorded. In addition, efforts will be made to perform all early 
termination procedures specified in the schedule of events (Section 8.1, Appendix A and 
Section 8.2, Appendix B). The AE eCRF will be completed for each AE. 
 
5.3.3. 
Stopping Criteria for Individual Subjects 
 
5.3.3.1. 
Part 1 
A subject will be withdrawn from the study if he or she meets any of the following 
criteria: 
• Alanine aminotransferase ≥5 × ULN, confirmed on a repeat measurement, 


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not due to an obvious nondrug etiology. 
• ECG criteria 
Note: The QTcF is always used, regardless of the HR. 
IMPORTANT: When evaluating the safety signals below, the QTcF or arrhythmia 
must be confirmed by a cardiologist who is specifically trained and experienced in 
ECG interval measurements or a cardiac electrophysiologist. 
o Torsades de Pointes associated with a QTcF >500 ms 
o Repetitive pause-dependent ventricular ectopy associated with at least a 35% 
increase in the QTc interval. 
o Potential dose-down titration. Note: These measurements will be manually 
confirmed by a cardiologist specifically trained and experienced in ECG interval 
measurements. The ECG measurements at baseline and at 3 hours postdose on 
Day 1 of Period 1 will only be evaluated by the same technician and cardiologist. 
If on Day 1 at 3 hours postdose in Period 1 only, the mean QTcF on the triplicate 
ECGs, when repeated within 30 minutes, show a mean increase >80 ms from the 
mean baseline QTcF on the 3 (triplicate) repeated ECGs, the dose of dofetilide 
will be reduced to 250 µg BID. 
o If at any time after the first dose of dofetilide, a subject develops a QTcF 
>500 ms, 2 additional ECGs will be immediately performed, and then the ECG 
will be repeated approximately 30 minutes later, in triplicate. Note: If the subject 
has a new QRS >110 ms or a new bundle branch block, then an adjusted QTcF 
will be utilized to account for the widened QRS interval (Adjusted QTcF = QTcF 
[ms] – [QRS interval [ms] – 90 ms]). If the mean QTcF increase of the triplicate 
ECGs is confirmed (mean QTcF of the 3 (triplicate) repeated ECGs is >500 ms): 
 If this occurs on Day 1, the dose of dofetilide will be reduced to 250 µg BID. 
 If this occurs on Day 2 or afterwards (or any time in Period 2), the subject will 
be discontinued from the study. 


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Findings that meet any of these criteria should be reported to the sponsor 
immediately. 
 
5.3.3.2. 
Part 2 
A participant with LQT2 or LQT3 will be withdrawn from the study if he or she meets any 
of the following criteria: 
• Alanine aminotransferase (ALT) or aspartate transaminase (AST) ≥8 × 
upper limit of normal, confirmed on a repeat measurement, not due to an 
obvious nondrug etiology. 
 
 
ALT or AST >3 times the ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (treatment emergent 
>5% with at least a 75% increase from baseline) 
 
• ALT or AST ≥3 × ULN in conjunction with total bilirubin > 2× ULN, 
without initial findings of cholestasis (elevated serum alkaline phosphatase) 
confirmed on a repeat measurement, not due to an obvious nondrug 
etiology. 
• ECG criteria 
Note: The QTcF is always used, regardless of the HR. 
IMPORTANT: When evaluating the safety signals below, the QTcF or arrhythmia 
must be confirmed by a cardiologist who is specifically trained and experienced in 
ECG interval measurements or a cardiac electrophysiologist. 
If at any time after the first dose of LQT-1213, a participant develops a QTcF 
>600 ms with an increase from baseline >50 ms; or an increase from baseline 
>70 ms, 2 additional ECGs will immediately be performed, and then the ECG will 
be repeated approximately 30 minutes later, in triplicate. If the criteria are met 
(participant develops a QTcF >600 ms with an increase from baseline >50 ms; or 
an increase from baseline >70 ms) on the second triplicate ECG, the participant 
will be withdrawn from the study. 
o Episodes of Torsades de Pointes will be evaluated by the sponsor’s medical 
monitor and principal investigator. Further dosing will be held until a decision 
regarding participant disposition is made. 


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5.3.4. 
Stopping Criteria for the Study 
 
5.3.4.1. 
Part 1 
The study may be terminated if any of the following stopping criteria are met: 
• 2 or more subjects experience documented Torsade de Pointes ventricular tachycardia 
with a QTcF >500 ms (which are not associated with hypokalemia or 
hypomagnesemia) confirmed by a cardiac electrophysiologist. 
• 2 subjects with confirmed alanine aminotransferase ≥10 × upper limit of normal, 
confirmed on a repeat measurement, not due to an obvious nondrug etiology. 
 
5.3.4.2. 
Part 2 
The study may be terminated upon the following: 
• 2 participants with confirmed ALT or AST ≥10 × ULN, confirmed on a repeat 
measurement, not due to an obvious nondrug etiology. 
• 2 participants with confirmed ALT or AST ≥3 × ULN in conjunction with 
total bilirubin > 2× ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) confirmed on a repeat measurement, not due to 
an obvious nondrug etiology 
• Potentially significant QTc prolongations or clinically significant cardiac arrhythmias 
will be promptly reviewed by the SRC and it will be decided if a new participant can 
receive study drug or if the study will be stopped or modified. 
Any potentially clinically significant QTc prolongations or clinically 
significant cardiac arrhythmias must be reported to the sponsor’s medical 
monitor. 
 
5.3.5. 
Replacement Subjects 
Parts 1 and 2: Any subject who is withdrawn or discontinued from the study may be 
replaced after mutual agreement between the sponsor and the investigator, except for drug- 
related hepatic adverse events of special interest (AESI) leading to study discontinuation. 
 
5.4. 
Study Procedures 
Note: When assessment time points coincide, the order of assessments will be 
ECGs/ECG extraction window, PK blood sample collection followed by vital sign 


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measurements. When a PK blood sample collection time point coincides with study drug 
dosing, the PK sample will be collected before study drug dosing. Extractions and ECG 
analysis will not be performed on all Holter data collected. 
 
5.4.1. 
Pharmacodynamic Assessments 
5.4.1.1. 
Part 1 
Pharmacodynamics will be evaluated using extracted ECG data obtained from continuous 
12-lead Holter monitors placed on all subjects in Periods 1 and 2 at time points specified 
in the PK and PD time points table (Section 8.3, Appendix C) and will be analyzed based 
on accumulating safety and PK data, which may result in changes in the PK and ECG 
extraction time points. In both treatment periods, Holter recordings on Day 1 (predose 
time points only) and Days 4, 6, and 8 may be analyzed. The Holter recordings from 
Day –1, the other time points on Day 1, and Days 2, 3, 5, and 7 will be stored at the CRU 
for possible future analysis. Up to 10 replicate 12-lead ECG recordings will be extracted 
from the Holter monitor data within a 5-minute window with time points scheduled 
before the PK blood sample collections. Holter and PK data and extractions may be 
modified based on the evolving data. Holter recordings will be collected for 2 hours 
predose on Day 1 and 3 ECG extractions will be performed. Continuous 12-Lead ECG 
acquisition for Part 1 will be described in the statistical analysis plan (SAP). 
 
5.4.1.2. 
Part 2 
Pharmacodynamic endpoint data will be evaluated using SGK-1 protein targets. Central 
ECG analysis is not planned at this time but may be performed after database lock. 
Part 2 only: Human PBMC and plasma samples will be harvested and isolated from 
the blood samples and stored for potential analysis of PD biomarkers, including SGK 
protein targets. Details for PD sample collection are specified in Section 8.2, 
Appendix B. 
 
5.4.2. 
Pharmacokinetic Assessments 
Parts 1 and 2: Where PK sampling time points coincide with the triplicate ECG time 
points, the extraction window will end before each PK collection nominal time point. 
Details for PK blood sample collection are specified in Section 8.3, Appendix C and 
Section 8.4, Appendix D. 
Detailed instructions for the handling and shipping of PK samples will be outlined in the 
laboratory manual. 


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5.4.2.1. 
Part 1 
Blood samples for dofetilide and LQT-1213 PK analysis will be collected in both 
treatment periods on Days 4, 6, and 8 at the following time points: predose (time 0 for 
dofetilide) and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7.75, 9.5, 12, and 24 hours postdose. 
 
5.4.2.2. 
Part 2 
 
Blood samples for LQT-1213 PK analysis will be collected as detailed in Section 8.4, 
Appendix D. 
 
5.4.3. 
Safety Assessments 
Safety will be determined by monitoring AEs, clinical laboratory test results 
(hematology, serum chemistry, coagulation, and urinalysis), vital sign measurements 
(blood pressure, HR, respiratory rate, and oral body temperature), continuous telemetry 
ECG monitoring (Part 2 only), 12-lead ECG results, and physical examination findings. 
Part 1: An emergency physician will be present for at least the first 6 hours for initial 
dosing of dofetilide. Advanced Cardiovascular Life Support (ACLS)-experienced nurses 
or paramedics will be present for at least 72 hours for initial dofetilide dosing, and 
ACLS-trained physicians, physicians assistants, nurse practitioners, paramedics, or 
registered nurses will be present on Days 1 through 9. The CRU is equipped with 
appropriate emergency equipment and medications, including a defibrillator and ACLS 
medications. The staff will be trained in the management of ventricular arrythmias and 
Torsades de Pointes. 
Part 2: An emergency physician will be present for at least the first 6 hours for initial 
dosing of LQT-1213 on Day 2. Advanced Cardiovascular Life Support-experienced 
nurses or paramedics will be present for at least 48 hours for initial LQT-1213 dosing, 
and ACLS-trained physicians, physicians assistants, nurse practitioners, paramedics, or 
registered nurses will be present on Days 1 through 5. The CRU is equipped with 
appropriate emergency equipment and medications, including a defibrillator and ACLS 
medications. The staff will be trained in the management of ventricular arrythmias and 
Torsades de Pointes. 
At the discretion of the investigator, additional safety assessments may be performed as 
needed to ensure participant safety. 
 
5.4.3.1. 
Adverse Events 
An AE is defined (per ICH of Technical Requirements for Registration of 
Pharmaceuticals for Human Use E2A) as any untoward medical occurrence in a patient 


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or clinical investigation subject administered a pharmaceutical product whether there was 
a causal relationship with this treatment. 
An AE can, therefore, be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom, or disease that is temporally associated with the use of a 
medicinal (investigational) product, whether it is related to the medicinal (investigational) 
product or not related to the medicinal (investigational) product. 
For Part 1, a treatment-emergent AE (TEAE) is defined as an AE with onset date/time 
after LQT-1213 or placebo matched to LQT-1213 administration or a continuing AE with 
an onset date/time before LQT-1213 or placebo matched to LQT-1213 administration. 
For Part 2, a TEAE is defined as an AE with onset date/time after LQT-1213 
administration. 
All AEs occurring before LQT-1213 administration will be provided in a data listing. 
An adverse reaction is any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there are reasons to conclude that the drug caused 
the event. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
study drug caused the AE. For the purposes of investigational new drug safety reporting, 
“reasonable possibility” means that there is evidence to suggest a causal relationship 
between the study drug and the AE. A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any AE caused by a study 
drug. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator’s brochure or at the specificity or severity that has been observed with the 
study drug being tested; or, if an investigator’s brochure is not required or available, is 
not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator’s brochure referred 
only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater specificity) if the 
investigator’s brochure listed only cerebral vascular accidents. “Unexpected,” as used in 
this definition, also refers to AEs or suspected adverse reactions that are mentioned in the 
investigator’s brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation. 
Adverse events will be recorded from the time of provision of written informed consent 
through Follow-up (Section 8.1, Appendix A and Section 8.2, Appendix B). At each 
study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question such as, “How have you been feeling since your last visit?” will be 
asked. Participant may report AEs that occur at any other time during the study. 


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All participants experiencing AEs, whether considered associated with the use of the 
study drug or not, will be followed until resolution or until the investigator judges that 
further follow-up is not necessary. All AEs will be documented on the AE page of the 
eCRF, whether or not the investigator concludes the event is related to the study drug. 
The event term, start and stop date, and severity will be documented, along with the 
investigator’s opinion of the causal relationship between the event and study drug 
administration (not, unlikely, possibly, or probably related). 
 
Severity of Adverse Events 
An AE may occur during or following the administration of the investigational compound 
or control agent. Each AE will be graded according to severity using the following 
criteria as appropriate: 
• Mild: The experience does not cause substantial discomfort; symptoms are well 
tolerated and do not interrupt or hinder the subject’s daily activities; the experience 
resolves spontaneously, and no treatment is required beyond administration of 
nonprescription medication. 
• Moderate: The experience causes some discomfort and the symptoms experienced 
interfere with but do not interrupt the subject’s daily activities; the experience may 
require treatment with prescription medication. 
• Severe: The experience substantially hinders or interrupts the subject’s daily 
activities; the subject may be incapacitated and may require prolonged treatment with 
prescription medication. 
Causality of Adverse Events 
The investigator must attempt to explain each AE and its relationship to study drug 
(eg, possibly or unlikely). Criteria for determining the relationship of clinical adverse 
reactions to test drug administration are as follows: 
• Not Related: Onset of the AE has no reasonable temporal relationship to 
administration of the study drug, a causal relationship to administration of the study 
drug is biologically implausible, or the event is attributed to an alternative etiology. 
• Unlikely Related: Onset of the AE has a reasonable temporal relationship to study 
drug administration and, although a causal relationship is unlikely, it is biologically 
plausible. 
• Possibly Related: Onset of the AE has a strong temporal relationship to 
administration of the study drug, cannot be explained by the subject’s clinical state or 
other factors, and a causal relationship is biologically plausible. 
• Probably Related: Onset of the AE shows a distinct temporal relationship to 
administration of the study drug that cannot be explained by the subject’s clinical 


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state or other factors, and the AE is a known reaction to the product or chemical 
group or can be predicted by the product’s pharmacology. 
Adverse Events of Special Interest (Part 2) 
The following events are considered to be AESIs: 
• 
Hepatic AEs, including liver function tests (LFT) abnormalities considered 
clinically significant by the Investigator. 
For AEs that are considered AESIs, additional clinical information may be collected 
based upon the severity or nature of the event. If a patient has a hepatic AESI 
meeting any of the above criteria, the Investigator, or designee, should contact the 
Medical Monitor. A detailed narrative of the event should be reported to the Sponsor 
within 24 hours of the event. All AESIs must be reported for the duration of the 
study regardless of causality. For participants with hepatic AEs, additional 
information, including clinical history, course of events, and unscheduled laboratory 
results to monitor LFT levels or other laboratory parameters, may be collected. 
Serious Adverse Events 
An SAE is an AE that results in any of the following: 
• Death 
• Is life threatening (ie, the subject was at risk of death from the event. “Life 
threatening” in the definition of “serious” refers to an event in which the subject was 
at immediate risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• An important medical event that does not result in death, is not life threatening, or 
does not require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, it may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
If an SAE occurs, appropriate therapy will be administered based on the investigator’s 
judgment. Subjects will then be monitored closely as appropriate. 


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5.4.3.2. 
Additional Points to Consider for Adverse Events 
Diagnoses versus signs and symptoms: 
• Each AE will be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms will NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) will be 
recorded as an AE(s). 
Clinical laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be AEs if 
they are judged to be clinically significant (ie, if some action or intervention is 
required or if the investigator judges the change to be beyond the range of normal 
physiological fluctuation). 
• If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (eg, increased creatinine in renal failure), then only the 
diagnosis will be reported as an AE, not the abnormal laboratory values or ECG 
findings. 
Pre-existing conditions: 
• Pre-existing conditions (present before the start of the AE collection period) are 
considered concurrent medical conditions and will NOT be recorded as AEs. 
However, if the subject experiences a worsening or complication of such a concurrent 
condition, the worsening or complication will be recorded as an AE. Investigator will 
ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”). 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled before the start of 
AE collection are not considered AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing 
condition, the worsening of the condition will be captured as an AE. 
Elective surgeries or procedures: 
• Preplanned or performed elective procedures (surgeries or therapies) where there is 
no change in the subject’s medical condition will not be recorded as AEs but will be 
documented in the subject’s source documents. 
Overdose: 
• Cases of study drug overdose without manifested side effects are NOT considered 
AEs. 


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Reporting of Serious Adverse Events 
Serious AEs require immediate reporting to the sponsor and the medical monitor (contact 
details provided below), within 24 hours of the investigator’s knowledge of the event, 
whether or not the investigator believes that the experience is related to study drug. 
An SAE form must be completed, signed by the investigator, and include at a minimum: 
the event term(s), a short description of the AE, the reason why the AE is categorized as 
serious, the investigator’s current opinion of the relationship between the experience and 
the study drug (causality assessment), as well as the subject’s identification number, sex, 
age, and relevant medical history. 
Additional information, as appropriate, can be sent to the sponsor and medical monitor 
when it becomes available (eg, copies of relevant subject records, autopsy reports, and 
other documents). A corresponding AE eCRF must also be completed. 
The investigator is responsible for notifying the IRB in writing of any SAE. All SAEs are 
to be documented in the eCRF with the date of onset and resolution, determination of 
seriousness, severity, action taken, outcome, and relationship to study drug. 
Any SAE, including death, occurring while the subject is receiving study drug 
irrespective of the investigator’s opinion regarding study drug relationship, will be 
reported. Within 24 hours, the investigator must complete, sign, and date the SAE pages, 
verify the accuracy of the information recorded on the SAE pages with the corresponding 
source documents, and send a copy by fax or email. 
Serious AEs that occur within 30 days after study drug administration that come to the 
attention of the investigator, and are thought to be related to study drug, will be reported 
to the sponsor and the medical monitor. 
Regulatory Group Name: Intrinsik Corp.   
Information and updates related to the medical monitoring of SAEs will be presented and 
shared via a shared drive folder hosted by Spaulding Clinical Research. 
Sponsor Study Physician Contact Information: 
Name: Pirouz Shamszad, MD 
Title: Medical Monitor 
Telephone: 732-354-1563 
Email: pirouz@thryvtrx.com 


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Follow-Up of Serious Adverse Events 
All SAEs will be followed until the outcome is known or the subject’s condition has 
stabilized. 
All follow-up information for SAEs is to be reported within 24 hours of receipt by the 
investigator in the manner described previously. 
The FDA requires that all SAEs that are unexpected and potentially related to the study 
drug must be reported to the FDA in writing within 15 calendar days of notification to the 
sponsor. Serious AEs that result in death or are immediately life threatening require the 
sponsor to notify the FDA as soon as possible but no later than 7 calendar days after the 
first knowledge that the case qualifies, followed by a complete report within 8 additional 
calendar days. 
Spaulding will prepare the expedited report for the FDA, and Intrinsik Corp. will be 
responsible for submitting the expedited report to the FDA. Copies will be distributed to 
the investigator.  
Expedited reports, as addenda to the investigator’s brochure, will be placed in the back 
pocket of the brochure by the investigator upon receipt. The investigator will also 
forward a copy of all expedited reports to his or her IRB. 
Subject Deaths 
All subject deaths, regardless of cause, occurring within 30 days after subject termination 
from the study, and which are known to the investigator, will be reported on the 
appropriate page of the eCRF. Documentation of the subject’s cause of death and a copy 
of the autopsy report, if any, will also be provided. Intrinsik Corp. must be notified by fax 
and the sponsor’s study physician must be notified by telephone of all subject deaths 
immediately (contact details provided in Section 5.4.3.2.1). Fax/email modes of 
communication must be utilized in case of any difficulty with telephone lines; written 
follow-up must be received within 3 working days of initial notification.  
Death should not be reported as an SAE term, but rather as a clinical outcome. The cause 
of death on a source document, such as the death certificate or autopsy report, will be 
used as the event term for the SAE. The SAE that is the cause of death will be marked as 
fatal with the date of death as the end date. If concurrent AEs or SAEs are present at the 
time of death, but are not the cause of death, those AEs or SAEs will be marked as not 
recovered/not resolved and ongoing. 
Adverse Event Collection Period 
Collection of AEs will commence from the time that the subject signs the informed 
consent form (ICF). Any AE that occurs between the time the subject signs the ICF to 


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before the first dose of study drug will be documented as medical history, unless the AE 
is related to a protocol-required procedure, in which case the event will be documented as 
an AE unrelated to study drug. Routine collection of AEs will continue until the End of 
Study Visit or Early Termination. 
Reporting of Pregnancy 
An exposure during pregnancy (also referred to as exposure in-utero) will be reported as 
follows: 
• Pregnancies occurring up to 30 days after study drug administration must be reported 
to the investigator. The investigator will make arrangements for the subject to be 
counseled by a specialist, to discuss the risks of continuing with the pregnancy, and 
the possible effects on the fetus. Monitoring of the subject should continue until the 
outcome of the pregnancy is known. 
• The investigator should report all pregnancies in female subjects to the sponsor within 
1 working day of becoming aware of them. 
• If the investigator becomes aware of a pregnancy occurring in the partner of a male 
subject participating in the study up to 90 days after the completion of the study drug, 
the pregnancy should be reported to the sponsor within 1 working day of obtaining 
written consent from the pregnant partner. The investigator will make arrangements 
for the partner to be counseled by a specialist, to discuss the risks of continuing with 
the pregnancy, and the possible effects on the fetus. Monitoring of the partner should 
continue until the outcome of the pregnancy is known. 
During the conduct of the study, if pregnancy is reported in a female subject, the 
investigator will withdraw the subject immediately from the study and inform Intrinsik 
Corp. and the sponsor’s medical monitor within 24 hours of knowledge of the event using 
the information provided in Section 0. The investigator will complete and send the signed 
Exposure in Pregnancy Form to Intrinsik Corp. using the information provided in Section 
0. Any other maternal SAE in the course of pregnancy will be reported on a separate SAE 
form. If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly [in a live birth, a terminated fetus, an intrauterine fetal demise, or a neonatal 
death]), the investigator will follow the procedures for reporting SAEs.  
Additional information about pregnancy outcomes that are reported as SAEs are as 
follows:  
• Spontaneous abortion includes miscarriage and missed abortion; neonatal deaths that 
occur within 1 month of birth will be reported, without regard to causality, as SAEs. 
In addition, infant death after 1 month will be reported as an SAE when the 
investigator assesses the neonatal death as related or possibly related to exposure to 
investigational product. 


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• In the case of paternal exposure, the study subject will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner. The investigator must 
document on the Exposure in Pregnancy Form that the subject was given this letter to 
provide to his partner. If the pregnancy outcome fulfills the criteria for an SAE, it will 
be reported to the respective regulatory authorities in an expedited manner. 
• Pregnant female subjects will be contacted within 15 calendar days after the expected 
date of delivery for the pregnancy outcome. A second follow-up will be performed 
after 30 calendar days of pregnancy outcome. 
• Additional information regarding the exposure during pregnancy may be requested by 
the investigator. Further follow-up of birth outcomes will be handled on a 
case-by-case basis (eg, follow-up on preterm infants to identify developmental 
delays). 
 
5.4.3.3. 
Clinical Laboratory Tests 
5.4.3.3.1 
Part 1 
Clinical laboratory samples and samples for diagnostic screening tests will be collected at 
the time points specified in the schedule of events (Section 8.1, Appendix A). All 
subjects will fast overnight for a minimum of 6 hours (no food or fluid except water) 
before blood collection for clinical laboratory testing. All samples will be collected in 
accordance with acceptable laboratory procedures. The tests that will be performed are 
presented in Table 5-1. 
Hematology, serum chemistry, urinalysis, and diagnostic screening tests will be 
performed at Spaulding Clinical Laboratory. The results of laboratory tests will be 
returned to the investigator or medically qualified designee, who will review the results 
together with the data in the eCRF. The investigator will maintain a copy of the 
laboratory accreditation and the reference ranges used by the laboratory. 
The investigator will review the clinical laboratory test results and any values outside the 
reference range will be evaluated for clinical significance. The investigator may repeat 
the clinical laboratory tests if deemed appropriate. 


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Table 5-1 
Clinical Laboratory Tests – Part 1 
 
Hematology 
Serum Chemistry 
Urinalysis 
Complete Blood Count 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell count (with 
automated differential) 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine Phosphokinase 
Creatinine 
Direct bilirubin 
Estimated glomerular filtration rate 
(eGFR)a 
Glucose 
Lactic dehydrogenase 
Magnesiumb 
Phosphorus 
Potassiumb 
Sodium 
Total bilirubin 
Total protein 
Uric acid 
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination: red 
blood cells; white blood 
cells; epithelial cells; 
bacteria, crystals, casts, etc. 
(if present) 
Diagnostic Screening Tests: 
Blood 
Urine 
Serology: hepatitis panel (hepatitis B surface 
antigen and hepatitis C virus antibody) and HIV 
antibody 
Serum pregnancy test (all female subjects) 
Urine drug screen: amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, ethanol, 
opiates, phencyclidine, propoxyphene, cotinine, 
and methadone 
Abbreviation: eGFR, estimated glomerular filtration rate. 
a 
eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula. 
b 
Serum potassium and magnesium will be checked each day on Days –1, 1, and 2 and thereafter, 
beginning on Day 3, potassium and magnesium will be checked every other day. Potassium 
<3.8 mg/dL and magnesium <1.9 mg/dL will result in additional electrolyte supplementation. It is 
preferred, especially on Days 1, 4, 6, and 8, that this be done in the evening (after the 12-hour time 
point). Electrolyte supplementation is allowed at any time as long as it is >4 hours before dosing. 


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5.4.3.3.2 
Part 2 
Clinical laboratory samples and samples for diagnostic screening tests will be collected at 
the time points specified in the schedule of events (Section 8.2, Appendix B). All 
participants will fast overnight for a minimum of 6 hours (no food or fluid except water) 
before blood collection for clinical laboratory testing. All samples will be collected in 
accordance with acceptable laboratory procedures. The tests that will be performed are 
presented in Table 5-2. 
Note: An intravenous catheter will be placed, at the investigator's discretion, as needed to 
facilitate study procedures or for participant safety reasons. 
Hematology, serum chemistry, coagulation, urinalysis, and diagnostic screening tests 
will be performed at Spaulding Clinical Laboratory or a local laboratory. The results of 
laboratory tests will be returned to the investigator or medically qualified designee, who 
will review the results together with the data in the eCRF. The investigator will maintain 
a copy of the laboratory accreditation and the reference ranges used by the laboratory. 
The investigator will review the clinical laboratory test results and any values outside the 
reference range will be evaluated for clinical significance. The investigator may repeat 
the clinical laboratory tests if deemed appropriate. 


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Table 5-2 
Clinical Laboratory Tests – Part 2 
 
Hematology 
Serum Chemistry 
Urinalysis 
Complete Blood Count 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell count (with 
automated differential) 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine Phosphokinase 
Creatinine 
Direct bilirubin 
Estimated glomerular filtration rate 
(eGFR) 
Gamma-glutamyl transpeptidase 
(GGT) 
Glucose 
Lactic dehydrogenase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total protein 
Uric acid 
Coagulation 
(PT/PTT) 
Appearance 
Bilirubin 
Blood 
Color 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination: red 
blood cells; white blood 
cells; epithelial cells; 
bacteria, crystals, casts, etc. 
(if present) 
Diagnostic Screening Tests: 
Blood 
Urine 
Serology: hepatitis panel (hepatitis B surface 
antigen and hepatitis C virus antibody) and HIV 
antibody 
Serum pregnancy test (females of childbearing 
potential) 
Urine drug screen: amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, 
ethanol (Day -1 only), opiates, phencyclidine, 
propoxyphene, cotinine, and methadone 


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5.4.3.4. 
Vital Sign Measurements 
Vital signs (blood pressure, HR, respiratory rate, and oral body temperature [°C]) will be 
measured at the time points specified in the schedule of events (Section 8.1, Appendix A 
and Section 8.2, Appendix B) using a calibrated digital device and a cuff size that is 
matched to the subject. This must be verified. Vital signs will be measured daily during 
confinement. Subjects will be in a supine position, if possible, for no less than 5 minutes 
before vital signs are measured. A window of ±30 minutes for each time point will be 
utilized for vital sign measurements. 
 
5.4.3.5. 
Safety 12-Lead Electrocardiograms 
 
Part 1 
Standard digital safety 12-lead ECGs will be recorded as specified in the schedule of 
events (Section 8.1, Appendix A). Subjects will be in a supine position for no less than 
5 minutes before the safety 12-lead ECG is performed. Triplicate ECGs, when 
collected, will be 30 seconds to 1 minute apart. The safety 12-lead ECG may be 
collected using the Holter devices, when applicable. If a safety 12-lead ECG is 
scheduled at the same time point as blood sample collection, the ECG will be 
performed first. 
Clinically significant, abnormal 12-lead safety ECGs should be repeated so that an 
investigator can determine if an AE has occurred. The final ECG interval read will be 
manually confirmed by a cardiologist experienced in ECG interval measurements. 
Part 2 
Standard digital safety 12-lead ECGs will be recorded as specified in the schedule of 
events (Section 8.2, Appendix B). Participants will be in a supine position for no less 
than 5 minutes before the safety 12-lead ECG is performed. Triplicate ECGs, when 
collected, will be approximately 30 seconds to 1 minute apart. The safety 12-lead 
ECG may be collected using the Holter devices, when applicable. If a safety 12-lead 
ECG is scheduled at the same time point as blood sample collection or vital sign, the 
ECG will be performed first. 
Triplicate ECGs will also be collected as described Section 8.4, Appendix D and sent to 
Clario for storage. 
 


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Clinically significant, abnormal 12-lead safety ECGs should be repeated so that an 
investigator can determine if an AE has occurred. The final ECG interval read will be 
manually confirmed by a cardiologist experienced in ECG interval measurements. In 
general, ECG changes will only be reported as AEs if they are clinically significant or as 
at the investigator’s discretion. 
 
5.4.3.6. 
Physical Examinations 
Part 1 
Physical examinations will be performed at the time points specified in the schedule of 
events (Section 8.1, Appendix A). The complete physical examination will consist of the 
following body systems: head, eyes, ears, nose, throat; cardiovascular, respiratory, 
gastrointestinal, dermatologic, musculoskeletal, and nervous systems; extremities; lymph 
nodes; and other. The abbreviated physical examination will consist of the following 
body systems: dermatologic, cardiovascular, respiratory, and gastrointestinal. Additional 
body systems may be evaluated at the investigator’s discretion. 
At Screening, the complete physical examination will include height and body weight for 
calculation of body mass index. The subject’s weight (kg) and height (cm) will be 
measured using a calibrated scale while the subject is wearing light street clothing and no 
shoes. 
The subject’s body mass index will be calculated using metric units and rounded to the 
nearest tenth according to the following formula: 
Body mass index = weight (kg)/height (m)2 
Any abnormal treatment-emergent physical examination finding during the study that 
represents a change from baseline (ie, a change from the examination at Screening) will 
be documented as an AE, with causality assigned by the investigator as described in 
Section 5.4.3.1.2. 
Part 2 
Physical examinations will be performed at the time points specified in the schedule of 
events (Section 8.2, Appendix B). The complete physical examination will consist of the 
following body systems: head, eyes, ears, nose, throat; cardiovascular, respiratory, 
gastrointestinal, dermatologic, musculoskeletal, and nervous systems; extremities; lymph 
nodes; and other. The abbreviated physical examination will consist of the following 
body systems: dermatologic, cardiovascular, respiratory, and gastrointestinal. Additional 
body systems may be evaluated at the investigator’s discretion. 


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At Screening height and body weight will be measured. On Day −1 body weight will be 
measured. Height and weight measurement will be used to calculate body mass index. 
The participant’s weight (kg) and height (cm) will be measured using a calibrated scale 
while the participant is wearing light street clothing and no shoes. 
The participant’s body mass index will be calculated using metric units and rounded to 
the nearest tenth according to the following formula: 
Body mass index = weight (kg)/height (m)2 
Any abnormal treatment-emergent physical examination finding during the study that 
represents a change from baseline (ie, a change from the examination at Day-1) will be 
documented as an AE, with causality assigned by the investigator as described in 
Section 0. 
 
5.4.4. 
Demographics, Medical History, and Other Baseline 
Assessments 
Demographics will include date of birth, sex (at birth), ethnicity, and race as provided by 
the subject. 
The complete medical history will include a review of all major body systems, 
reproductive status, and menstrual history (ie, regularity), if applicable. Any conditions 
and diseases that arise after Screening (ie, after the ICF is signed) are to be reported as 
AEs. 
Smoking, ethanol, and caffeine use will also be recorded, as will any medications taken 
during the 30 days before study drug administration. 
 
5.4.5. 
Documentation of Concomitant Medications 
Prior and concomitant medication information will be recorded beginning 30 days before 
study drug administration through Follow-up. Any therapy administered before informed 
consent is obtained will be recorded as a prior medication and medication ongoing at the 
time of signing the ICF or administered after informed consent will be recorded as a 
concomitant medication. Relevant information (ie, name of medication, dose, unit, 
frequency of administration, dates, and reasons for use) will be recorded in the source 
documents and in the eCRF. All changes in medication will be noted. If the reason for 
medication use meets the definition of an AE, the AE will be recorded on the appropriate 
page of the eCRF and in the source documents for that subject. 
At the discretion of the principal investigator and/or medical monitor, additional 
potassium and/or magnesium can be administered to increase the electrolyte serum 
concentrations. 


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5.4.6. 
Total Blood Volume 
The total blood volume to be collected during the study will be specified in the ICF. 
5.5. 
Study Treatments 
5.5.1. 
Method of Assigning Subjects to Treatment Groups 
5.5.1.1. 
Part 1 
The randomization schedule will be generated by the unblinded randomization 
statistician. Randomized subjects will be assigned unique subject numbers in sequential 
order based on their order of qualification. An attempt will be made to achieve an equal 
balance between sexes. 
A sentinel group of up to 5 subjects may be enrolled first if warranted by the principal 
investigator. 
The subject number assigns a randomized treatment to each subject and determines the 
study drug that the subject will receive. In both treatment periods, all subjects will receive 
dofetilide on Days 1 and 2 of each period. Randomization will take place before Day 3 of 
Period 1. Subjects will be randomly assigned to 1 of 2 treatment sequences: AB or BA. 
At the end of the washout period following Period 1, subjects who meet a satisfactory 
review of safety and PK data from Period 1 will be brought back for treatment in 
Period 2. Subjects randomized to LQT-1213 in Period 1 will start receiving placebo in 
Period 2. Subjects randomized to placebo matched to LQT-1213 in Period 1 will start 
receiving LQT-1213 in Period 2. 
In order to maintain the blind, a suspension of LQT-1213 in sugar-free Gatorade™ will 
be prepared before dosing. Placebo will consist of the sugar-free Gatorade™ and 
cornstarch. 
The following LQT-1213 doses will be evaluated: 
• Low dose: 3 doses on Day 3 and the first 2 doses on Day 4 
• Mid dose: Last dose on Day 4, 3 doses on Day 5, and the first 2 doses on Day 6 
• High dose or 0.747 mg/kg: Last dose on Day 6, 3 doses on Day 7, and the first dose 
on Day 8 
Note: Only 1 dose of dofetilide and LQT-1213 (or placebo) will be administered on 
Day 8. 
Blinding information is provided in Section 5.5.5. 


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5.5.1.2. 
Part 2 
Participants will be assigned unique participant numbers in sequential order based on 
their order of qualification. 
Participants will undergo a 1 day, single-blind placebo run-in period followed by 
LQT-1213. Placebo will consist of sugar-free Gatorade™ and cornstarch. 
The following doses will be administered: 
• Placebo: Day 1 TID 
• LQT-1213 dose: 3 doses on Day 2 and 3, and 1 dose on Day 4 
Blinding information is provided in Section 5.5.5. 
5.5.2. 
Treatments Administered 
5.5.2.1. 
Part 1 
All eligible subjects will be administered dofetilide 500 µg BID (2 × 250 µg capsules), 
orally for approximately 8 days (Days 1 to 8; only 1 dose will be administered on Day 8) 
in both treatment periods. The first dose will be administered at time 0 and the second 
dose at 12 hours after the first dose (± 10 minutes). 
All subjects will fast overnight for a minimum of 6 hours (no food or fluid except water) 
before study drug administration. LQT-1213 will be dispensed based on the body weight 
of the subject. Randomized subjects will receive LQT-1213 or matching placebo as 
follows: 
• Low dose: 3 doses on Day 3 and the first 2 doses on Day 4 
• Mid dose: Last dose on Day 4, 3 doses on Day 5, and the first 2 doses on Day 6 
• High dose or 0.747 mg/kg: Last dose on Day 6, 3 doses on Day 7, and the first dose 
on Day 8 
Note: Only 1 dose of dofetilide and LQT-1213 (or placebo) will be administered on 
Day 8. 
LQT-1213 will be administered orally and diluted in sugar-free Gatorade™. The high 
dose is not to exceed 0.747 mg/kg TID (daily dose 2.24 mg/kg). 
Dose-down titration will occur if the mean QTcF increase of the triplicate ECGs after 
assessment by a cardiac electrophysiologist is confirmed on Day 1, and the dose of 


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dofetilide will be reduced to 250 µg BID. If the mean QTcF increase of the triplicate 
ECGs occurs on Day 2 or afterwards (or any time in Period 2), the subject will be 
discontinued from the study as described in Section 5.3.2. 
After dosing, water will be available ad libitum and meals (lunch, dinner, and light meal) 
will be served as regularly scheduled. Meal timing and components, activity levels, and 
general conditions in the CRU will be as similar as possible on each dosing day. 
5.5.2.2. 
Part 2 
All participants with LQT2 or LQT3 will fast overnight for a minimum of 6 hours (no 
food or fluid except water) before study drug administration. Participants will receive 
study drug as follows: 
The following doses will be administered: 
• Placebo: TID on Day 1 
• LQT-1213 dose: 3 doses on Day 2 and 3, and 1 dose on Day 4 
 
LQT-1213 will be administered orally and diluted in sugar-free Gatorade™. The dose 
is not to exceed daily dose 2.24 mg/kg. 
5.5.3. 
Identity of Study Drug 
5.5.3.1. 
Part 1 
LQT-1213 for suspension will be provided as powder. LQT-1213 will be diluted in 
sugar-free Gatorade™ for oral administration. The placebo matched to LQT-1213 will 
consist of sugar-free Gatorade™ and cornstarch. 
Dofetilide is a sulfonamide class of antiarrhythmic agents and will be utilized in this 
study in its 250 and 500 µg capsule formulation. 


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5.5.3.2. 
Part 2 
LQT-1213 for suspension will be provided as powder. LQT-1213 will be diluted in 
sugar-free Gatorade™ for oral administration. 
5.5.4. 
Management of Clinical Supplies 
5.5.4.1. 
Study Drug Packaging and Storage 
Study drug must be kept in a secure cabinet or room with access restricted to necessary 
study site personnel. 
LQT-1213 will be stored at 20°C to 25°C (68°F to 77°F) and protected from light. 
Dofetilide will be stored at 15°C to 30°C (59°F to 86°F) and protected from moisture and 
humidity. Placebo matched to LQT-1213 will be stored at 25ºC (77ºF) with excursions 
permitted to 15°C to 30°C (59°F to 86°F). 
All study drugs will be dispensed by the investigator or a person under the investigator’s 
supervision. The investigational products will be dispensed based on the body weight of 
the subject. The calculated amount will be weighed, recorded, and transferred to the 
dispensing container. For the oral suspension, sugar-free Gatorade™ will be added to the 
drug substance and mixed until the drug is dissolved or evenly dispersed according to the 
pharmacy manual. 
Additional study drug packaging, storage, and dispensing information will be detailed in 
the pharmacy manual. 
5.5.4.2. 
Study Drug Accountability 
In accordance with Code of Federal Regulations (CFR) (21 CFR 312.62), the investigator 
is required to keep accurate records showing final disposition of all investigational drugs. 
THE INVESTIGATOR MUST NOT USE MATERIAL PROVIDED FOR THIS 
PARTICULAR STUDY IN ANOTHER STUDY WITHOUT PRIOR WRITTEN 
APPROVAL FROM THE SPONSOR. 
The investigator or his or her designee will record: 
• Person Responsible: On the Distribution Log, if the same individual signs the forms 
from day to day, his or her title need not be recorded after the first time. 
• Lot Number: The lot number is indicated on the label applied to each container of 
study drug. 
• Manufacture/Expiration Date: The manufacture and expiration date may be listed on 
the study drug. 
• Date Used: Date administered or dispensed to the subject. 


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• Disposition of Material: Indicate if administered, destroyed, damaged in transit and 
destroyed, or other final disposition of material. Material cannot be transferred for 
preclinical or other use without prior written approval from the sponsor. 
• Date Returned to the Sponsor/Designee or Destroyed: At the termination of the study, 
unused and opened and partially used containers may be returned to the sponsor or 
designee. However, the investigator or designee will not destroy the supplies without 
immediate prior consultation with the sponsor. Indicate the date when unused 
containers are returned (mo/day/yr-Ret.) or destroyed (mo/day/yr-Des.). 
Ultimate accountability for receiving, dispensing, and inventory of the test material lies 
with the investigator or designee. Federal regulation requires that storage of the substance 
be in a secure enclosure, access to which is limited, to prevent theft or diversion, and in 
accordance with the labeling and storage guidelines. 
Material that is not outdated at the completion of the study will be returned to the sponsor 
or will be handled otherwise according to written instructions from the sponsor. 
5.5.5. 
Blinding 
5.5.5.1. 
Part 1 
This is a double-blind study. For study drug dosing, study drug administration will be 
double blinded only on Days 3 through 8. The randomization schedule will be generated 
by the unblinded randomization statistician. The sponsor, study participants, and site 
personnel performing study evaluations will be blinded to random treatment assignments. 
The blinded dose information may only be received by the investigator (or designee) in 
an emergency when the information may have an impact on further treatment decisions 
or aid in the emergency treatment of the subject. Every effort will be made to contact the 
sponsor before unblinding. 
The study blind will be maintained for all personnel through the end of the study until the 
database is locked. Once the database is locked, a blind-break approval form will be 
signed by the sponsor, study statistician, and data manager, after which the randomization 
schedule will be provided to unblind the study. 
The laboratory performing the PK analysis will not be blinded. 
 
5.5.5.1.1 
Breaking the Blind 
The study blind will not be broken by the sponsor or the investigator or designee unless 
information concerning the study drug is necessary for the medical treatment of a subject. 
For unblinding a subject, the randomization information can be obtained by contacting 
the dispensing pharmacist. The sponsor or medical monitor must be notified immediately 
if the study blind is broken. The date, time, and reason that the blind was broken will be 


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recorded in the source documents. The study drug must be stopped immediately, and the 
subject must be withdrawn from the study. Data or specimens already collected from 
subjects who discontinue prematurely and for whom the blind is broken may be made 
available for analysis. 
5.5.5.2. 
Part 2 
This is a single-blind study, with the participants with LQT2 or LQT3 blinded to 
the treatment they are receiving. 
5.5.6. 
Treatment Compliance 
All doses of study drug will be administered in the CRU under direct observation of 
study personnel and recorded in the eCRF. Clinic personnel will confirm that the 
participant has received and ingested the entire dose of study drug. 
5.5.7. 
Prior and Concomitant Medications 
5.5.7.1. 
Part 1 
Subjects will be instructed not to take any medications, including over-the-counter and 
herbal products, without first consulting the investigator (excluding oral and other 
contraceptives [eg, depot formulations, transdermals, intrauterine devices]). After dosing, 
acetaminophen (up to 2 g per 24 hours) will also be allowed with investigator approval. If 
needed, appropriate management and treatment of any AEs or clinically relevant 
abnormal laboratory values will be permitted during the study. 
The study site will notify the sponsor immediately if a subject receives a prohibited 
medication/therapy while on study. 
The following is prohibited within 6 months before Screening and throughout the course 
of study: 
• Tobacco- or nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, 
snuff, etc.) 
The following is prohibited within 30 days before study drug administration and 
throughout the course of study: 
• Hepatic or renal clearance altering agents 
The following are prohibited within 14 days before study drug administration and 
throughout the course of study: 
• Prescription and nonprescription medications (with the exception of hormonal 
contraception) 


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• Herbal preparations (including ginseng, kava kava, ginkgo biloba) 
• Vitamin supplements 
The following is prohibited within 14 days before Check-in (Day –2) and throughout the 
course of study: 
• Seville oranges (sour), grapefruit, grapefruit juice 
The following are prohibited within 28 days before Day 1 or 5 half-lives (whichever is 
longer) and throughout the course of study: 
• Use of any drugs known to be significant strong inducers of CYP 3A enzymes, 
including St. John’s Wort 
The following are prohibited within 7 days before Check-in (Day –2) and throughout the 
course of study: 
• Consumption of cruciferous vegetables (eg, kale, broccoli, watercress, collard greens, 
kohlrabi, Brussels sprouts, and mustard greens) or charbroiled meats 
The following are prohibited for 96 hours before Check-in (Day –2) until the final PK 
sample of the study has been collected: 
• Caffeine- or xanthine-containing products 
The following are prohibited for 48 hours before Check-in (Day –2) until the final PK 
sample of the study has been collected: 
• Alcohol-containing products 
5.5.7.2. 
Part 2 
Participants with LQT2 or LQT3 will be instructed not to take any antiarrhythmic 
medications (including mexilitene), other than beta-blockers or drugs known to affect the 
QT interval (including ranolazine; refer to drug lists for “Drugs with known, possible, or 
conditional risk of TdP” that are known to prolong the QT interval at 
https://crediblemeds.org), and antacids, proton pump inhibitors, or histamine H2 receptor 
antagonists, unless approved by the sponsor and principal investigator. If needed, 
appropriate management and treatment of any AEs or clinically relevant abnormal 
laboratory values will be permitted during the study. The study site will notify the 
sponsor immediately if a participant receives a prohibited medication/therapy while on 
study. 


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The following are prohibited within 28 days before Day 1 or 5 half-lives (whichever is 
longer) and throughout the course of study: 
• Use of any drugs known to be significant strong inducers of CYP 3A enzymes, 
including St. John’s Wort 
The following is prohibited within 14 days before Check-in (Day –1) and throughout the 
course of study: 
• Seville oranges (sour), grapefruit, grapefruit juice 
The following are prohibited for 96 hours before Check-in (Day –1) until the final PK 
sample of the study has been collected: 
• Caffeine- or xanthine-containing products 
The following are prohibited for 48 hours before Check-in (Day –1) until the final PK 
sample of the study has been collected: 
• Alcohol-containing products 
• Antacids, proton pump inhibitors, or histamine H2 receptor are prohibited from time of 
admission to time of discharge. 
 
5.5.8. 
Diet, Fluid, Activity Control, and Subject Housing 
5.5.8.1. 
Part 1 
Subjects will be confined in the CRU in Periods 1 and 2 on the day of Check-in (Day –2) 
until after all study procedures are completed on Day 9 or Day 10 for a total of up to 
11 nights of confinement. 
All subjects will fast overnight for a minimum of 6 hours (no food or fluid except water) 
on Days –1 through 8 and will remain fasted until immediately after the 6-hour ECG 
extraction, when a light meal will be provided, followed by a meal right after the 9.5- and 
12-hour ECG extraction time points. No food or fluids will be served containing caffeine. 
Strenuous exercise (eg, marathon running) is not allowed from 7 days before Check-in 
and throughout the study. Subjects will not be allowed to sleep during the ECG resting or 
collection times. Subjects will be supine, with legs uncrossed, arms at the side, remain 
quiet, and refrain from laughing and talking for 10 minutes before, during, and 
approximately 5 minutes after each scheduled ECG extraction time point for motion-free 
recordings. Staff will work quietly during this same period, keeping conversation to a 
minimum. 


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5.5.8.2. 
Part 2 
Participants will be confined in the CRU on the day of Check-in (Day –1) until after 
all study procedures are completed on Day 5 for a total of up to 5 nights of 
confinement. 
On Day −1, there are no fasting requirements with the exception of an overnight 6-hour 
fast for clinical laboratory collections. On Days 1, 2, and 4, participants will begin fasting 
at midnight and will remain fasted until immediately after the 6-hour ECG extraction 
time point when a light low carbohydrate meal will be provided, which should be 
consumed within 30 minutes. Participants will then fast until after the 10-hour (Day 1) or 
12-hour (Days 2 and 4) ECG extraction when food will be provided ad libitum until 
midnight. On Day 3, participants will begin fasting at midnight and will remain fasted 
until the 2- hour time point when food will be provided ad libitum until the 6- hour time 
point. Fasting will resume at the 6-hour time point until the 10- hour time point when 
food will be provided ad libitum until midnight. Food intake must be completed prior to 
the midnight fast to ensure the midnight fasting requirement is met (no food or fluid 
except water). On Day 5, normal food intake will begin ad libitum after the 29-hour ECG 
extraction. Participants will not be allowed to sleep during the ECG resting or collection 
times. Participants will be supine, with legs uncrossed, arms at the side, remain quiet, and 
refrain from laughing and talking for 10 minutes before, during, and approximately 5 
minutes after each scheduled ECG extraction time point for motion-free recordings. Staff 
will work quietly during this same period, keeping conversation to a minimum. 
5.6. 
Statistical Analysis Plan 
Details of all statistical analyses will be described in a separate SAP. 
All data collected will be presented in data listings. Data from subjects excluded from an 
analysis population will be presented in the data listings, but not included in the 
calculation of summary statistics. For categorical variables, number of 
subjects/participants/number of observations, frequencies and percentages will be 
presented. Continuous variables will be summarized using descriptive statistics (number 
of subjects/participants/number of observations, mean, SD, median, minimum, and 
maximum, unless otherwise specified). In addition, for PK concentrations and 
parameters, the percent coefficient of variation (CV%) for arithmetic mean, geometric 
mean, and geometric CV% will be included. 
The number of subjects/participants who enroll in the study and the number and 
percentage of subjects/participants who discontinue and reasons for discontinuation will 
be presented. Demographic and baseline characteristics will be summarized by sequence 
and overall for Part 1 and by LQT subtype and overall for Part 2 participants. 
Missing data will not be imputed. Measurements that are excluded from the descriptive 
and inferential analyses will be included in the subject data listings. This will include 


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those measurements from excluded subjects/participants, or measurements from 
unscheduled collections. 
All summary tables and figures will be generated using SAS® version 9.4 or above. 


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5.6.1. 
Sample Size Considerations 
5.6.1.1. 
Part 1 
Based on the calculation of the sample size for a Thorough QT study (Zhang and 
Machado, 2008), as the test is performed at 5 time points separately, a 1-sided 5% 
significance level (with adjusted 1-sided significance levels of (5%, 2.5%, 1.67%, 1.25%, 
and 1%) is used along with a within-subject SD of 8 ms for ΔQTcF for all treatment 
groups. A sample size of 20 evaluable subjects in a crossover design who complete the 
study will provide a power of 90% to detect 7 ms QTc effect, ie, the lower bound of all 
the 2-sided 90% CIs on ΔΔQTcF will exceed 7 ms at least 1 of the 5 prespecified time 
points. Multiplicity will be controlled by using a Hochberg procedure (Hochberg 1988). 
Twenty-eight subjects will be enrolled to account for dropouts. 
5.6.1.2. 
Part 2 
In this exploratory safety study, up to 12 participants with LQT2 and up to 
12 participants with LQT3 will be recruited. The sample size was not estimated based 
on statistical considerations but was considered sufficient to achieve the primary safety 
objectives of the study. 
5.6.2. 
Analysis Populations 
5.6.2.1. 
Part 1 
Seven analysis populations are defined, as follows: 
• The primary QT/QTc population will be those subjects in the total QT/QTc 
population meeting a threshold effect of dofetilide to prolong the QTc interval as will 
be defined in the SAP. 
• The total QT/QTc population will include all subjects in the safety population with 
measurements at baseline as well as on-treatment with at least 1 postdose time point 
with a valid change from baseline in QTc (ΔQTc) value. The QT/QTc population will 
be used for the by-time point and categorical analyses of cardiodynamic ECG 
parameters. 
• The PK population will include all subjects who received at least 1 dose of study drug 
and provided at least 1 evaluable PK concentration for LQT-1213 or dofetilide. 
• The primary PK/QTc population will include all subjects who are in both the PK 
and primary QT/QTc populations with at least 1 pair of postdose PK and QTc data 
from the same time point in each period. The PK/QTc population will be used for 
the concentration-QTc analysis. 
• The safety population will include all subjects who received at least 1 dose of study 


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dofetilide and provide at least 1 postdose safety assessment. 
 
5.6.2.2. 
Part 2 
Three analysis populations are defined, as follows: 
• The safety population will include all participants with LQT2 or LQT3 who 
received at least 1 dose of study drug (placebo or LQT-1213) and provide at least 
1 postdose safety assessment. 
• The PK population will include all participants with LQT2 or LQT3 who received 
at least 1 dose of LQT-1213 and provided at least 1 evaluable PK concentration for 
LQT-1213. 
• The PD population (SGK-1 protein targets) will include all participants who 
received at least 1 dose of study drug (placebo or LQT-1213) and have at least 
1 PD measurement. 
5.7. 
Statistical Analyses 
Data from Parts 1 and 2 will be collected in separate databases. Analysis of each part 
will be described in independent SAPs and reported in independent clinical study reports. 
5.7.1. 
Pharmacodynamic Analyses 
5.7.1.1. 
Part 1 
The analysis will be described in the SAP. All QTc data will represent the means of the 
extracted QTc intervals, based on ECGs extracted from the Holters at the defined time 
points. Each individual QT and RR interval will be used to calculate a QTc interval. The 
individual QTc intervals will then be averaged for analysis. Baseline will be defined as 
the mean of the triplicate ECG data collected predose for each period. 
Fridericia’s formula will be the default correction method for QT intervals to remove HR 
dependence. 
If the QTcF is not an adequate correction, other methods will be reviewed. For each 
method tested (including Fridericia's correction), the relationship between the QTc and 
RR will be evaluated with a linear-regression model. Mean QTc and RR values at all 
nominal time points will be used. The model with the slope closest to zero will be 
selected as the primary QTc endpoint. The additional correction methods and definition 
of an adequate correction will be detailed in the SAP. 
A statistical analysis will be performed per International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) E14 guidance using 
the appropriate population and will be detailed in the SAP. The specifics of the 
concentration-QTc and categorical analyses will be detailed in the SAP. 


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5.7.1.2. 
Part 2 
Human PBMCs and plasma samples will be isolated and stored for potential analysis of 
potential PD biomarkers, including SGK-1 targets. 
5.7.1.3. 
Categorical Analyses 
 
5.7.1.3.1 
Part 1 
Categorical analyses of QTc, PR, QRS, and HR will be provided to determine the number 
and percentage of subjects, by treatment, who meet the following criteria overall and at 
each time point: 
• QTc results >450 and ≤480, >480 and ≤500, and >500 ms 
• ΔQTc from baseline >30 and ≤60, and >60 ms 
• ΔQTc from dofetilide/placebo reduction of >10, >15, >20, >25, >30, and >40 ms 
• PR outliers (PR >200 ms and a 25% or greater increase from baseline) 
• QRS outliers (QRS >120 ms and a 25% or greater increase from baseline) 
• HR outliers (HR <50 bpm and a 25% or greater decrease from baseline) 
• HR outliers (HR >100 bpm and a 25% or greater increase from baseline) 


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5.7.1.3.2 
Part 2 
None planned. 
5.7.2. 
Pharmacokinetic Analyses 
5.7.2.1. 
Concentrations in Plasma 
5.7.2.1.1 
Part 1 
The analysis will be detailed in the SAP, which will be finalized before database lock. 
Data will be listed and summarized, where applicable. Plasma concentrations of 
dofetilide and LQT-1213 will be listed and summarized by treatment for each sample 
time point using descriptive statistics. Mean and individual plasma dofetilide and 
LQT-1213 concentration-time profiles will be presented in figures on linear and 
semilogarithmic scales. Assessment of drug interaction between dofetilide and LQT-1213 
will be performed. 
5.7.2.1.2 
Part 2 
The analysis will be detailed in the SAP which will be finalized before database lock. 
Data will be listed and summarized, where applicable. Plasma concentrations of 
LQT-1213 will be listed and summarized by LQT subtype for each sample time point 
using descriptive statistics. Mean and individual LQT-1213 concentration-time 
profiles will be presented in figures on linear and semilogarithmic scales. 
 
5.7.2.2. 
Pharmacokinetic Parameters 
5.7.2.2.1 
Part 1 
The PK parameters of dofetilide and LQT-1213 will be determined from the 
concentration-time profiles for all evaluable subjects. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times. 
The following plasma PK parameters will be calculated for LQT-1213 using 
noncompartmental methods with Phoenix® WinNonlin® (version 8.3 or later): 
• AUC0-t: Area under the concentration-time curve (AUC) from time 0 to the time of 
the last measurable concentration 
• AUCtau: AUC from time 0 to the end of the dosing interval 
• Cmax: Maximum observed plasma drug concentration 
• Tmax: Time to the maximum observed plasma concentration 
• t1/2: Terminal half-life 


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• CLss/F: Apparent clearance at steady state 
• Vd/F: Volume of distribution 
• λz: apparent terminal rate constant 
Dofetilide and LQT-1213 PK parameters will be summarized using descriptive statistics. 
Additional statistical analysis may be performed. 
5.7.2.2.2 
Part 2 
The PK parameters of LQT-1213 will be determined from the concentration-time profiles 
for all evaluable participants. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. 
The following plasma PK parameters will be calculated for LQT-1213 using 
noncompartmental methods with Phoenix® WinNonlin® (version 8.3 or later): 
• AUC0-t: AUC from time 0 to the time of the last measurable concentration 
• AUCtau: AUC from time 0 to the end of the dosing interval 
• Cmax: Maximum observed plasma drug concentration 
• Ctrough: Concentration at the end of the dosing interval 
• Tmax: Time to the maximum observed plasma concentration 
• t1/2: Terminal half-life 
• CLss/F: Apparent clearance at steady state 
• Vd/F: Volume of distribution 
• λz: apparent terminal rate constant 
Other PK parameters as identified and documented in the SAP. 
LQT-1213 PK parameters will be summarized using descriptive statistics. Additional 
statistical analysis may be performed. 
5.7.3. 
Safety Analyses 
The safety analyses will be based on the safety population. Safety data, including AEs, 
clinical laboratory test results, vital sign measurements, and 12-lead safety ECG results 
will be summarized by treatment, if appropriate. 
5.7.3.1. 
Adverse Events 
All AEs captured in the database will be presented in by-subject/participant data listings; 
however, only TEAEs will be summarized. All answers will be interpreted by the 
investigator using the Medical Dictionary for Regulatory Activities (MedDRA, most 
recent version) for AEs and will be recorded in the eCRF. Each verbatim term will be 


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mapped to a system organ class and preferred term. 
An overall summary of TEAEs will be provided summarizing subjects/participants with 
at least 1: TEAE, related TEAE, serious TEAE, related serious TEAE, TEAE leading to 
study withdrawal, or related TEAE leading to study withdrawal, as well as the number of 
events within each of the previously mentioned categories by treatment and overall for 
Part 1 and by LQT subtype, and overall for Part 2. In addition, summaries of unique 
TEAEs will be presented by system organ class, preferred term, and by treatment and 
overall for Part 1 and by LQT subtype, and overall for Part 2, and will include the 
number and percentage of subjects/participants who experience the unique event for: all 
TEAEs, all TEAEs by relationship, all TEAEs by severity grade, and all TEAEs leading 
to study withdrawal. 
Data listings will be provided for all AEs, AEs leading to study withdrawal, and SAEs. 
5.7.3.2. 
Clinical Laboratory Tests 
All continuous clinical laboratory test results and change from baseline will be 
summarized for each treatment (Part 1) or LQT subtype (Part 2) using descriptive 
statistics (number of subjects/participants/ observations, mean, SD, minimum, median, 
and maximum) at each scheduled time point, as appropriate. All categorical laboratory 
parameters (ie, urinalysis) will be summarized at baseline and at each planned 
postbaseline visit by treatment. All clinical laboratory data will be presented in data 
listings. 
5.7.3.3. 
Vital Sign Measurements 
Descriptive statistics (number of subjects/participants, mean, SD, median, minimum, and 
maximum) of each vital sign measurement and changes from baseline will be tabulated 
for each treatment (Part 1) or LQT subtype (Part 2). All vital sign data will be listed in 
the data listings. 
5.7.3.4. 
Safety 12-Lead Electrocardiograms 
Descriptive statistics (number of subjects/participants, mean, SD, median, minimum, and 
maximum) of each safety 12-lead ECG measurement and changes from baseline will be 
tabulated for each treatment (Part 1) or LQT subtype (Part 2). All safety 12-lead ECG 
data will be presented in the data listings. 
5.7.3.5. 
Physical Examination 
Physical examination findings will be presented in the data listings. 
5.7.3.6. 
Interim Analyses 
No interim analysis is planned. 


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5.7.4. 
Pharmacodynamic Biomarker Analyses 
Part 2 only: Details of the potential analysis of PD biomarkers will be provided in a 
separate analysis plan. 
5.7.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
Part 2 only: Details of the potential exploratory PK (LQT-1213)/PD (SGK-1 protein 
targets) endpoints and analyses to derive PK/PD relationships between drug exposure and 
target engagement will be provided in a separate analysis plan. 
5.8. 
Data Quality Assurance 
The sponsor or its designee will perform the quality assurance and quality control 
activities of this study; however, responsibility for the accuracy, completeness, and 
reliability of the study data presented to the sponsor lies with the investigator generating 
the data. 
Before study initiation, the sponsor or designee will explain the protocol, investigator’s 
brochure, and eCRFs to the investigator. In addition, the monitor will be available to 
explain applicable regulations and to answer any questions regarding the conduct of the 
study. 
At its discretion, the sponsor may conduct audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the ICH 
harmonised tripartite guideline E6(R2): Good Clinical Practice (GCP; Department of 
Health and Human Services [DHHS] 2018), the protocol, standard operating procedures, 
and all applicable regulatory requirements. Audits will be independent of and separate 
from the routine monitoring and quality control functions. The clinic may also be 
compelled to undergo an inspection by a regulatory authority. 
The following administrative items are meant to guide the investigator or subinvestigator 
in the conduct of the study but may be subject to change based on industry and 
government standard operating procedures or working practice documents or guidelines. 
Changes will be reported to the IRB but will not result in protocol amendments. 
The investigator will permit study-related monitoring, audit(s), IRB review(s), and 
regulatory inspection(s), with direct access to all of the required source documents and 
associated records. Source documents and records need to be preserved for at least 
15 years after the completion, discontinuation of, or withdrawal from the study or 2 years after 
the last approval of a marketing application of the sponsor in an ICH region, whichever is 
longest. Refer to Section 8.5, Appendix E for details of the responsibilities of the investigator. 
6. 
Investigator’s Obligations 
The following administrative items are meant to guide the investigator or subinvestigator 
in the conduct of the study but may be subject to change based on industry and 


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government standard operating procedures or working practice documents or guidelines. 
Changes will be reported to the IRB but will not result in protocol amendments. 
The investigator will permit study-related monitoring, audit(s), IRB review(s), and 
regulatory inspection(s), with direct access to all of the required source documents and 
associated records. Source documents and records need to be preserved for at least 
15 years after the completion, discontinuation of, or withdrawal from the study or for 
2 years after the last approval of a marketing application of the sponsor in an ICH region, 
whichever is longest. Refer to Section 8.5, Appendix E for details of the responsibilities 
of the investigator. 
 
6.1. 
Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data will 
only be linked to the sponsor’s clinical study database or documentation via a unique 
identification number. As permitted by all applicable laws and regulations, limited 
subject attributes such as sex, age or date of birth, and subject initials may be used to 
verify the subject and accuracy of the subject’s unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires that the investigator permit its monitor or designee’s monitor, 
representatives from any regulatory authority (eg, FDA), the sponsor’s designated 
auditors, and the appropriate IRBs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring 
during a subject’s study participation, and autopsy reports. Access to a subject’s original 
medical records requires the specific authorization by the subject as part of the informed 
consent process (Section 6.3). 
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (ie, subject name, address, and other 
identifier fields not collected in the subject’s eCRF). 
 
6.2. 
Institutional Review 
The IRB must be constituted according to the applicable state and federal 
requirements of the participating region. The sponsor or designee will require 
documentation noting all names and titles of members who comprise the respective 
IRB. If any member of the IRB has direct participation in this study, written 
notification regarding his or her abstinence from voting must also be obtained. If the 
US center is unwilling to provide names and titles of all members due to privacy and 
conflict of interest concerns, the center will instead provide a Federal Wide Assurance 
Number or comparable number assigned by the DHHS. 


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The sponsor or designee will supply relevant documents for submission to the IRB for the 
protocol’s review and approval. This protocol, the investigator’s brochure or package 
insert, a copy of the ICF, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must 
be submitted to the local IRB for approval. Written approval by the IRB of the protocol 
and subject ICF must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the study drug). The IRB approval 
must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. 
The site must adhere to all requirements stipulated by the IRB. This may include 
notification to the IRB regarding: protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports 
and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. The IRB 
approval and relevant documentation for these items must be provided to the sponsor or 
designee. 
 
6.3. 
Subject Consent 
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki, the ICH guidelines for GCP, and in accordance with all 
applicable laws and regulations. The ICF may be in paper or electronic form. The ICF 
describes the planned and permitted uses, transfers, and disclosures of the subject’s 
personal and personal health information for purposes of conducting the study. The ICF 
further explains the nature of the study, its objectives, and potential risks and benefits, as 
well as the date informed consent is given. The ICF will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a 
reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF. 
The ICF must be approved by both the IRB and the sponsor before use. 
The ICF must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the ICF to 
the subject. Information will be given in both oral and written form whenever possible 
and in the manner deemed appropriate by the IRB. 
The subject, or subject’s legally acceptable representative, must be given ample 
opportunity to: 1) inquire about details of the study and 2) decide whether to participate 
in the study. If the subject, or subject’s legally acceptable representative, determines that 
he or she will participate in the study, then the ICF must be signed and dated by the 
subject, or the subject’s legally acceptable representative, at the time of consent and 
before the subject enters into the study. Subjects will be instructed to sign using their 
legal names, not nicknames, using blue or black ballpoint ink (if paper ICF). The person 


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obtaining consent must also sign and date the ICF at the time of consent and before the 
subject enters into the study. 
Once signed, the ICF will be stored in the investigator’s site file; the original version will 
be retained if a paper ICF was used. The investigator must document the date that the 
subject signs the ICF in the subject’s medical record. A copy of the signed ICF will be 
given to the subject. 
All revised ICFs must be reviewed and signed in the same manner as the original ICF. 
The date the revised consent was obtained will be recorded in the subject’s medical 
record and the subject will receive a copy of the revised ICF. 
 
6.4. 
Study Reporting Requirements 
The investigator is obliged to provide the sponsor with complete test results and all data 
derived by the investigator from the study. During the study, only the sponsor may make 
study information available to the study investigators or to regulatory agencies, except as 
required by law or regulation. 
 
6.5. 
Financial Disclosure and Obligations 
The investigator or subinvestigators are required to provide financial disclosure 
information to allow the sponsor to submit the complete and accurate certification or 
disclosure statements required under 21 CFR 54. In addition, the investigator or 
subinvestigators must provide to the sponsor a commitment to update this information 
promptly if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
Neither the sponsor nor Spaulding is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the sponsor nor Spaulding is 
financially responsible for further treatment of the subject’s disease.  
 
6.6. 
Investigator Documentation 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subjects’ health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 
164 (the Health Insurance Portability and Accountability Act of 1996 privacy regulation). 
The investigator shall ensure that study subjects authorize the use 
and disclosure of protected health information in accordance with the privacy regulations 
of the Health Insurance Portability and Accountability Act and in a form satisfactory to 
the sponsor. 


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6.7. 
Study Conduct 
The investigator will conduct all aspects of this study in accordance with US FDA 
regulations, the ICH E6(R2), and applicable local, state, and federal laws. 
 
6.8. 
Data Management 
The full details of procedures for data handling will be documented in the Data 
Management Plan. Adverse events, medical history, and concurrent conditions will be 
coded using MedDRA. 
 
6.8.1. 
Case Report Forms and Source Documents 
Completed eCRFs are required for each subject randomly assigned to study drug. 
Electronic data entry is accomplished through the ClinSpark® (Foundry Health) remote 
data capture application, which allows for onsite data entry and data management. This 
provides immediate, direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner. Each person involved with the study will have an individual identification code 
and password that allows for record traceability. Thus, the system, and subsequently any 
investigative reviews, will be able to identify coordinators, investigators, and individuals 
who have entered or modified records. Furthermore, the investigator retains full 
responsibility for the accuracy and authenticity of all data entered into the electronic data 
capture system. The completed dataset and associated files are the sole property of the 
sponsor and will not be made available in any form to third parties, except for authorized 
business representatives or appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
Source documents are defined as original documents, data, and records. The investigator 
and institution guarantee access to source documents by the sponsor or designee and by 
the IRB. 
 
6.9. 
Adherence to the Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance 
with the ICH E6(R2) and all applicable guidelines and regulations. 
6.10. 
Reporting Adverse Events 
By participating in this study, the investigator or subinvestigator agrees to submit reports 
of SAEs according to the timeline and method outlined in the protocol. 


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6.11. 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, will inform the 
institution; the investigator or institution will provide the IRB with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any required reports. 
 
6.12. 
Records Retention 
The investigator agrees to keep the records stipulated in Section 6.8.1 and those 
documents that include (but are not limited to) the study-specific documents, 
identification log of all participating subjects, medical records, source worksheets, all 
original signed and dated ICFs, copies of all eCRFs, query responses, and detailed 
records of drug disposition, to enable evaluations or audits from regulatory authorities, 
the sponsor, or its designees. Furthermore, ICH 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the 
approval of a marketing application for a specified drug indication being investigated or, 
if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH 4.9.5 states that the 
study records will be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the clinical study site agreement between the 
investigator and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements on record 
retention. The investigator will contact and receive written approval from the sponsor 
before disposing of any such documents. 
 
6.13. 
Publications 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
Manuscript authorship for any peer-reviewed publication will appropriately reflect 
contributions to the production and review of the document. Publication of study results 
will be in-line with the agreement executed by Spaulding and the sponsor for the conduct 
of the study.  
7. 
Study Management 
 
7.1. 
Monitoring 


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7.1.1. 
Monitoring of the Study 
Study site monitoring visits will be performed by the sponsor or designee periodically 
during the study to ensure that all aspects of the protocol are followed. Source documents 
will be reviewed for verification of data recorded in the eCRFs. Additionally, all aspects 
of the study and its documentation will be subject to review, including but not limited to, 
the investigator’s binder, study drug, subject medical records, informed consent 
documentation, eCRFs, and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
 
7.1.2. 
Inspection of Records 
The investigator involved in the study will permit study-related monitoring, audits, IRB 
review, and regulatory inspection(s). In the event of an audit, the investigator agrees to 
allow the sponsor, representatives of the sponsor, the competent authority, or other 
regulatory agency access to all study records. The investigator will promptly notify the 
sponsor of any audits scheduled by any regulatory authorities and promptly forward 
copies of any audit reports received to the sponsor. 
 
7.2. 
Management of Protocol Amendments and Deviations 
 
7.2.1. 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to a subject, must be reviewed and approved by the sponsor or 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
or subinvestigator’s IRB for approval before subjects can be enrolled into an amended 
protocol. 
 
7.2.2. 
Protocol Deviations 
The investigator will conduct the study in compliance with the protocol agreed to by the 
sponsor and, if required, by the regulatory authority and that was given 
approval/favorable opinion by the IRB. 
The investigator, or designee, will document and explain any deviation from the 
approved protocol. 
The investigator will notify the IRB of any deviations from the protocol in accordance 
with local procedures. 


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7.3. 
Study Termination 
The study will be completed as planned unless the following criteria are satisfied that 
require early termination of the study: 
1. New information regarding the safety or efficacy of the study drug that indicates a 
change in the known risk/benefit profile for the investigational product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
2. Significant violation of GCP that compromises the ability to achieve the primary 
study objectives or compromises subject safety. 
The sponsor reserves the right to suspend or terminate the study at any time. 
The study site may be terminated if the site (including the investigator) is found in 
significant violation of GCP, protocol, or contractual agreement, or is unable to ensure 
adequate performance of the study. 
 
7.4. 
Final Report 
Whether the study is completed or prematurely terminated, the sponsor’s designee will 
ensure preparation of the clinical study report and provision of it to the regulatory 
agency(ies) as required by the applicable regulatory requirement(s). The clinical study 
report will be structured in accordance with the FDA guideline document entitled, “ICH 
E3 Structure and Content of Clinical Study Reports” (DHHS 1996). 


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8. 
Appendices 
8.1. 
Appendix A: Schedule of Events – Part 1 
 
 
 
 
Day(s)
 
Screening 
 
Treatment Period 1 
End of 
Treatment 
Period 1 
 
Washoutb 
 
Treatment Period 2 
EOS/ 
ET 
 
F/Uc 
–30 to –3 –2 –1 
1 
2 
3-8 
9a 
10a 
–2 
–1 
1 
2 
3-8 
9a 
10a 
Informed consent/Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Physical examinationd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Body mass index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/Weight-based dose 
calculation 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
X Xe 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
24-h Holterf 
 
 
X Xf 
X 
Continuous  
 
 
 
X 
Xf 
X Continuous  
 
 
Holter data extractionsg 
 
 
X 
X Xg 
X 
 
 
 
 
X 
X Xg 
X 
 
 
 
Vital sign measurements (full) 
X 
X  
 
 
X (predose) X 
X 
 
X 
 
 
 
X (predose) X 
X 
 
Blood pressure & heart rate onlyh  
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X  
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Serum chemistryi 
X 
X Xi Xi Xi 
Xi 
 
X 
 
X 
Xi 
Xi Xi 
Xi 
 
X 
 
Coagulation 
X 
X  
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Urinalysisj 
X 
X  
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Urine drug screen 
X 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine alcohol test 
X 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Cotinine test 
X 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Admission 
 
X  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
CRU confinement 
 
Continuous 
 
 
Continuous 
 
 
Randomizationk 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Dofetilide administrationl 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Study drug administrationm 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
PK blood sample collectionn 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 


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Protocol No. LQT-1213-0061 
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Confidential 
05 December 2023 
Page 105 of 117 
Version 7.0 
 
 
 
 
 
 
Day(s)
 
Screening 
 
Treatment Period 1 
End of 
Treatment 
Period 1 
 
Washoutb 
 
Treatment Period 2 
EOS/ 
ET 
 
F/Uc 
–30 to –3 –2 –1 
1 
2 
3-8 
9a 
10a 
–2 
–1 
1 
2 
3-8 
9a 
10a 
Telephone contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
Continuous 
Continuous 
Concomitant medications 
 
Continuous 
Continuous 
Continuous telemetryo 
 
 
Continuous 
 
 
 
Continuous 
 
 
Abbreviations: CRU, clinical research facility; ECG, electrocardiogram; EOS, end of study; ET, early termination; PK, pharmacokinetic. 
Note: When assessment time points coincide, the order of assessments will be ECGs/ECG extraction window, PK blood sample collection followed by vital sign 
measurements. When a PK blood sample collection time point coincides with study drug dosing, the PK sample will be collected before study drug dosing. Extractions and 
ECG analysis will not be performed on all Holter data collected. 
a 
Subjects will be discharged from the CRU on Day 9 or 10 (safety washout) in each period if the QT interval corrected for heart rate by Fridericia’s formula (QTcF) is <460 
ms and the increase from baseline is <40 ms. Day 10 evaluations will be performed if the subject is not discharged on Day 9. 
b 
There will be a washout of at least 4 days (or at least 5 times the half-life) after the last dose of study drug. Subjects will return to the CRU on Day –2 and crossover to 
receive the alternate treatment in Period 2. 
c 
Approximately 7 days after the end of treatment in Period 2, the Follow-up Visit will be conducted remotely via telephone call. 
d 
A symptom-directed abbreviated physical examination may be performed at any time at the investigator’s discretion for adverse events or if warranted. 
e 
12-lead ECGs will be obtained on Day –1 at 1, 3, and 6 h. On Day 1, ECGs will be obtained at 30- and 15-min predose (triplicate ECG) and at 1 h (single ECG), 3 h 
(triplicate ECGs), and 15 h (single ECGs) postdose. Details are provided in Section 8.3. 
f 
24-h Holter monitor recordings will be obtained on Days –1, 1 (predose through Hour 15), and 2-8. Holters will be placed on Day –1 (corresponding to predose on Day 1). 
Details are provided in Section 8.3. On each day, the Holter data card will be removed and a new one inserted 90 min before dosing. 
g 
ECG Holter data will be collected continuously on Day –1 through Day 8 for later ECG extractions. ECG extractions will be at the prespecified time points in Section 
8.3. h 
Blood pressure and heart rate only: Days –1, 1, and 2: 3 times a day; on Days 3-8, at predose and at 3 and 12 h postdose. Vital signs will be measured daily 
during 
confinement. Subjects will be in a supine position, if possible, for no less than 5 min before vital signs are measured. A window of ±30 min for each time point will be 
utilized 
for vital sign measurements. 
i 
Serum chemistry samples will be collected after the subject has fasted for at least 6 h, if possible. Serum potassium and magnesium will be checked each day on Days –1, 
1, and 2 and thereafter, beginning on Day 3, potassium and magnesium will be checked every other day. Potassium <3.8 mg/dL and magnesium <1.9 mg/dL will result in 
additional electrolyte supplementation. It is preferred, especially on Days 1, 4, 6, and 8, that this be done in the evening (after the 12-h time point). Electrolyte 
supplementation is allowed at any time as long as it is >4 h before dosing. 
j 
Urinalysis will include, at a minimum, leukocyte esterase, blood, pH, and specific gravity (microscopic tests to be completed if dipstick urinalysis is 
abnormal). k 
Randomization will take place before Day 3 of Period 1. 
l 
Dofetilide 500 µg: twice daily on Days 1-8 (at 0 and 12 h, morning dose only on Day 8). Dose may change based on safety 
parameters. 
m 
LQT-1213 or matching placebo dosing: 
• 
Low dose: 3 doses on Day 3 and the first 2 doses on Day 4 
• 
Mid dose: Last dose on Day 4, 3 doses on Day 5, and the first 2 doses on Day 6 
• 
High dose: Last dose on Day 6, 3 doses on Day 7, and the first dose on Day 8 
Note: Only 1 dose of dofetilide and LQT-1213 (or placebo) will be administered on Day 8. 
n 
Blood samples for dofetilide and LQT-1213 PK analysis will be collected in both treatment periods on Days 4, 6, and 8 at the following time points: predose (time 0 for 


Thryv Therapeutics Inc. 
Protocol No. LQT-1213-0061 
LQT-1213 
Confidential 
05 December 2023 
Page 106 of 117 
Version 7.0 
 
 
 
 
 
 
Day(s)
 
Screening 
 
Treatment Period 1 
End of 
Treatment 
Period 1 
 
Washoutb 
 
Treatment Period 2 
EOS/ 
ET 
 
F/Uc 
–30 to –3 –2 –1 
1 
2 
3-8 
9a 
10a 
–2 
–1 
1 
2 
3-8 
9a 
10a 
dofetilide) and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7.75, 9.5, 12, and 24 h postdose. Details are provided in Section 8.3. 
o 
Continuous telemetry recordings will start on Day –1 for 12 h and resume prior to dosing on Day 1 until subjects meet QTcF discharge criteria. 


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Confidential 
05 December 2023 
Page 107 of 117 
Version 7.0 
 
 
 
8.2. 
Appendix B: Schedule of Events – Part 2 
 
 
 
Day(s) 
 
Screeninga 
 
 
Treatment Period 
 
 
EOT/ ET 
 
 
EOS/F/U 
–61 to –2 
–1 
1 
2 
3 
4 
5b 
12c 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
Physical examinationd 
 
X 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight/Body mass index 
X 
X 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
X 
X 
X 
X 
X 
 
24-h Holterf 
 
X 
X 
Continuous 
X 
 
Holter data extractiong 
 
X 
X 
X 
X 
X 
X 
 
Vital sign measurements (full)h 
X 
X 
 
 
 
 
X 
 
Blood pressure & heart rate 
onlyi 
 
 
X 
X 
X 
X 
 
 
Serology 
X 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
X 
 
Serum chemistry 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
 
Coagulation 
X 
X 
 
 
 
 
X 
 
Urinalysisk 
X 
X 
 
 
 
 
X 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
Urine alcohol test 
 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serum pregnancy test 
X 
X 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
CRU confinement 
 
Continuous 
 
Study drug administrationl 
 
 
X 
X 
X 
X 
 
 
PK blood sample collectionm 
 
 
 
X 
X 
X 
X 
 
PD sample collectionn 
 
 
 
X 
X 
X 
 
 
Telephone contact 
 
 
 
 
 
 
 
X 
Adverse events 
 
Continuous 
Concomitant medications 
 
Continuous 
Telemetry 
 
Continuous 
 
Abbreviations: CRU, clinical research facility; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; ET, early termination; F/U, follow-up; 
PD, pharmacodynamic; PK, pharmacokinetic. 
Note: When assessment time points coincide, the order of assessments will be ECGs/ECG extraction window, PK blood sample collection followed by vital 
sign measurements. When a PK blood sample collection time point coincides with study drug dosing, the PK sample will be collected before study drug 


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LQT-1213 
Confidential 
05 December 2023 
Page 108 of 117 
Version 7.0 
 
 
dosing. Extractions and ECG analysis will not be performed on all Holter data collected. 
a 
Screening may be conducted remotely or in-person within 60 days of CRU admission. 
b 
Participants will be discharged from the CRU on Day 5. In the case of ET, Day 5 assessments will be conducted. 
c 
Approximately 7 days after discharge from the CRU, the Follow-up Visit will be conducted remotely via telephone call. 
d 
A symptom-directed abbreviated physical examination may be performed at any time at the investigator’s discretion for adverse events or if warranted. 
e 
Details are provided in Section 8.4, Appendix D. 
f 
24-h Holter monitor: Continuous 12-lead 24-hour Holter data will be collected on Days -1 through 5, as detailed in the PK and PD time points table (Section 8.4, Appendix 
D). On each day, the Holter data card will be removed and a new one inserted approximately 90 min before first dosing. 
g 
ECG Holter data will be collected continuously on Days 1 through 5. ECG extractions will be at the prespecified time points in Section 8.4, Appendix D. 
h 
Vital signs will be measured at Screening and on Day −1 and EOT/ET. Participants will be in a supine position, if possible, for no less than 5 min before vital signs are 
measured. A window of ±30 min for each time point will be utilized for vital sign measurements. Only partial vital signs will be taken on Days 2 through Day 4. 
i 
Blood pressure and heart rate only: Days 1 through 4 at predose and approximately 3 h postdose. 
j 
Serum chemistry samples should be collected predose (study drug administration days) and on Day 5. Serum chemistry samples will be collected after the participant has 
fasted for at least 6 h. Serum potassium and magnesium tested daily and may be repeated at any time at the investigator’s discretion. Potassium <3.8 mg/dL and magnesium 
<1.8 mg/dL will result in additional electrolyte supplementation. Electrolyte supplementation can be administered 12-18 hours after the morning dose of LQT-1213. 
Estimated glomerular filtration rate will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. 
k 
Urinalysis will include, at a minimum, leukocyte esterase, blood, pH, and specific gravity (microscopic tests to be completed if dipstick urinalysis is abnormal). 
l 
Placebo: Day 1 TID. 
LQT-1213: TID on Days 2 and 3 and 1 dose on Day 4 (morning dose). 
m 
Blood samples for LQT-1213 PK analysis will be collected as specified in Section 8.4, Appendix D. 
n 
Blood samples for PD analysis (peripheral blood mononuclear cells and plasma) as specified in Section 8.4, Appendix D. 


Thryv Therapeutics Inc. 
Protocol No. LQT-1213-0061 
LQT-1213 
Confidential 
05 December 2023 
Page 109 of 117 
Version 7.0 
 
 
 
8.3. 
Appendix C: Pharmacokinetic and Pharmacodynamic Time 
Points - Part 1 
 
Day(s) 
Time 
(h) 
Collection Window 
Relative to PK Time Point 
PK Blood 
Sample 
Collectiona 
12-Lead 
ECGb 
 
Holterc 
 
ECG Extractiond 
Screening & 
–2 
 
 
 
X 
 
 
 
 
 
 
 
–1 
0 
~90 min 
(triplicate corresponding to 
predose on Day 1) 
 
 
X 
(placed) 
Xd 
(45, 30, and 15 min) 
1 
±5 min 
 
X 
 
X 
2 
±5 min 
 
 
 
X 
2.5 
±5 min 
 
 
 
X 
3 
±5 min 
 
X 
 
X 
3.5 
±5 min 
 
 
 
X 
4 
±5 min 
 
 
 
X 
5 
±5 min 
 
 
 
X 
6 
±5 min 
 
X 
 
X 
9.5 
±5 min 
 
 
 
X 
12 
±5 min 
 
 
 
X 
 
 
 
 
 
1 
 
0 
 
Predose 
(triplicate within 60 min) 
 
X 
(triplicate 
–30 and 
–15 min) 
For 2h 
predose 
Xd 
(predose at 45, 30, and 
15 min) 
1 
±5 min 
 
X 
 
 
2 
±5 min 
 
 
 
X 
2.5 
±5 min 
 
 
 
X 
3 
±5 min 
 
Xb 
(triplicate) 
 
X 
4 
±5 min 
 
 
 
X 
5 
±5 min 
 
 
 
X 
6 
±5 min 
 
 
 
X 
15 
±5 min 
 
X 
 
 
 
 
 
 
 
 
2 
0 
Predose (within 10 min) 
 
X 
 
Xd 
1 
±5 min 
 
X 
 
X 
2 
±5 min 
 
 
 
X 
2.5 
±5 min 
 
 
 
X 
3 
±5 min 
 
X 
 
X 
3.5 
±5 min 
 
 
 
X 
4 
±5 min 
 
 
 
X 
4.5 
±5 min 
 
 
 
X 
5 
±5 min 
 
 
 
X 
5.5 
±5 min 
 
 
 
X 
6 
±5 min 
 
X 
 
X 
7.75 
±5 min 
 
 
 
X 
9.5 
±5 min 
 
 
 
X 
12 
±5 min 
 
 
 
X 
15 
±5 min 
 
X 
 
 
 
 
3 
0 
 
 
 
 
Xd 
1 
 
 
X 
 
X 
2 
 
 
 
 
X 
2.5  
 
 
 
X 
3 
 
 
X 
 
X 
3.5  
 
 
 
X 


Thryv Therapeutics Inc. 
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Day(s) 
Time 
(h) 
Collection Window 
Relative to PK Time Point 
PK Blood 
Sample 
Collectiona 
12-Lead 
ECGb 
 
Holterc 
 
ECG Extractiond 
 
4 
 
 
 
 
X 
4.5  
 
 
 
X 
5 
 
 
 
 
X 
5.5  
 
 
 
X 
6 
 
 
X 
 
X 
7.75  
 
 
 
X 
9.5  
 
 
 
X 
12 
 
 
 
 
X 
15 
 
 
X 
 
 
24 
 
 
X 
 
X 
 
 
 
 
 
 
4-8 
0 
Before dofetilide dosing 
X 
 
 
Xd 
1 
±5 min 
X 
X 
 
X 
2 
±5 min 
X 
 
 
X 
2.5 
±5 min 
X 
 
 
X 
3 
±5 min 
X 
 
 
X 
3.5 
±5 min 
X 
 
 
X 
4 
±5 min 
X 
X 
 
X 
4.5 
±5 min 
X 
 
 
X 
5 
±5 min 
X 
 
 
X 
5.5 
±5 min 
X 
 
 
X 
6 
±5 min 
X 
 
 
X 
7.75 
±5 min 
Xe 
 
 
X 
9.5 
±5 min 
Xf 
 
 
X 
12 
±5 min 
Xg 
 
 
X 
24 
±5 min 
Xh 
X 
 
X 
9 
24 
±5 min 
Xh 
Xb 
 
X 
10 
48 
±5 min 
 
Xb 
 
 
Abbreviations: ECG, electrocardiogram; PK, pharmacokinetic. 
Note: When assessment time points coincide, the order of assessments will be ECGs/ECG extraction 
window, PK blood sample collection followed by vital sign measurements. When a PK blood sample 
collection time point coincides with study drug dosing, the PK sample will be collected before study drug 
dosing. Extractions and ECG analysis will not be performed on all Holter data collected. 
Dofetilide 500 µg: twice daily (BID) on Days 1-8 (at 0 and 12 h, morning dose only on Day 8). If the 
dose is reduced on Day 1 in Period 1 to 250 µg BID, this will be the dose used in Period 2. Dose may 
change based on safety parameters. 
LQT-1213 or matching placebo: 3 doses on Day 3 and first 2 doses on Day 4 (low dose); last dose on Day 
4, 3 doses on Day 5 and the first 2 doses on Day 6 (mid dose); and last dose on Day 6, 3 doses on Days 7, 
and the first dose on Day 8 (at 0 h, immediately after the 7.75-h ECG extraction time point, and 17 h). Only 
1 dose of dofetilide and LQT-1213 (or placebo) will be administered on Day 8. 
a 
Blood samples will be collected for plasma dofetilide and LQT-1213 concentrations in both 
treatment periods on Days 4, 6, and 8 only. 
b 
On Day 1 at 3 h postdose in Period 1 only, the QT interval corrected for heart rate by Fridericia’s 
formula (QTcF) will be measured in the 3 ECGs and the mean value calculated. Measurements will 
be manually confirmed by a cardiologist who is specifically trained and experienced in ECG 
interval measurements. The ECG measurements at baseline and at the 3-h time points will be 
performed by the same technician and cardiologist. If the mean QTcF increase is <25 ms on the 
triplicate safety ECGs compared with the mean from baseline (triplicate –30 min and triplicate –15 
min), the subject will be discontinued from the study. If on Day 1 at 3 h postdose in Period 1 only, 
the mean QTcF on the triplicate ECGs, when repeated within 30 min and manually confirmed by a 
cardiologist specifically trained and experienced in ECG interval measurements, has a mean value 
on the 6 ECGs >80 ms from the mean baseline QTcF, the dose of dofetilide will be reduced to 250 
µg BID. If the mean QTcF is >500 ms on Day 1 in Period 1 only (repeated in triplicate within 30 
min), the dose of dofetilide will be reduced to 250 µg BID. If the safety ECGs (repeated in 
triplicate within 30 min) shows a mean value on the 6 ECGs of a QTcF of >500 ms on Day 2 in 
Period 1 or afterwards (or any time in Period 2), the subject will be discontinued from the study. 
Triplicate ECGs, when collected, will be approximately 30 seconds to 1 min apart. All ECGs for 
these safety assessments must be manually confirmed by a cardiologist who is specifically trained 
and experienced in ECG interval measurements before actions are taken. If the dose is reduced to 
250 µg BID, this will be the dose used in Period 2. Note: If the subject has a new QRS >110 ms or 


Thryv Therapeutics Inc. 
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Confidential 
05 December 2023 
Page 111 of 117 
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a new bundle branch block, then an adjusted QTcF will be utilized to account for the widened QRS 
interval (Adjusted QTcF = QTcF [ms] – [QRS interval [ms] – 90 ms]). 
c 
24-h Holter monitor recordings will be obtained on Days –1, 1 (predose through Hour 15), and 2-8. 
Holters will be placed on Day 1 at the approximate 90-min time point (corresponding to predose on 
Day 3) and stored, and on Day 1 starting 2 h before dosing through Day 8. On each day, the Holter 
data card will be removed and a new one inserted 90 min before dosing. Holter analysis will be 
performed in the first instance on Day 1 (predose time points only) and on Days 4, 6, and 8. The 
Holter recordings from Day –1, the other time points on Day 1, and Days 2, 3, 5, and 7 will be 
stored at the CRU for possible future analysis. 
d 
ECG Holter data will be collected continuously on Days –1 through 8 and evaluated using 
extracted ECG data. On Day –1, and 1 (predose at 45, 30, and 15 min and on Day –1). Subjects 
will be supine, with legs uncrossed, arms at the side, remain quiet, and refrain from laughing and 
talking for 10 min before, during, and approximately 5 min after each scheduled ECG extraction 
time point for motion-free recordings. 
e 
At 7.75 h, blood samples will be collected before the second dose of study drug on Days 4 and 6. 
f 
At 9.5 h, blood samples will be collected before a meal is provided. 
g 
At 12 h, blood samples will be collected before the last dose of dofetilide on Days 4 and 6. 
h 
At 24 h, blood samples will be collected before the first dose of study drug on Days 5 and 7. 


Thryv Therapeutics Inc. 
Protocol No. LQT-1213-0061 
LQT-1213 
Confidential 
05 December 2023 
Page 112 of 117 
Version 7.0 
 
 
 
8.4. 
Appendix D: Pharmacokinetic, Pharmacodynamic, and Meal Time 
Points – Part 2 
 
 
 
 
 
Day(s) 
 
 
Time 
(h) 
 
 
Study Drug 
administration 
Collection 
Window 
Relative to 
PK Time 
Point 
 
 
PK Blood 
Sample 
Collectiona 
 
Single 
Safety 12- 
Lead 
ECGb 
 
 
12-Lead 
Triplicate 
ECGs d 
 
 
 
 
Holterc 
 
 
 
ECG 
Extractiond 
 
 
 
 
Meal 
 
0- 
 
 
 
 
 
X 
 
 
-1 (No 
 
(placed) 
extractions 
 
 
1.0 
 
 
 
X 
 
 
X 
 
after 8pm 2.0 
 
 
 
 
 
 
X 
 
local 
4.0 
 
 
 
 
 
 
X 
 
time)C 
6.0  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
(triplicates 
(triplicate at 
(predose at 
 
0 
 
performed 
twice ~15 
min apart) 
predose at 45, 
30, 
and 15 min 
45, 30, and 
15 min) 
 
1 
 
 
 
 
X (triplicate)  
X 
 
1 
2 
 
 
 
X 
X (triplicate)  
X 
 
3 
 
 
 
 
X (triplicate)  
X 
 
 
4 
 
 
 
X 
X (triplicate)  
X 
 
 
6 
 
 
 
 
X (triplicate)  
X 
X 
 
8 
X 
 
 
 
X (triplicate)  
X 
 
 
10 
 
 
 
 
X (triplicate)  
X 
 
 
12 
 
 
 
 
X (triplicate)  
X 
X-start 
 
16 
X 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
X- 
 
 
end 
2 
 
0 
 
X 
 
Predose 
(within 
10 min) 
X 
(within 
60 min of 
predose) 
X 
(triplicates 
performed 
twice ~15 
min apart) 
X 
(triplicate at 
45, 30, 15 min, 
predose) 
 
X 
(45, 30, 
and 
15 min 
predose) 
 
 
1 
 
±5 min 
X 
 
X (triplicate) 
 
X 
 
 
1.5  
±5 min 
X 
 
 
 
X 
 
 
2 
 
±5 min 
X 
X 
X (triplicate) 
 
X 
 
 
3 
 
±5 min 
X 
 
X (triplicate)  
X 
 
 
4 
 
±5 min 
X 
 
X (triplicate)  
X 
 
 
5 
 
±5 min 
X 
 
X (triplicate)  
X 
 
 
6 
 
±5 min 
Xe 
X 
X (triplicate)  
X 
X 
 
8 
X 
±5 min 
X 
 
X (triplicate) 
 
X 
 
 
10 
 
±5 min 
 
 
X (triplicate)  
X 
 
 
12 
 
±5 min 
 
 
X (triplicate)  
X 
X-start 
 
16 
X 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
X-end 


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Day(s) 
 
 
Time 
(h) 
 
 
Study Drug 
administration 
Collection 
Window 
Relative to 
PK Time 
Point 
 
 
PK Blood 
Sample 
Collectiona 
 
Single 
Safety 12- 
Lead 
ECGb 
 
 
12-Lead 
Triplicate 
ECGs d 
 
 
 
 
Holterc 
 
 
 
ECG 
Extractiond 
 
 
 
 
Meal 
3 
0 
X 
Predose 
(within 
10 min) 
X 
(within 
60 min of 
predose) 
X 
X (triplicate)  
X 
 
2 
 
±5 min 
 
X 
 
 
 
X-Start 
6 
 
±5 min 
 
X 
 
 
 
X-end 
8 
X 
±5 min 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
X-start 
16 
X 
±5 min 
 
 
 
 
 
 
18  
 
 
 
 
 
 
X- 
end 
 
 
 
 
4 
0 
X 
Predose 
(within 10 
min) 
X 
(within 
60 min of 
predose) 
X 
X 
pre-dose 
(triplicate) 
 
X 
(Pre-dose 
 
1 
 
±5 min 
X 
 
X (triplicate)  
X 
 
1.5  
±5 min 
X 
 
 
 
X 
 
2 
 
±5 min 
X 
X 
X 
(triplicate) 
 
X 
 
3 
 
±5 min 
X 
 
X 
(triplicate) 
 
X 
 
4 
 
±5 min 
X 
 
X 
(triplicate) 
 
X 
 
5 
 
±5 min 
X 
 
X 
(triplicate) 
 
X 
 
6 
 
±5 min 
Xe 
X 
X 
(triplicate) 
 
X 
X 
8 
 
±5 min 
X 
 
X 
(triplicate) 
 
X 
 
10 
 
±5 min 
 
 
X (triplicate)  
X 
 
12 
 
±5 min 
 
 
X (triplicate)  
X 
X-start 
18 
 
 
 
 
 
 
 
X-end 
 
5 
0 
 
±5 min 
X 
X 
X (triplicate)  
X 
 
2 
 
±5 min 
 
 
 
 
X 
 
3 
 
±5 min 
 
 
X 
(triplicate) 
 
X 
 
 
5f 
 
±5 min 
X 
X 
X 
(triplicate) 
X 
(removed 
after 29-h 
time point) 
X 
 
 
Abbreviations: ECG, electrocardiogram; h, hour; min, minutes; PK, pharmacokinetic. 
 
Note: When assessment time points coincide, the order of assessments will be ECGs/ECG extraction window, PK blood sample 
collection followed by vital sign measurements. When a PK blood sample collection time point coincides with study drug dosing, 
the PK sample will be collected before study drug dosing. Extractions and ECG analysis will not be performed on all Holter data 
collected. 
a 
Blood samples for human peripheral blood mononuclear cells (PBMCs) will be collected predose on Days 2,3, and 4 and 
postdose at 1, 2, 3, 4, 5, 6, 8 hours on Day 2 and Day 4 only. Blood samples will be centrifuged and human PBMCs will be 
isolated and stored for potential assessment of pharmacodynamic biomarkers. 


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b 
All ECGs will be collected with participants supine, with legs uncrossed, arms at the side, remain quiet without external 
stimulation, and refrains from laughing and talking for 10 min before during, and approximately 5 min after each scheduled 
ECG extraction time point for motion-free recordings. In addition single safety ECGs will be collected and reviewed at the 
indicated time points by Spaulding. 
c 
24-h Holter monitor recordings will be obtained on Days -1 after arrival into the CPU through 5. On Day -1, time 0 represents 
the time the Holter is placed and may be variable for each patient depending on their arrival time at the CPU. Subsequent time 
points on Day-1 are relative to Holter placement for each participant. On Day -1, no extractions should be performed after 8 
PM local time. On each day, the Holter data card will be removed and a new one inserted approximately 90 min before 
morning dose. Holter analysis will be performed in the first instance on Days 2 and 3. All Holter recordings from all time 
points will be collected and stored for possible future analysis. The ECG analysis and extraction time points may be modified 
as deemed appropriate and the time points for ECGs and PK may be modified as deemed appropriate. 
d 
ECG Holter data will be collected continuously on Days -1 through 5 (5 h on Day 5) and evaluated using extracted ECG data. 
At all ECG extraction time points (including predose at 45, 30, and 15 min on Days 1 and 2), participants will be supine, with 
legs uncrossed, arms at the side, remain quiet without external stimulation, and refrain from laughing and talking for 10 min 
before, during, and approximately 5 min after each scheduled ECG extraction time point for motion-free recordings. The 
triplicate ECGs will be acquired at the extraction time points from the Clario Holter devices and sent to Clario. 
e 
At 6 h, blood samples will be collected before a meal is provided.  
f 
At 5 h on Day 5 (at 29 h following the dose on Day 4), blood samples and ECGs may be collected as close as possible to the 
nominal time point. If the participant needs to leave earlier due to travel, then the 29-hour time point will be the latest feasible 
time point. 


Thryv Therapeutics Inc. 
Protocol No. LQT-1213-0061 
LQT-1213 
Confidential 
05 December 2023 
Page 115 of 117 
Version 7.0 
 
 
 
8.5. 
Appendix E: Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to the regulations of the 
FDA. The responsibilities imposed on the investigator by the FDA are summarized in the 
“Statement of Investigator” (Form FDA 1572), which must be completed and signed 
before the investigator may participate in this study. 
In signing a Form FDA 1572, the investigator agrees to assume the following 
responsibilities: 
1. 
Conduct the study in accordance with the protocol. 
2. 
Personally conduct or supervise the staff who will assist in the conduct of the study. 
3. 
Ensure that all colleagues and employees assisting in the conduct of the study are 
informed of these obligations. 
4. 
Secure prior approval of the study and any changes by an appropriate IRB that 
conforms to FDA requirements. 
5. 
Ensure that the IRB will be responsible for initial, continuing review, and approval of 
the protocol. Promptly report to the IRB all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study 
to the IRB and issue a final report within 3 months of study completion. 
6. 
Ensure that requirements for informed consent as outlined in 21 CFR Part 50 are met. 
7. 
Obtain valid informed consent from each subject who participates in the study and 
document the date of consent in the subject’s medical chart. Each ICF will contain a 
subject authorization section that describes the uses and disclosures of a subject’s 
personal information (including personal health information) that will take place in 
connection with the study. 
8. 
Prepare and maintain adequate case histories of all persons entered into the study, 
including eCRFs, hospital records, laboratory results, etc, and maintain this data for a 
minimum of 2 years after notification by the sponsor that all investigations have been 
discontinued or that the FDA has approved the New Drug Application. Before 
disposing of any records, the sponsor must be contacted. 
9. 
Allow possible inspection and copying by the FDA of eCRFs and records of drug 
distribution. 
10. Maintain current records of the receipt, administration, and disposition of study 
medication, and return all unused study medication to the sponsor. 
11. Report adverse reactions to the sponsor promptly. In the event of an SAE, immediately 
notify the sponsor and medical monitor within 24 hours of knowledge of the event. 


Thryv Therapeutics Inc. 
Protocol No. LQT-1213-0061 
LQT-1213 
Confidential 
05 December 2023 
Page 116 of 117 
Version 7.0 
 
 
 
9. 
Reference List 
Allen MJ, Nichols DJ, Oliver SD. The pharmacokinetics and pharmacodynamics of oral 
dofetilide after twice daily and three times daily dosing. Br J Clin Pharmacol. 
2000;50(3):247-53. https://doi.org/10.1046/j.1365-2125.2000.00243.x 
Bapat A, Li G, Xiao L, et al. Genetic Inhibition of Serum Glucocorticoid Kinase I Prevents 
Obesity-related Atrial Fibrillation. bioRxiv. 2021:2021-05. 
https://doi.org/10.1101/2021.05.20.444790 
Bezzerides VJ, Zhang A, Xiao L, et al. Inhibition of serum and glucocorticoid-regulated 
kinase-1 as novel therapy for cardiac arrhythmia disorders. Scientific Reports. 2017;7(1). 
https://doi.org/10.1038/s41598-017-00413-3 
Das S, Aiba T, Rosenberg M, et al. Pathological Role of Serum and 
Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling. Circulation. 
2012;126(18):2208-19. https://doi.org/10.1161/CIRCULATIONAHA.112.115592 
Department of Health and Human Services, Food and Drug Administration (US). Issue: 
Guideline for Industry: ICH E3 Structure and content of clinical study reports. July 
1996. Accessed 27 February 2023. https://www.fda.gov/media/71271/download 
Department of Health and Human Services, Food and Drug Administration (US). Issue: 
Guidance for Industry: E14 Clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs – Questions and Answers (R3). 
June 2017. Accessed 27 February 2023. https://www.fda.gov/files/drugs/published/E14- 
Clinical-Evaluation-of-QT-QTc-Interval-Prolongation-and-Proarrhythmic-Potential-for- Non- 
Antiarrhythmic-Drugs-Questions-and-Answers-%28R3%29-Guidance-for- Industry.pdf 
Department of Health and Human Services, Food and Drug Administration (US). Issue: 
Guidance for Industry: ICH E6(R2) Good Clinical Practice: Integrated Addendum to ICH 
E6(R1). March 2018. Accessed 27 February 2023. 
https://www.fda.gov/media/93884/download 
Han L, Liu F, Li Q, et al. The Efficacy of Beta-Blockers in Patients with Long QT Syndrom 
1-3 According to Individuals’ Gender, Age, and QTc Intervals : A Network Meta-Analysis. 
Front Pharmacol. 2020;11:579525. https://doi.org/10.3389/fphar.2020.579525 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75(4):800-2. https://doi.org/10.1093/biomet/75.4.800 
Johannesen L, Vicente J, Mason JW, et al. Differentiating drug-induced multichannel block 
on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and 
verapamil. Clin Pharmacol Ther. 2014;96(5):549-58 


 
Kim M, Sager PT, Tester DJ, et al. SGK1 Inhibition Attenuates the Action Potential Duration 
in Re-Engineered Heart Cell Models of Drug-Induced QT Prolongation. Heart Rhythm. 2023. 
doi: https://doi.org/10.1016/j.hrthm.2022.12.036 
Le Coz F, Funck-Brentano C, Morell T, et al. Pharmacokinetic and pharmacodynamic 
modeling of the effects of oral and intravenous administrations of dofetilide on ventricular 
repolarization. Clin Pharmacol Ther 1995;57(5):533-42. https://doi.org/10.1016/0009- 
9236(95)90038-1 
Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N 
Engl J Med. 2003;348(19):1866-74. https://doi.org/10.1056/NEJMoa022147 
Sala L, Gnecchi M, Schwartz PJ. Long QT syndrome modelling with cardiomyocytes derived 
from human-induced pluripotent stem cells. Arrythm Electrophysiol Rev. 
2019;8(2):105-10. https://doi.org/10.15420/aer.2019.1.1 
Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT 
syndrome. Circulation. 2009;120(18):1761-7. 
https://doi.org/10.1161/CIRCULATIONAHA.109.863209 
Tham TC, MacLennan BA, Burke MT, et al. Pharmacodynamics and pharmacokinetics of the 
class III antiarrhythmic agent dofetilide (UK-68,798) in humans. J Cardiovasc Pharmacol. 
1993;21(3):507-12. https://doi.org/10.1097/00005344-199303000-00024 
Zhang J, Machado SG. Statistical issues including design and sample size calculation in 
thorough QT/QTc studies. J Biopharm Stat. 2008;18(3):451-67. 
https://doi.org/10.1080/10543400802020938 
 

SAP_001.pdf: 
Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
Confidential 
Page 1 of 14 
 
 
 
 
 
NCT Number: NCT05906732 
 
 
SAP  
 
Title: A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-
Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced 
QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients 
Diagnosed With Type 2 or 3 Long QT Syndrome 
 
 
 
 
 
Study Number: LQT-1213 061  
 
 
 
 
 
 
 
 
 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
Confidential 
Page 2 of 14 
 
 
 
 
 
Amendment of Cardiac Statistical Analysis Plan 
Part 2 
 
A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, 
Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc 
Prolongation in Healthy Adult Subjects. 
Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed 
With Type 2 or 3 Long QT Syndrome 
 
 
Protocol: LQT-1213-0061 
 
Prepared For: 
Thryv Therapeutics, Inc. 
999 Blvd. De Maisonneuve West Suite 1250 
Montreal, Quebec, Canada 
 
 
 
 
 
Version: 2.0 (Amendment) 
Date: 19 SEP 2024 
 
Version: 1.0 
Date: 16 FEB 2024 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
Confidential 
Page 3 of 14 
 
 
 
 
 
VERSION 2.0 
PREPARED BY: 
 
 
 
 
 
Jenny Han, MS 
Executive Director, Statistics 
Pharmapace, Inc. 
 
 
 
 
Sep-19-2024 
 
Date 
 
 
VERSION 1.0 
PREPARED BY: 
 
 
 
 
REVIEWED BY: 
Caiyan Li, Ph.D. 
Senior Statistical Consultant 
Pharmapace, Inc. 
 
 
Philip Sager, M.D. 
Chief Medical Officer 
Thryv Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
 
Sep-19-2024 
 
Date 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
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Page 4 of 14 
 
 
1 Abbreviations 
 
Abbreviation 
Term/Description 
AUC 
Area under the curve 
CI 
Confidence interval 
CRU 
Clinical research unit 
ECG 
Electrocardiogram 
HR 
Heart rate 
LQT2 
Long QT Syndrome Type 2 
LQT3 
Long QT Syndrome Type 3 
LQTS 
Long QT syndrome 
Min 
Minimum 
Max 
Maximum 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
PR interval of the ECG 
QRS 
QRS interval of the ECG 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using Fridericia’s formula 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SGK-1 
Serum and glucocorticoid- regulated kinase 1 
TID 
Three times a day 
 
2 Introduction 
Congenital long QT syndrome (LQTS) is a rare cardiac disorder most commonly caused 
by mutations in 1 of 3 genes that encode for ion channels involved in ventricular 
repolarization. Thryv Therapeutics, Inc. is developing LQT-1213, a potent and selective 
small molecule drug that inhibits the activity of serum and glucocorticoid- regulated 
kinase 1 (SGK-1), for the treatment of individuals with congenital or acquired LQTS. 
This statistical analysis plan (SAP) was developed after review of the protocol LQT- 
1213-0061 (Version 4.0, dated 17 April 2023). This document will describe the data 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
Confidential 
Page 5 of 14 
 
 
 
summaries and analyses for electrocardiogram (ECG) data from Part 2 of the study. The 
demographic and safety data analyses will be described in a separate document. 
This SAP should be read in conjunction with the protocol and the Part 1 SAP for more 
details on study designs, assessments and endpoints definitions. 
After the Part 2 study database lock, additional post-hoc analyses were conducted. This 
SAP amendment is prepared to document the post-hoc analyses, as well as to clarify 
several analyses defined in the original SAP. Additionally, the Protocol Version 7.0 
(dated 05 December 2023) should have been based on at the time of preparing the 
original SAP (dated 16 February 2024). Thus, this SAP amendment is to also update the 
study procedures per Protocol Version 7.0. 
The table below summarizes key revision of this amendment. 
 
Section 
Original Text 
Amended Text 
Rationale 
3 
This will be a Phase 2, single-blind, 
placebo run-in, multiple-dose safety 
study to evaluate the safety, 
tolerability, and PK of LQT-1213 in 
patients with LQT2 and LQT3. All 
patients will have a QTcF >490 and 
<600ms. Patients will be recruited 
by the sponsor using a network of 
cardiologists who treat LQTS 
patients and transported to the 
inpatient clinical research unit to 
participate in the study. 
After initial remote screening by the 
clinical research unit, individual 
patients will undergo a 2-day, single 
blind run-in period followed by 
dosing of LQT- 1213. 
 
 
 
 
 
 
 
Approximately 7 days after the end 
of treatment in Period 2, the Follow- 
up visit will be conducted remotely 
via telephone call. The duration of 
treatment for each subject in the 
study will be approximately 13 
days, from admission on Day –2 to 
the telephone follow-up call. This 
This will be a Phase 2a, single-blind, 
placebo run-in, multiple-dose safety 
study to evaluate the safety, 
tolerability, and PK of LQT-1213 in 
patients with LQT2 and LQT3. All 
patients will have a QTcF ≥480 and 
≤560 ms. Up to 12 participants with 
LQT2 and up to 12 participants with 
LQT3 will be enrolled. 
 
 
 
After initial remote screening by the 
clinical research unit (CRU), 
individual patients will undergo a 
1-day, single blind run-in period 
followed by 3 dosing days of 
LQT-1213, administered three times 
a day (TID) at time 0, 8, and 16 
hours on Days 2 and 3, with the final 
dose on Day 4 at time 0, though 
these time points may be adjusted 
based upon emerging data. 
 
Approximately 7 days after 
discharge from the CRU, the 
Follow-up visit will be conducted 
remotely via telephone call. The 
duration of treatment for each 
subject in the study will be 
approximately 13 days, from 
admission on Day -1 to the 
Update per 
Protocol v7.0. 


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Study LQT-1213-0061 Part 2 
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does not include the 28-day 
screening period. 
telephone follow-up call. This does 
not include the 60-day screening 
period. 
 
4 
In Part 2, ECG data will be collected 
from Day -1 through Day 5. At each 
timepoint, three ECGs will be 
recorded and 3 beats analyzed per 
ECG. For analysis purpose, the 
average of all analyzed ECG 
complexes on the triplicate ECGs 
will be averaged in all ECG 
analyses. While 24-hour Holter were 
collected from which ECGs can be 
extracted, this analysis utilizes 
concomitantly recorded 12 lead 
ECGs. 
The timepoints for cardiodynamic 
ECG assessments can be found in 
Appendix 8 of the protocol. 
In Part 2, ECG data will be collected 
from Day -1 through Day 5. At each 
time point, three (triplicate) ECGs 
will be recorded. For analysis 
purpose, the average of the 
triplicates ECGs will be analyzed. 
Additional post-hoc analyses based 
on all values of the triplicates were 
also conducted. While 24-hour 
Holter were collected from which 
ECGs can be extracted, this analysis 
utilizes concomitantly recorded 12 
lead ECGs. 
The time points for cardiodynamic 
ECG assessments can be found in 
Appendix D of the protocol. 
Update per 
Protocol v7.0. 
5.1 
None 
New sentences were added: 
All ECG data will be summarized by 
LQT-1213 dose groups of 16 mg 
and 7 mg, unless otherwise 
specified. 
 
Typically, the confidence intervals 
(CIs) shall be rounded to two 
decimal places greater than the 
precision of the original value; 
however, due to space constraint on 
the printout, as well as for easier 
review, the CIs were rounded (post- 
hoc) to one decimal place greater 
than the precision of the original 
value. 
Clarification 
on general 
approach for 
data 
summaries 
and analyses. 
6.1 
Each ECG parameter will be 
summarized by visit. All data will 
be listed, including each reading and 
the average of all readings for each 
timepoint. Descriptive statistics 
(e.g., number of subjects, mean, SD, 
median, maximum and minimum) 
will be used to summarize the 
absolute values of the ECG 
variables and the corresponding 
change- from-baseline values for all 
subjects at each time point on each 
of Days 1-5. Data-based (i.e., not 
model-based) 2-sided 90%, 85%, 
Each ECG parameter will be 
summarized by visit. The average of 
the triplicates at each time point will 
be presented in listings. Descriptive 
statistics will be used to summarize 
the values of the ECG variables and 
the corresponding changes (and 
percent changes) from baseline 
values at each time point on each of 
Days 1-5. The 2-sided 90%, 85%, 
and 80% CIs of the means will be 
derived based on t-test. 
Clarification 
on general 
approach for 
data 
summaries 
and by-subject 
listings. 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
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and 80% 2-sided CI of the mean will 
be summarized for the absolute and 
change-from-baseline data only. 
 
 
6.2 
In this analysis, QTcF values at each 
timepoint on Day 2, 4, and 5 will be 
compared to the time-matched 
QTcF values on Day 1 (placebo) 
using paired t-test. 
 
 
 
The null hypothesis (Ho) is that the 
difference between Day 2, 4 and 5 
(LQT-1213) and Day 1 (placebo) 
matched time-points will be equal to 
0 (zero). Point estimate of 
difference, median, SD, min, max 
and 2-sided 90%, 85%, and 80% 
CIs, together with p-values for each 
level of significance will be 
reported. 
In this analysis, QTcF values at each 
time point on Days 2 and 4 will be 
compared to the time-matched QTcF 
values on Day 1 (placebo) using 
paired t-test, which is the same as 
analyzing the difference of the time- 
matched QTcF values using one- 
sample t-test. 
The null hypothesis is that the 
difference between Day 2 
(LQT-1213) and Day 1 (placebo), 
and between Day 4 (LQT-1213) and 
Day 1, on matched time-points will 
be equal to 0 (zero). The mean 
difference, median, SD, min, max, 
2-sided 90%, 85%, and 80% CIs, 
and p-value will be reported. The 
null hypothesis will be rejected at 
significance levels of 0.1, 0.15, or 
0.2 if the p-value is less than 0.1, 
0.15, or 0.2, corresponding to 2- 
sided 90%, 85%, and 80% CIs, 
respectively. 
 
Additional post-hoc analyses were 
conducted for all time-matched 
placebo-corrected analyses by 
pooling subjects in the LQT-1213 16 
mg and 7 mg dose groups together. 
Deletion of 
Day 5 as the 
time points 
are not the 
same as Day 
1; 
Clarification 
on analysis 
methods and 
correction on 
multiple 
p-values; 
 
Addition of 
statistical 
interpretation 
on p-value 
versus 
multiple CIs; 
Addition of 
new post-hoc 
analyses that 
pooled 16 mg 
and 7 mg dose 
group 
together. 
6.3 
In this analysis, change from 
baseline and percent change from 
baseline QTcF values on Days 1 
(Baseline 1 only), 2, 4 and 5 will be 
tested by t-test using Baseline 1 and 
2 at each time point. 
The hypothesis is that there is no 
change in QTcF post-dose as 
compared to pre-dose baseline 
values. Point estimate of difference, 
median, SD, min, max and 2-sided 
90%, 85%, and 80% CIs, together 
with p-values for each level of 
significance will be reported. 
In this analysis, change from 
baseline and percent change from 
baseline in QTcF at all time points 
on Days 1, 2, 3, 4, and 5, using 
Baseline 1 and Baseline 2 (for Days 
2, 3, 4, and 5 only), will be tested by 
t-test. 
The null hypothesis is that there is 
no change in QTcF at post-baseline 
time points as compared to the 
baseline values. The mean 
difference, median, SD, min, max, 
2-sided 90%, 85%, and 80% CIs, 
and p-value will be reported. The 
null hypothesis will be rejected at 
significance levels of 0.1, 0.15, or 
Addition of 
Day 3 to 
explore the 
change from 
baseline; 
Clarification 
on analysis 
methods and 
correction on 
multiple 
p-values; 
Addition of 
statistical 
interpretation 
on p-value 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
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The same change from baseline 
analyses (no percent change from 
baseline) will be done for HR, QRS, 
and PR intervals. 
0.2 if the p-value is less than 0.1, 
0.15, or 0.2, corresponding to 2- 
sided 90%, 85%, and 80% CIs, 
respectively. 
The same change from baseline 
analyses will be done for HR, QRS, 
and PR intervals. 
versus 
multiple CIs. 
6.4 
Key Placebo-Corrected Analyses  
 The QTcF values on Days 2, 4 
and 5 during the following 
times, will be compared to the 
values on Day 1 (placebo) 
utilizing the trapezoidal 
methodology (AUC). 
 
o 
Hours 2-6 
o 
Hours 0-8 
o 
Hours 0-12 
Key Placebo-corrected Analyses  
 The QTcF values collected on 
Days 2 and 4 during the 
following time intervals will be 
compared to the values on Day 1 
(placebo) utilizing the 
trapezoidal methodology for area 
under the curve (AUC) 
calculation. Furthermore, the 
average AUC, which is defined 
as the AUC divided by the actual 
time span of the AUC time 
interval within each subject, 
were analyzed as post-hoc 
analyses. An additional time 
interval from hours 3 to 6 was 
added after examining the time 
course of the QTcF data. 
 
o 
Hours 2-6 
o 
Hours 0-8 
o 
Hours 0-12 
o 
Hours 3-6 
Deletion of 
Day 5 as the 
time points 
are not the 
same as Day 
1; 
Clarification 
on analysis 
methods using 
AUC; 
 
Addition of 
new post-hoc 
analyses using 
average AUC; 
 
Addition of 
new post-hoc 
analyses using 
time interval 
of Hours 3-6. 
6.4 
Key Time-based Analyses 
 The change from baseline QTcF 
values on Days 2, 4 and 5, using 
Baseline 1 and Baseline 2. Each 
day will be analyzed separately. 
The Day 2, 4 and 5 QTcF values 
to be used in this analysis are the 
average of the QTcF values 
measured between: 
 
o 
Hours 2-6 
o 
Hours 0-8 
o 
Hours 0-12 
Key Time-based Analyses 
 The change from baseline QTcF 
values on Days 2 and 4, using 
Baseline 1 and Baseline 2, will 
be summarized for the following 
time intervals. The QTcF values 
to be analyzed are the average of 
the QTcF values measured in 
each time interval of interest. 
 
o 
Hours 2-6 
o 
Hours 0-8 
o 
Hours 0-12 
Deletion of 
Day 5 as the 
time points 
are not the 
same as Day 
1. 
6.4 
Categorical Analyses (Descriptive  
only) 
Categorical Analyses (Descriptive  
only) 
For any QTcF values that meet the 
following thresholds, the count and 
Addition of 
Day 3 to 
explore the 


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 Proportion of participants with 
any post-baseline QTcF < 480 
ms on Days 1, 2, 4 and 5, 
separately
 Proportion of timepoints 
(pooling all timepoints together 
across participants) with any 
post-baseline QTcF < 480 ms on 
Days 1, 2, 4 and 5, separately
 Proportion of participants with 
any post-baseline QTcF < 460 
ms on Days 1, 2, 4 and 5, 
separately
 Proportion of timepoints 
(pooling all timepoints together 
across participants) with any 
post-baseline QTcF < 460 ms on 
Days 1, 2, 4 and 5, separately
 Proportion of participants with 
any change from baseline QTcF
>20 ms on Days 1 (Baseline 1 
only), 2, 4 and 5 
 Proportion of timepoints 
(pooling all timepoints together 
across participants) with any 
change from baseline QTcF >20 
ms on Days 1 (Baseline 1 only), 
2, 4 and 5
 Proportion of timepoints 
(pooling all timepoints together 
across participants) with any 
change from baseline QTcF >15 
ms on Days 1 (Baseline 1 only), 
2, 4 and 5
percentage will be summarized by 
pre-dose and post-dose on Days 1, 2, 
3, 4, and 5 separately. 
 Proportion of participants with 
any QTcF <480 ms 
 Proportion of time points 
(pooling all time points together 
across participants) with any 
QTcF <480 ms 
 Proportion of participants with 
any QTcF <460 ms 
 Proportion of time points 
(pooling all time points together 
across participants) with any 
QTcF <460 ms 
 Proportion of participants with 
any reductions from baseline 
QTcF >20 ms 
 Proportion of time points 
(pooling all time points together 
across participants) with any 
reductions from baseline QTcF 
>20 ms 
 Proportion of participants with 
any reductions from baseline 
QTcF >15 ms 
 Proportion of time points 
(pooling all time points together 
across participants) with any 
reductions from baseline QTcF 
>15 ms 
change from 
baseline; 
Clarification 
on analysis 
methods; 
Clarification 
on the 
“change from 
baseline” was 
meant for 
“reduction 
from 
baseline”; 
 
Addition of 
the second to 
the last bullet 
point. 
6.4 
None 
Analyses using all Values of the  
Individual ECGs 
Unlike the previous analyses that 
used the average of the triplicates, 
additional post-hoc analyses were 
conducted to assess the differences 
in QTcF between the highest 
baseline values and the lowest post- 
baseline values using all individual 
QTcF values instead of the mean of 
the triplicates; treating all QTcF as 
individual data points. Specifically, 
within each subject, the differences 
between the highest Baseline 2 value 
of the triplicates and the lowest post- 
baseline value of the QTcF on Days 
Addition of 
new post-hoc 
analyses using 
all values of 
the ECGs. 


Amendment of Cardiac Statistical Analysis Plan, v2.0 
Study LQT-1213-0061 Part 2 
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Page 10 of 14 
 
 
 
 
 
2 and 4 (up to 4 hours in duration), 
and the differences between the 
highest Baseline 1 value of the 
triplicates and the lowest post- 
baseline value of the QTcF on Day 1 
(up to 4 hours in duration) were 
summarized. The differences 
between the highest Baseline 1 value 
of the triplicates and the lowest post- 
baseline value of the QTcF on Day 1 
were further evaluated in a subgroup 
of subjects with any reduction 
greater than 20 msec. A summary of 
QTcF collected from time intervals 
of 0-8 hours and 0-12 hours on Days 
1, 2, and 4 were also provided 
 
6.5 
 The SD of the difference in 
QTcF between Day 2 and Day 1 
(placebo) at each hour during 
hours 1-6 as specified in Section 
6.2
 The SD of the difference in 
QTcF between Day 4 and Day 1 
(placebo) at each hour during 
hours 1-6 as specified in Section 
6.2
 The SD of the change from 
baseline in QTcF on Day 2 
(using Baseline 1 and 2) at each 
hour during hours 1-6 as 
specified in Section 6.4
 The SD of the change from 
baseline in QTcF on Day 4 
(using Baseline 1 and 2) at each 
hour during hours 1-6 as 
specified in Section 6.4
 The SD of the difference in 
QTcF between Day 2 and Day 1 
(placebo) at each hour as 
specified in Section 6.2 
 The SD of the difference in 
QTcF between Day 4 and Day 1 
(placebo) at each hour as 
specified in Section 6.2 
 The SD of the change from 
baseline in QTcF on Day 2 
(using Baselines 1 and 2) at each 
hour as specified in Section 6.3 
 The SD of the change from 
baseline in QTcF on Day 4 
(using Baselines 1 and 2) at each 
hour as specified in Section 6.3 
Deletion of 
the restriction 
of hours 1-6 
as all time 
points are of 
interest; 
Correction on 
section 
number for 
the last two 
bullet points. 
 
3 Study Design 
The study is a Phase 1b/2a two-part (Part 1 and Part 2) trial in male and female subjects 
between 19 and 60 years of age (inclusive). Part 1 is a randomized, double-blind, 
crossover, dose escalation, placebo-controlled study to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of SGK-1 kinase inhibition by 
LQT-1213 on dofetilide-induced corrected QT (QTc) prolongation in healthy adult 
subjects. Part 2 is a single-blind, multiple-dose escalation safety study to evaluate the 
safety, tolerability, and PK of LQT-1213 in patients diagnosed with Long QT Syndrome 


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Type 2 (LQT2) and Long QT Syndrome Type 3 (LQT3). 
Part 1 
The design of Part 1 can be found in the protocol. The statistical plan for Part 1 was 
described in a separate statistical analysis plan. 
Part 2 
This will be a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to 
evaluate the safety, tolerability, and PK of LQT-1213 in patients with LQT2 and LQT3. 
All patients will have a QTcF ≥480 and ≤560 ms. Up to 12 participants with LQT2 and 
up to 12 participants with LQT3 will be enrolled. 
After initial remote screening by the clinical research unit (CRU), individual patients will 
undergo a 1-day, single blind run-in period followed by 3 dosing days of LQT-1213, 
administered three times a day (TID) at time 0, 8, and 16 hours on Days 2 and 3, with the 
final dose on Day 4 at time 0, though these time points may be adjusted based upon 
emerging data. 
Approximately 7 days after discharge from the CRU, the Follow-up visit will be 
conducted remotely via telephone call. The duration of treatment for each subject in the 
study will be approximately 13 days, from admission on Day -1 to the telephone follow- 
up call. This does not include the 60-day screening period. 
 
4 Cardiodynamic ECG Assessment 
In Part 2, ECG data will be collected from Day -1 through Day 5. At each time point, 
three (triplicate) ECGs will be recorded. For analysis purpose, the average of the 
triplicate ECGs will be analyzed. Additional post-hoc analyses based on all values of the 
triplicates were also conducted. While 24-hour Holter were collected from which ECGs 
can be extracted, this analysis utilizes concomitantly recorded 12 lead ECGs. 
The time points for cardiodynamic ECG assessments can be found in Appendix D of the 
protocol. 
4.1 Cardiodynamic ECG Objectives and Endpoints 
The objectives of the study are to: 
1) 
Evaluate the effect of up to two separate oral doses of LQT-1213 on QTcF 
prolongation in patients with LQT2 and LQT3 using the QTc interval corrected for 
heart rate by the Fridericia’s formula (QTcF). 


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2) 
Evaluate the effect of oral LQT-1213 on additional ECG parameters including 
Heart Rate (HR), PR interval, and QRS interval in patients with LQT2 and LQT3. 
 
5 Statistical Methods 
5.1 General Methodology 
For continuous variables the following descriptive statistics will be provided: number of 
subjects, mean, standard error of the mean (SE), standard deviation (SD), minimum 
(min), maximum (max), and median. For categorical variables, descriptive statistics will 
include the number and percentage of subjects in each category, using either the number 
of subjects in the treatment group or the number of subjects with non-missing values as 
the denominator for the percentages. All ECG data will be summarized by LQT-1213 
dose groups of 16 mg and 7 mg, unless otherwise specified. Min and max values will be 
rounded to the precision of the original value. Means and medians will be rounded to one 
decimal place greater than the precision of the original value. SDs and SEs will be 
rounded to two decimal places greater than the precision of the original value. Typically, 
the confidence intervals (CIs) shall be rounded to two decimal places greater than the 
precision of the original value; however, due to space constraint on the printout, as well 
as for easier review, the CIs were rounded (post-hoc) to one decimal place greater than 
the precision of the original value. Percentages for summarizing categorical data will be 
rounded to one decimal place. P-values will be presented with four decimal places and 
values less than 0.0001 will be presented as <0.0001. All inferential statistical testing will 
be two-sided, and log-transformation of values may be performed when applicable. 
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, 
a value of x will be taken for summary. In listings, these data will be presented as 
recorded with the sign. 
By-subject listings, including data at scheduled and unscheduled visits, will be sorted by 
treatment group, subject number, study visit and time point. 
5.2 Baseline 
Two baselines will be defined for analyses: 
Baseline 1: The average of the measured ECG intervals from the 3 sets of triplicate 
ECGs recorded pre-dose (-45, -30, and -15 minutes) on Day 1. 
Baseline 2: The average of the measured ECG intervals from the 3 sets of triplicate 
ECGs recorded pre-dose (-45, -30, and -15 minutes) on Day 2. 


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6 Analysis 
6.1 Summary Statistics Analysis 
Each ECG parameter will be summarized by visit. The average of the triplicates at each 
time point will be presented in listings. Descriptive statistics will be used to summarize 
the values of the ECG variables and the corresponding changes (and percent changes) 
from baseline values at each time point on each of Days 1-5. The 2-sided 90%, 85%, and 
80% CIs of the means will be derived based on t-test. 
6.2 Time-based Placebo-corrected Analysis 
In this analysis, QTcF values at each time point on Days 2 and 4 will be compared to the 
time-matched QTcF values on Day 1 (placebo) using paired t-test, which is the same as 
analyzing the difference of the time-matched QTcF values using one-sample t-test. 
The null hypothesis is that the difference between Day 2 (LQT-1213) and Day 1 
(placebo), and between Day 4 (LQT-1213) and Day 1, on matched time-points will be 
equal to 0 (zero). The mean difference, median, SD, min, max, 2-sided 90%, 85%, and 
80% CIs, and p-value will be reported. The null hypothesis will be rejected at 
significance levels of 0.1, 0.15, or 0.2 if the p-value is less than 0.1, 0.15, or 0.2, 
corresponding to 2-sided 90%, 85%, and 80% CIs, respectively. 
Additional post-hoc analyses were conducted for all time-matched placebo-corrected 
analyses by pooling subjects in the LQT-1213 16 mg and 7 mg dose groups together. 
The same analyses will be conducted on HR, PR and QRS. 
6.3 Time-based Change from Baseline Analysis 
In this analysis, change from baseline and percent change from baseline in QTcF at all 
time points on Days 1, 2, 3, 4, and 5, using Baseline 1 and Baseline 2, will be tested by t- 
test. 
The null hypothesis is that there is no change in QTcF at post-baseline time points as 
compared to the baseline values. The mean difference, median, SD, min, max, 2-sided 
90%, 85%, and 80% CIs, and p-value will be reported. The null hypothesis will be 
rejected at significance levels of 0.1, 0.15, or 0.2 if the p-value is less than 0.1, 0.15, or 
0.2, corresponding to 2-sided 90%, 85%, and 80% CIs, respectively. 
The same change from baseline analyses will be done for HR, QRS, and PR intervals. 


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6.4 Additional Key Analysis 
Key Placebo-corrected Analyses  
 The QTcF values collected on Days 2 and 4 during the following time intervals, 
will be compared to the values on Day 1 (placebo) utilizing the trapezoidal 
methodology for area under the curve (AUC) calculation. Furthermore, the 
average AUC, which is defined as the AUC divided by the actual time span of the 
AUC time interval within each subject, were analyzed as post-hoc analyses. An 
additional time interval from hours 3 to 6 was added after examining the time 
course of the QTcF data. 
o Hours 2-6 
o Hours 0-8 
o Hours 0-12 
o Hours 3-6 
Key Time-based Analyses 
 The change from baseline QTcF values on Days 2 and 4, using Baseline 1 and 
Baseline 2, will be summarized for the following time intervals. The QTcF values 
to be analyzed are the average of the QTcF values measured in each time interval 
of interest. 
o Hours 2-6 
o Hours 0-8 
o Hours 0-12 
Subgroup Analyses 
QTcF analyses specified in Section 6.2 and 6.3 will be repeated for the following cohorts: 
 Subjects with a Day 1 predose baseline QTc <500 ms, if there are at least 2 subjects 
 Subjects with a Day 1 predose baseline QTc ≥500 ms, if there are at least 2 subjects 
 Subjects with LQT2, if there are at least 2 subjects 
 Subjects with LQT3, if there are at least 2 subjects 
Categorical Analyses (Descriptive only) 
For any QTcF values that meet the following thresholds, the count and percentage will be 
summarized by pre-dose and post-dose on Days 1, 2, 3, 4, and 5 separately. 
 Proportion of participants with any QTcF <480 ms 
 Proportion of time points (pooling all time points together across participants) with 
any QTcF <480 ms 


 
 
 
 Proportion of participants with any QTcF <460 ms 
 Proportion of time points (pooling all time points together across participants) with 
any QTcF <460 ms 
 Proportion of participants with any reductions from baseline QTcF >20 ms 
 Proportion of time points (pooling all time points together across participants) with 
any reductions from baseline QTcF >20 ms 
 Proportion of participants with any reductions from baseline QTcF >15 ms 
 Proportion of time points (pooling all time points together across participants) with 
any reductions from baseline QTcF >15 ms 
 
Analyses using all Values of the Individual ECGs 
Unlike the previous analyses that used the average of the triplicates, additional post-hoc 
analyses were conducted to assess the differences in QTcF between the highest baseline 
values and the lowest post-baseline values using all individual QTcF values instead of the 
mean of the triplicates; treating all QTcF as individual data points. Specifically, within each 
subject, the differences between the highest Baseline 2 value of the triplicates and the lowest 
post-baseline value of the QTcF on Days 2 and 4 (up to 4 hours in duration), and the 
differences between the highest Baseline 1 value of the triplicates and the lowest post- 
baseline value of the QTcF on Day 1 (up to 4 hours in duration) were summarized. The 
differences between the highest Baseline 1 value of the triplicates and the lowest post- 
baseline value of the QTcF on Day 1 were further evaluated in a subgroup of subjects with 
any reduction greater than 20 msec. A summary of QTcF collected from time intervals of 
0-8 hours and 0-12 hours on Days 1, 2, and 4 were also provided. 
6.5 Interim Standard Deviation Analysis 
Prior to the full SAP analysis, the following standard deviation analysis will be computed 
to evaluate the power and sample sizes after the first 6 subjects. 
 The SD of the difference in QTcF between Day 2 and Day 1 (placebo) at each hour 
as specified in Section 6.2 
 The SD of the difference in QTcF between Day 4 and Day 1 (placebo) at each hour 
as specified in Section 6.2 
 The SD of the change from baseline in QTcF on Day 2 (using Baselines 1 and 2) at 
each hour as specified in Section 6.3 
 The SD of the change from baseline in QTcF on Day 4 (using Baselines 1 and 2) at 
each hour as specified in Section 6.3