Clinical trial NCT05208866
Conditions: Polycystic Kidney Disease, Adult
Sponsor: Palladio Biosciences
Start date: 2022-02-10; Completion date: 2022-07-29
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, open-label, roll-over study to demonstrate the continued hepatic and non-hepatic safety and renal efficacy of lixivaptan in participants with ADPKD who previously experienced abnormal liver chemistry test results while treated with tolvaptan, were permanently discontinued from the drug for that reason, and subsequently completed study PA-ADPKD-303, the open-label lead-in study with lixivaptan.

Detailed description:
This is a Phase 3, open-label, roll-over study to demonstrate the continued hepatic and non-hepatic safety and renal efficacy of lixivaptan in participants with ADPKD who previously experienced abnormal liver chemistry test results while treated with tolvaptan that resulted in permanent discontinuation of tolvaptan for that reason, and subsequently completed study PA-ADPKD-303, the open-label lead-in study with lixivaptan.

Assessments completed during the final 4 visits of PA-ADPKD-303, the lead-in study, will serve as the screening and baseline assessments for this roll-over study. Evaluation of eligibility will be completed at Visit 1 of this study, following signing of informed consent. Participants satisfying all study entry criteria at Visit 1 will be considered enrolled following completion of all Visit 1 study procedures and will be dispensed lixivaptan treatment to start the Lixivaptan Re-titration Period (1 to 2 weeks). During the Lixivaptan Re-titration Period, participants will have their dose of lixivaptan re-established based on the dose they were receiving at the completion of the lead-in study. Participants will continue on lixivaptan treatment for up to 104 weeks during the Maintenance Treatment Period and will be assessed at a study visit every 12 weeks. In between the quarterly study visits, participants will be required to have blood drawn for liver chemistry determinations every 4 weeks. At the end of 104 weeks, lixivaptan treatment will be stopped, and participants will enter a 4-week Follow-up Period during which final assessments of safety and efficacy will be obtained over 3 visits during a 28-day period.

Arms: arm 1: Lixivaptan capsules 100-200mg twice daily
Interventions: intervention 1: Lixivaptan
Intervention descriptions: intervention 1: Oral vasopressin V2 receptor antagonist

Protocol documents:
Prot_000.pdf: 
Study Title: PA-ADPKD-304: A Phase 3, Open-label, Roll-over Study to Assess Long-term 
Safety of Lixivaptan in Participants With Autosomal Dominant Polycystic Kidney Disease 
Who Completed Study PA-ADPKD-303: The ALERT Study 
ClinicalTrials.gov ID: NCT05208866 
Clinical Study Protocol Version 2.0, dated 20-May-2022 
Clinical Study Protocol Version 2.0, dated 20-May-2022, Summary of Changes 


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CLINICAL STUDY PROTOCOL 
PA-ADPKD-304: A Phase 3, Open-label, Roll-over Study to Assess Long-
term Safety of Lixivaptan in Participants with Autosomal Dominant 
Polycystic Kidney Disease Who Completed Study PA-ADPKD-303: The 
ALERT Study  
Protocol Number: PA-ADPKD-304 
IND Number: 136,419 
Sponsor: 
Sponsor Contact: 
Medical Monitor: 
Version of Protocol: 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
Neil Shusterman, MD FACP 
Chief Medical Officer 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive, Suite 120 
Horsham, PA 19044 
Email: nshusterman@palladiobio.com 
Joyce Johnsrud, MD 
ICON Clinical Research 
Email:  Joyce.Johnsrud@iconplc.com 
In a study related health emergency, when the assigned 
medical monitor cannot be reached, please refer to Section 
7.2.8.3 for further contact information. 
2.0  
Date of Protocol:  
20-MAY-2022
CONFIDENTIAL
All financial and nonfinancial support for this study will be provided by Palladio Biosciences.  
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 expressed, 
written consent of Palladio Biosciences.  


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PROTOCOL APPROVAL - SPONSOR SIGNATURE 
Protocol Title 
PA-ADPKD-304: A Phase 3, Open-label, Roll-over Study to Assess 
Long-term Safety of Lixivaptan in Participants with Autosomal 
Dominant Polycystic Kidney Disease Who Completed Study              PA-
ADPKD-303: The ALERT Study 
Protocol Number PA-ADPKD-304 
Protocol Version 
2.0 
Protocol Date 
20 MAY 2022 
Protocol accepted and approved by: 
Neil H. Shusterman, MD FACP 
Chief Medical Officer 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044  
______   
20May2022________________ 
Signature   
Date 


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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol titled “PA-ADPKD-304: A Phase 3, 
Open-label, Roll-over Study to Assess Long-term Safety of Lixivaptan in Participants with 
Autosomal Dominant Polycystic Kidney Disease Who Completed Study PA-ADPKD-303: 
The ALERT Study” 
 
Protocol Number: PA-ADPKD-304 
 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the protocol, the ICH harmonized tripartite guideline E6(R2) Good Clinical 
Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry, the Declaration of 
Helsinki, and all applicable government regulations.  I will not make changes to the protocol 
before consulting with Palladio Biosciences or implement protocol changes without 
Institutional Review Board (IRB)/Ethics Committee (EC) approval except to eliminate an 
immediate risk to participants.  I agree to administer study treatment only to participants 
under my personal supervision or the supervision of a Sub-Investigator. 
I will not supply the investigational drug to any person not authorized to receive it.  
Confidentiality will be protected.  Participant identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Palladio Biosciences. 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL - SPONSOR SIGNATURE ........................................................2 
DECLARATION OF INVESTIGATOR ................................................................................3 
TABLE OF CONTENTS .........................................................................................................4 
LIST OF TABLES ....................................................................................................................8 
LIST OF FIGURES .................................................................................................................8 
PROTOCOL SYNOPSIS ........................................................................................................9 
LIST OF ABBREVIATIONS ................................................................................................21 
1 
INTRODUCTION ..........................................................................................................23 
1.1 
Background .............................................................................................................23 
1.2 
Study Rationale .......................................................................................................23 
1.3 
Dose Rationale ........................................................................................................26 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................27 
2.1 
Study Objectives .....................................................................................................27 
2.1.1 
Primary Objectives ..................................................................................27 
2.1.2 
Secondary Objectives ..............................................................................27 
2.2 
Study Endpoints ......................................................................................................27 
2.2.1 
Primary Endpoint .....................................................................................27 
2.2.2 
Secondary Endpoints ...............................................................................27 
3 
INVESTIGATIONAL PLAN ........................................................................................28 
3.1 
Study Design ...........................................................................................................28 
3.1.1 
Overview of Study Design .......................................................................28 
3.1.2 
Detailed Study Design .............................................................................29 
3.2 
Rationale for Study Design .....................................................................................30 
4 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA ...........................31 
4.1 
Selection of Study Population .................................................................................31 
4.1.1 
Inclusion Criteria .....................................................................................31 
4.1.2 
Exclusion Criteria ....................................................................................32 
4.2 
Completion and Withdrawal of Participants from the Study ..................................32 
4.2.1 
Definition of Completed Participants ......................................................32 


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4.2.2 
Screening Failures....................................................................................33 
4.2.3 
Participant Withdrawal Criteria ...............................................................33 
4.2.4 
Reasons for Withdrawal ...........................................................................33 
4.2.5 
Methods to Prevent Loss to Follow-up ....................................................34 
4.2.6 
Replacements ...........................................................................................34 
4.2.7 
Withdrawals Due to Abnormal Liver Chemistry Test Results .................35 
5 
LIXIVAPTAN TREATMENT AND CONCOMITANT MEDICATION ..................36 
5.1 
Lixivaptan Treatment ..............................................................................................36 
5.1.1 
Identity of the Investigational Product.....................................................36 
5.1.2 
Route of Administration...........................................................................36 
5.1.3 
Lixivaptan Packaging, Labeling, and Storage .........................................36 
5.1.4 
Accountability ..........................................................................................37 
5.2 
Dose Administered ..................................................................................................37 
5.3 
Method of Assigning Participants to Identification Numbers.................................38 
5.4 
Blinding...................................................................................................................38 
5.5 
Randomization and Treatment Assignment ............................................................38 
5.6 
Treatment Compliance ............................................................................................38 
5.7 
Prior and Concomitant Therapy ..............................................................................38 
5.7.1.1 
Permitted Therapy ....................................................................................39 
5.7.1.2 
Prohibited Therapy ..................................................................................39 
5.8 
Diet, Fluid, Activity, and Lifestyle Considerations .................................................40 
6 
TIMING OF STUDY PROCEDURES .........................................................................42 
6.1 
Screening Period .....................................................................................................42 
6.1.1 
Visit 1/Visit 27 of PA-ADPKD-303 .........................................................42 
6.2 
Re-titration Period ...................................................................................................43 
6.2.1.1 
Visit 2 .......................................................................................................43 
6.2.1.2 
Visit 3/Last Titration Visit ........................................................................44 
6.3 
Maintenance Treatment Period ...............................................................................44 
6.3.1 
Visits 4 to 28 ............................................................................................45 
6.3.1.1 
Visits 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, and 
28/Laboratory Only Visits .......................................................................45 
6.3.1.2 
Visits 6, 12, 18, 24, and 27/Clinic or Remote Visits ................................45 
6.3.1.3 
Visits 9, 15, and 21/Clinic Visits ..............................................................46 
6.3.2 
Visit 29/Early Termination .......................................................................46 
6.4 
Follow-up Period ....................................................................................................47 


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6.4.1 
Visit 30 .....................................................................................................47 
6.4.2 
Visit 31 .....................................................................................................47 
6.4.3 
Visit 32 (End of Study Visit) ....................................................................48 
6.4.4 
Early Termination Procedures..................................................................48 
7 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES ......................49 
7.1 
Efficacy Assessments ..............................................................................................49 
7.1.1 
eGFR ........................................................................................................49 
7.2 
Safety and Tolerability Assessments .......................................................................49 
7.2.1 
Body Height, Weight, and BMI ...............................................................49 
7.2.2 
Demographics and Medication History ...................................................50 
7.2.3 
Physical Examinations .............................................................................50 
7.2.4 
Vital Sign Measurements .........................................................................50 
7.2.5 
12-Lead ECGs..........................................................................................51 
7.2.6 
Clinical Laboratory Tests .........................................................................51 
7.2.6.1 
Sample Collections ..................................................................................52 
7.2.7 
Assessment of Liver Symptoms, Signs, or Test Abnormalities ...............53 
7.2.7.1 
Requirements for Additional Liver Chemistry Testing ............................53 
7.2.7.2 
Changes in Lixivaptan Dosing if Liver Chemistry Test Abnormalities 
Occur During the Titration or Maintenance Treatment Periods ..............53 
7.2.7.3 
Special Reporting of Liver Events ...........................................................54 
7.2.8 
Adverse Events ........................................................................................55 
7.2.8.1 
Definitions of Adverse Events .................................................................55 
7.2.8.2 
Eliciting and Documenting Adverse Events and Serious Adverse Events
 .................................................................................................................55 
7.2.8.3 
Reporting Adverse Events, Serious Adverse Events, and Adverse Events 
of Special Interest ....................................................................................56 
7.2.8.4 
Assessment of Severity ............................................................................57 
7.2.8.5 
Assessment of Causality ..........................................................................57 
7.2.8.6 
Follow-Up of Participants Reporting Adverse Events .............................59 
7.2.8.7 
Overdose Management ............................................................................59 
7.2.8.8 
Pregnancy.................................................................................................59 
7.2.9 
Clinical Laboratory and Other Safety Assessments .................................60 
7.2.10 
Hepatic Events Review Committee (HERC) ...........................................60 
8 
STATISTICAL AND ANALYTICAL PLAN ...............................................................61 
8.1 
Sample Size .............................................................................................................61 
8.2 
Populations for Analysis .........................................................................................61 
8.3 
Analysis of Demographic and Baseline Characteristics .........................................61 


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8.4 
Safety Analyses .......................................................................................................61 
8.4.1 
Primary Hepatic Safety Analysis .............................................................61 
8.4.2 
Secondary Hepatic Safety Analyses ........................................................61 
8.4.3 
Additional Hepatic Safety Analyses ........................................................62 
8.4.4 
Non-hepatic Safety Analyses: Adverse Events ........................................62 
8.4.5 
Clinical Laboratory Tests .........................................................................62 
8.4.6 
ECGs ........................................................................................................63 
8.4.7 
Vital Signs ................................................................................................63 
8.5 
Efficacy Analysis ....................................................................................................63 
8.6 
Statistical Analysis Methodology ...........................................................................64 
8.7 
Data Quality Assurance...........................................................................................64 
8.7.1 
Data Management ....................................................................................64 
9 
ETHICS ...........................................................................................................................66 
9.1 
Institutional Review Board (IRB)/Ethics Committee (EC) ....................................66 
9.2 
Ethical Conduct of the Study ..................................................................................66 
9.3 
Participant Information and Consent ......................................................................66 
10 INVESTIGATOR’S OBLIGATIONS AND STUDY PERSONNEL .........................67 
10.1 Confidentiality ........................................................................................................67 
10.2 Financial Disclosure and Obligations .....................................................................67 
10.3 Investigator Documentation ....................................................................................67 
10.4 Study Conduct .........................................................................................................68 
10.5 Adherence to Protocol.............................................................................................68 
10.6 Adverse Events and Study Report Requirements ...................................................68 
10.7 Investigator’s Final Report .....................................................................................68 
10.8 Records Retention ...................................................................................................68 
10.9 Publications .............................................................................................................69 
11 STUDY MANAGEMENT .............................................................................................70 
11.1 Monitoring ..............................................................................................................70 
11.1.1 
Monitoring of the Study ...........................................................................70 
11.1.2 
Inspection of Records and Quality Assurance .........................................70 
11.2 Management of Protocol Amendments and Deviations..........................................70 
11.2.1 
Modification of the Protocol ....................................................................70 
11.2.2 
Protocol Deviations..................................................................................70 
11.3 Study Termination ...................................................................................................71 


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11.4 Final Report ............................................................................................................71 
12 REFERENCE LIST .......................................................................................................72 
13 APPENDICES ................................................................................................................73 
13.1 Appendix 1: Chronic Kidney Disease Classification Criteria ................................73 
13.2 Appendix 2: DILI Network Causality Criteria, modified .......................................74 
13.3 Appendix 3: Additional Potential Hepatic Testing if Liver Chemistry 
Abnormalities Occur .......................................................................................75 
13.4 Appendix 4: Liver Dysfunction Checklist ..............................................................76 
 
LIST OF TABLES 
Table 1. Dose Titration Based on Dose Achieved at End of Maintenance Period in Lead-in 
Study PA-ADPKD-303 ................................................................................... 13 
Table 2. Dosing Diagram ........................................................................................................ 14 
Table 3. Schedule of Procedures ............................................................................................. 18 
Table 4. DILIsym simulations of lixivaptan and tolvaptan ..................................................... 24 
Table 5.  Investigational Product ............................................................................................ 36 
Table 6. Clinical Laboratory Parameters ................................................................................ 52 
Table 7. Additional Liver Chemistry Testing and Other Testing ............................................ 53 
Table 8. Guideline for Assessment of Adverse Event Causality ............................................. 59 
LIST OF FIGURES 
Figure 1. Study Schema .......................................................................................................... 17 
Figure 2. Time Course of ALT Levels in Relationship to Dosing of Tolvaptan in a Patient 
with Painful ADPKD ...................................................................................... 25 
Figure 3. Time Course of ALT Levels in Relationship to Dosing of Lixivaptan in a Patient 
with Painful ADPKD ...................................................................................... 26 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Number: 
PA-ADPKD-304 
Protocol Title: 
PA-ADPKD-304: A Phase 3, Open-label, Roll-over Study to Assess Long-
term Safety of Lixivaptan in Participants with Autosomal Dominant 
Polycystic Kidney Disease Who Completed Study PA-ADPKD-303: The 
ALERT Study 
Sponsor: 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
Study Phase: 
Phase 3 
Study Sites: 
Up to approximately 25 US sites  
Indication: 
Autosomal Dominant Polycystic Kidney Disease (ADPKD) 
Rationale: 
 
 
 
 
 
 
ADPKD is the most frequent inherited cause of end-stage renal failure. 
Animal models have shown that vasopressin activity is necessary for the 
disease to manifest and progress.  Studies of the vasopressin V2 receptor 
antagonist tolvaptan have shown that it can slow the progression of renal 
function deterioration in patients with ADPKD.  However, serious drug 
induced liver injury (DILI) occurs in a certain percentage of patients treated 
with tolvaptan, requiring diligent testing of liver chemistry in all patients and 
discontinuation of the drug when the test results are elevated in order to 
prevent serious outcomes.  The vasopressin V2 receptor antagonist, 
lixivaptan, has also been shown to ameliorate polycystic disease 
manifestations in animal models of disease.  Evidence from Quantitative 
Systems Toxicology modeling and initial clinical results suggest that 
lixivaptan does not have the same potential for liver injury.  Thus, lixivaptan 
may represent a safer alternative to tolvaptan with similar efficacy.  The 
ALERT Study (PA-ADPKD-303) is a Phase 3, open-label study of 
lixivaptan in participants who experienced abnormal liver chemistry test 
results on tolvaptan resulting in permanent discontinuation of tolvaptan.  
This roll-over study is designed to provide these participants with continued 
access to lixivaptan as well as allow for the assessment of long-term safety 
and efficacy of lixivaptan in this population.    
Objectives: 
 
 
 
The primary objective of this study is: 
• 
To assess the hepatic safety of lixivaptan with continued dosing. 
The secondary objectives of this study are: 
• 
To characterize the non-hepatic safety and tolerability of lixivaptan;  
• 
To assess renal function (efficacy) in participants while on 
lixivaptan using change in estimated glomerular filtration rate 
(eGFR). 
Participant 
Population: 
The following are requirements for entry into the study at Visit 1: 
Inclusion criteria: 
1. Male or female participants with ADPKD who completed study PA-


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ADPKD-303 
2. Female participants must: 
a. not be pregnant, lactating, or breastfeeding.   
b. be either postmenopausal (defined as amenorrhea for ≥ 12 
months), surgically sterile (defined as having undergone 
hysterectomy and/or bilateral oophorectomy), or if of child-
bearing potential (WOCBP) must agree to continue to 
practice appropriate methods of birth control or remain 
abstinent (only if this is the usual and preferred lifestyle of 
the participant) during the full duration of the study and for 
30 days after the last dose of lixivaptan treatment.  
Acceptable forms of contraception include the following: 
• hormonal contraceptives (i.e., oral, intravaginal, 
transdermal, injectable, implantable) 
• intrauterine device (IUD), including progestin-
containing intrauterine devices 
• intrauterine hormone-releasing system (IUS) 
• male sexual partner who has been vasectomized for at 
least 3 months prior to Screening and who has 
obtained a follow-up negative sperm count and is the 
sole sexual partner 
• bilateral tubal ligation 
• Essure® procedure (tubal occlusion) 
• male or female condom with spermicide (cream, 
spray, gel, suppository, or polymer film) 
• diaphragm, cervical cap, or contraceptive sponge with 
spermicide (with or without a male condom) 
3. Male participants must agree to continue to use an acceptable form 
of birth control (see list above) or remain abstinent (only if this is the 
usual and preferred lifestyle of the participant) during the full 
duration of the trial and for 30 days after the last dose of lixivaptan 
treatment 
4. Continued control of hypertension without the use of a diuretic in 
concert with KDIGO “Clinical Practice Guideline for the 
Management of Blood Pressure in Chronic Kidney Disease” 
5. Continued adherence to prohibitions on concomitant medications 
stated in the study PA-ADPKD-303 protocol and in Section 5.7.1.2 
of this protocol, including use of strong or moderate CYP3A4 or 
CYP2C8 inhibitors or inducers 
6. Read, understood, and provided written informed consent after the 
nature of the study has been fully explained and must be willing to 
comply with all study requirements and procedures. 
Exclusion criteria: 


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1. Any contraindication to continued treatment with lixivaptan   
2. Clinically significant (CS) incontinence, overactive bladder, or 
urinary retention (e.g., benign prostatic hyperplasia) 
3. New York Heart Association Functional Class 3 or 4 heart failure or 
other significant cardiac or electrocardiogram (ECG) findings that 
could pose a safety risk to the participant 
4. Hypovolemia on physical examination at Screening 
5. The following laboratory results based on serum drawn at Visit 24 of 
PA-ADPKD-303: 
a. Serum alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) values >1.5 × upper limit of normal 
(ULN)  
b. Total bilirubin values >1.5 × ULN 
6. eGFR <20 ml/min/1.73 m2 based on laboratory results from Visit 26 
of PA-ADPKD-303  
7. A finding at Screening that precludes safe participation in the study 
or participants who are likely to be non-compliant with study 
procedures in the opinion of the Investigator or medical monitor.        
Study Design: 
This is a Phase 3, open-label, roll-over study to demonstrate the continued 
hepatic and non-hepatic safety and renal efficacy of lixivaptan in participants 
with ADPKD who previously experienced abnormal liver chemistry test 
results while treated with tolvaptan, were permanently discontinued from the 
drug for that reason, and subsequently completed study PA-ADPKD-303, 
the open-label lead-in study with lixivaptan.  Up to 50 participants can be 
enrolled and treated with lixivaptan in study PA-ADPKD-303.  All 
participants completing the lead-in study and meeting eligibility criteria for 
this study will be able to enroll.  It is estimated that approximately up to 40 
participants will enroll in this study, assuming 90% of participants complete 
study PA-ADPKD-303 and 90% meet eligibility and elect to enroll in this 
study.   
The Screening period will be 4 weeks in duration.  Assessments completed 
during the final 4 visits (Visits 24, 25, 26, and 27) of the lead-in study will 
serve as the screening and baseline assessments for this study. Visit 27 of the 
lead-in study will also serve as Visit 1 of this study.  Liver chemistry tests 
assessed at Visit 24 and eGFR assessed at Visit 26 of the lead-in study will 
be used for assessment of laboratory-related eligibility criteria at Visit 1 of 
this study.  Safety assessments (e.g., ECG, physical examination) performed 
at Visits 25, 26, and 27 of the lead-in study will also be used for assessment 
of eligibility and will constitute the baseline values for this study.  The mean 
of the eGFR values obtained at Visits 25, 26, and 27 of the lead-in study will 
be used to determine the baseline eGFR value for this study.  Evaluation of 
eligibility will be completed at Visit 1 of this study, following signing of 
informed consent. Participants satisfying all study entry criteria at Visit 1 
will be considered enrolled following completion of all Visit 1 study 
procedures and will be dispensed lixivaptan treatment in accordance with 
Table 1 to start the Lixivaptan Re-titration Period. 
During the 1-to-2-week Lixivaptan Re-titration Period, participants whose 


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final dose during the Maintenance Period of the lead-in study was 100 mg 
BID or less will remain on that dose for one week and then proceed to the 
Maintenance Treatment Period.  Participants on doses greater than 100 mg 
BID will be directly titrated to their final dose of the lead-in study during a 
second week in the re-titration period (See Table 1).  Lixivaptan treatment 
titration and assignment will be programmed into the Interactive Response 
Technology (IRT) system. 
Participants will continue on lixivaptan treatment for up to 104 weeks during 
the Maintenance Period and will be assessed at a study visit every 12 weeks 
where study procedures will include clinical laboratory determinations, 
including liver chemistry panels.  In between the quarterly study visits, 
participants will be required to have blood drawn for liver chemistry 
determinations every 4 weeks.  Where available and approved, visits 
designated as “laboratory only” visits may be conducted remotely by a home 
healthcare clinician or by a designated third-party that will process samples 
for shipment to the central laboratory. In addition, liver chemistry tests may 
be drawn in the clinic if that is more convenient for the participant.  
At the end of 104 weeks, lixivaptan treatment will be stopped, and 
participants will enter a 4-week Follow-up Period during which final 
assessments will be obtained over 3 visits starting on the 8th day following 
the last dose of lixivaptan treatment and continuing through the 28th day.  
 
 


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Study Period 
Description and 
Estimated 
Duration: 
 
 
 
 
 
 
 
 
Screening Period: The Screening Period will be 4 weeks in duration.  
Screening values for assessment of eligibility for enrollment will be those 
obtained during the final 4 visits (Visits 24, 25, 26 and 27) of study PA-
ADPKD-303. Evaluation of eligibility will be initiated following the signing 
of the informed consent for this study (V27 of PA-ADPKD-303/V1 of PA-
ADPKD-304). Participants satisfying all study entry criteria at Visit 1 will 
be considered enrolled following completion of all Visit 1 study procedures 
and will be dispensed lixivaptan 100 mg BID to start the Lixivaptan Re-
titration Period.  Participants whose last dose in the lead-in study was 50 mg 
BID, can enter this roll-over study on that dose.  These participants will be 
dispensed 50 mg BID at Visit 1 to start the Lixivaptan Re-titration Period 
and remain on that dose for one week. 
Lixivaptan Re-titration Period: Titration of lixivaptan will occur over a 1-to-
2-week re-titration period. Following one week of dosing, the dose of 
lixivaptan will be increased from 100 mg BID to the final dose taken at the 
end of the Maintenance Period for those participants whose final dose at the 
end of the lead-in study was greater than 100 mg BID. Participants whose 
final dose was 100 mg BID or less in study PA-ADPKD-303, will proceed 
directly to Visit 3 following one week of re-titration.    
Table 1. Dose Titration Based on Dose Achieved at End of Maintenance 
Period in Lead-in Study PA-ADPKD-303 
Final Dose in study 
PA-ADPKD-303 
Week 1 
Week 2 
100 mg BID 
100mg BID 
N/A 
150 mg BID 
100mg BID 
150mg BID 
150/100 mg 
(AM/PM) 
100mg BID 
150/100mg  
(AM/PM) 
200 mg BID 
100mg BID 
200mg BID 
200/150 mg 
(AM/PM) 
100mg BID 
200/150mg (AM/PM) 
*Participants whose dose was reduced to 50 mg BID during the lead-in study, may continue 
on that dose in this study following one week of re-titration.  For those participants dosing 
will be one (1) 50 mg capsule twice daily 
Maintenance Treatment Period: Following completion of the Lixivaptan Re-
titration Period, participants will continue into the open-label Maintenance 
Treatment Period following completion of Visit 3 assessments for up to 104 
weeks.  Participants will be assessed at study visits scheduled every 12 
weeks but will have required liver chemistry testing every 4 weeks; those 
visits occurring between the 12-week study visits are designated as 
“laboratory-only visits”.  Where available and approved, the laboratory-only 
visits may be conducted remotely by a Home Healthcare Clinician (HHC) or 
by a designated third-party that will process samples for shipment to the 
central laboratory. In addition, liver chemistry tests may be drawn in the 
clinic if that is more convenient for the participant.  The 12-week study visits 
at Weeks 12, 36, 60 and 84 can be performed either on-site or remotely by 


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an HHC, if available and approved. 
Follow-up Period: Three (3) visits will occur over 4 weeks following the last 
dose of lixivaptan in order to obtain final assessments. Starting with the 8th 
day after the last dose of lixivaptan, serum creatinine will be drawn at 3 time 
points (no less than 24 hours apart between each sampling) over a period of 
up to 28 days post last dose of lixivaptan.   
The total duration of participation in this study from the signing of ICF at 
Visit 1 will be approximately 109 to 110 weeks.   
Lixivaptan 
Treatment, 
Dosage, and 
Route of 
Administration: 
The sponsor (Palladio Biosciences, Inc.) will supply lixivaptan 50 mg 
capsules for use during the study. Participants will take 2 to 4 capsules BID, 
dependent on the final dose from the Maintenance Period of study PA-
ADPKD-303. All doses will be self-administered by participants orally at 
home. 
Table 2. Dosing Diagram 
Dose Level* 
AM Dose 
50mg 
Capsules per 
Administration 
PM 
Dose 
50mg 
Capsules per 
Administration 
2** 
100 mg 
2 
100 mg 
2 
3 
150 mg 
3 
150 mg 
3 
3a*** 
150 mg 
3 
100 mg 
2 
4 
200 mg 
4 
200 mg 
4 
4a**** 
200 mg 
4 
150 mg 
3 
*Participants whose dose was reduced to 50 mg BID during the lead-in study, may continue 
on that dose in this study.  For those participants dosing will be one (1) 50 mg capsule 
twice daily.  In the event of newly emerging tolerability issues while on the 50 mg BID 
dose, the participant will be discontinued. 
**Participants on Level 2 who require a dose reduction as a result of newly emerging 
tolerability issues or treatment-emergent AEs can have their dose reduced to 50 mg BID if 
approved by the medical monitor.    
***Participants having difficulty tolerating Dose Level 3 can drop back to 150 mg in the 
AM and 100 mg in the PM (Dose Level 3a: 150/100 mg). 
****Participants having difficulty tolerating Dose Level 4 can drop back to 200 mg in the 
AM and 150 mg in the PM (Dose Level 4a: 200/150 mg). 
Study 
Assessments: 
Safety: Liver chemistry tests (ALT, AST, total bilirubin, direct bilirubin, 
alkaline phosphatase), clinical laboratory parameters (hematology, non-
hepatic clinical chemistry, and urinalysis), 12-lead ECGs, vital signs, 
physical examination, adverse events (AEs), and serious adverse events 
(SAEs). 
Efficacy: eGFR 
Criteria for 
Evaluation: 
Primary Endpoint  
Safety: 
Proportion of participants with serum ALT levels >3 × ULN during the 
Lixivaptan Re-titration or Maintenance Treatment Periods that were assessed 
by the independent Hepatic Events Review Committee (HERC) to be at least 


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probably related to lixivaptan and resulted in discontinuation of lixivaptan 
treatment. 
 
Secondary Endpoints 
Safety: 
Proportion of participants with serum ALT levels >5 × ULN during the 
Lixivaptan Re-titration or Maintenance Treatment Periods that were assessed 
by the independent HERC to be at least probably related to lixivaptan and 
resulted in discontinuation of lixivaptan treatment. 
Proportion of participants with serum ALT levels >3 × ULN during the 
Lixivaptan Re-titration or Maintenance Treatment Periods that were assessed 
by the independent HERC to be at least probably related to lixivaptan and 
resulted in dose reduction of lixivaptan treatment. 
Safety and tolerability of lixivaptan assessed through evaluation of AEs, 
clinical laboratory findings (clinical chemistry including additional analyses 
of liver chemistry tests, hematology, and urinalysis), vital signs, and 12-lead 
electrocardiograms (ECGs). 
Efficacy: 
Change in annualized eGFR from baseline (mean of 3 eGFR determinations 
obtained at Visits 25, 26, and 27 of study PA-ADPKD-303) to final 
assessment (mean of 3 eGFR determinations obtained during the Follow-up 
Period).  
Statistical 
Methods: 
Populations for Analysis: 
Enrolled Population: The Enrolled Population is defined as all participants 
who meet all eligibility criteria during the Screening Period and complete 
Visit 1.  All general summaries, except safety and efficacy analyses are 
based on the Enrolled Population, unless specified otherwise. 
Safety Population: The Safety Population is a subset of the Enrolled 
Population defined as those participants who received at least 1 dose of 
lixivaptan.  This population will be utilized for all safety analyses. 
Efficacy Population: The Efficacy Population is a subset of the Safety 
Population defined as those participants who have at least 1 eGFR 
determination during the Screening Period (Follow-up Period of study PA-
ADPKD-303) and have at least 1 eGFR determination during the Follow-up 
Period of this study.  This population will be used for all efficacy analyses. 
Primary Hepatic Safety Analysis: 
Descriptive statistics (n, percentage and 95% confidence intervals) will be 
used to present the proportion of participants with serum ALT levels >3 × 
ULN that were assessed by the independent HERC to be at least probably 
related to lixivaptan and resulted in discontinuation of lixivaptan treatment 
during the Lixivaptan Re-titration or Maintenance Treatment Periods. 
Secondary Hepatic Safety Analyses: 
Similarly, descriptive statistics (n, percentage and 95% confidence intervals) 


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will be utilized to present the 2 secondary endpoints: 1) the proportion of 
participants with serum ALT levels >5 × ULN during the Lixivaptan Re-
titration or Maintenance Treatment Periods that were assessed by the 
independent HERC to be at least probably related to lixivaptan and resulted 
in the discontinuation of lixivaptan treatment; and 2) the proportion of 
participants with serum ALT levels >3 × ULN during the Lixivaptan Re-
titration or Maintenance Treatment Periods that were assessed by the 
independent HERC to be at least probably related to lixivaptan and resulted 
in lixivaptan dose reduction. 
Additional Hepatic Safety Analyses: 
Proportion of participants who develop any of the following 
abnormalities during the Lixivaptan Re-titration or Maintenance 
Treatment Periods: 
• 
>3 ×, 5 ×, 10 ×, and 20 × ULN elevations for ALT  
• 
>3 ×, 5 ×, 10 ×, and 20 × ULN elevations for AST 
• 
>3 ×, 5 ×, 10 ×, and 20 × ULN elevations for either ALT or AST 
• 
ALT or AST levels >2 × their baseline 
• 
Any elevation of total bilirubin >2 × ULN 
• 
Any elevation of alkaline phosphatase >2 × ULN 
• 
Elevation of aminotransferase (>3 × ULN) accompanied by elevated 
bilirubin (>2 × ULN) and displayed as evaluation of Drug-Induced 
Serious Hepatotoxicity (eDISH) plots 
• 
Elevation of aminotransferase in temporal association with nausea, 
vomiting, anorexia, abdominal pain, or fatigue 
• 
Possible liver-related deaths and liver-related treatment 
discontinuations. 
Additional Non-hepatic Safety Analyses: 
The following safety variables will be summarized using appropriate 
descriptive statistics: 
Treatment-emergent adverse events, clinical laboratory data, vital signs, and 
12-lead ECGs.  Potentially clinically significant results in certain clinical 
laboratory tests, 12-lead ECGs, and vital signs identified using prospectively 
defined criteria will also be summarized descriptively. 
Efficacy Analysis: 
Baseline eGFR is defined as the mean of the 3 eGFR assessments obtained 
during the Screening Period (Visits 25, 26, and 27 of study PA-ADPKD-
303.)  The endpoint eGFR is defined as the mean of 3 eGFR assessments 
obtained during the Follow-up Period of this study.  Descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) will be 
presented for the change from baseline in annualized eGFR at endpoint. 
 


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Figure 1. Study Schema 
 
 
 
 


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Table 3. Schedule of Procedures 
Assessment 
Screening Perioda 
Lixivaptan  
Re-titration Periodb 
Maintenance Treatment Period 
Follow-up 
Periodc 
 
(4 weeks + 3 days) 
 
Telehealth 
Visite 
Clinic or 
Remote 
Visitf 
Laboratory Only 
Visitsd 
(every 4 weeks ± 5 
days) 
Study Visits  
(every 12 weeks 
± 5 days) 
EoT/ ET 
Visit  
(Week 104 
± 5 Days) 
Laboratory 
Only 
Visitsd 
Study 
Visits 
(1 to 2 weeks ± 3 
days) 
(104 weeks ± 3 days) 
(Up to 4 weeks ± 3 
days) 
Study Week 
(Week -6 to Week -2) 
(Week -1 to Week 0) 
Weeks 4, 8, 16, 20, 
28, 32, 40, 44, 52, 56, 
64, 68, 76, 80, 88, 92, 
100 
Weeks 12f, 24, 
36f, 48, 60f, 72, 
84f, 96f  
Week 104 
Day 8 
+ 3 
days 
after 
last 
dose 
Day 
12 to 
24 
days 
after 
last 
dose 
Day 28 
± 3 
days 
after 
last 
dose 
PA-ADPKD-303  
Study 
Visit Number 
V24 V25 
V26 
V27/  
[V1]a 
(V2e) 
V3/ Lastf 
V4, V5, V7, V8, V10, 
V11, V13, V14, V16, 
V17, V19, V20, V22, 
V23, V25, V26, V28 
V6f, V9, V12f, 
V15, V18f, V21, 
V24f, V27f 
V29/ET 
V30 
V31 
V32 
Informed consent 
 
 
 
[X] 
 
 
 
 
 
 
 
 
Review eligibility 
(Inclusion/Exclusion) 
 
 
 
[X] 
 
 
 
 
 
 
 
 
Vital signsg 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Body weighth 
X 
 
 
 
 
X 
 
V15 
X 
 
 
X 
Physical examinationi 
X 
 
 
X 
 
 
 
V9, V15,  
V21  
X 
 
 
X 
ECG 
X 
 
 
X 
 
 
 
V9, V15,  
V21 
X 
 
 
X 
Pregnancy test (WOCBP only)j 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
X 
 
 
 
V15 
X 
 
 
X 
Hematology 
X 
 
 
X 
 
X 
 
V9, V15, V21 
X 
 
 
 
Chemistry Blood Samplek 
X 
 
 
X 
 
 
 
 
 
 
 
 
Complete Chemistry Panel 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Liver Chemistry Panel 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
X 


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Assessment 
Screening Perioda 
Lixivaptan  
Re-titration Periodb 
Maintenance Treatment Period 
Follow-up 
Periodc 
 
(4 weeks + 3 days) 
 
Telehealth 
Visite 
Clinic or 
Remote 
Visitf 
Laboratory Only 
Visitsd 
(every 4 weeks ± 5 
days) 
Study Visits  
(every 12 weeks 
± 5 days) 
EoT/ ET 
Visit  
(Week 104 
± 5 Days) 
Laboratory 
Only 
Visitsd 
Study 
Visits 
(1 to 2 weeks ± 3 
days) 
(104 weeks ± 3 days) 
(Up to 4 weeks ± 3 
days) 
Study Week 
(Week -6 to Week -2) 
(Week -1 to Week 0) 
Weeks 4, 8, 16, 20, 
28, 32, 40, 44, 52, 56, 
64, 68, 76, 80, 88, 92, 
100 
Weeks 12f, 24, 
36f, 48, 60f, 72, 
84f, 96f  
Week 104 
Day 8 
+ 3 
days 
after 
last 
dose 
Day 
12 to 
24 
days 
after 
last 
dose 
Day 28 
± 3 
days 
after 
last 
dose 
PA-ADPKD-303  
Study 
Visit Number 
V24 V25 
V26 
V27/  
[V1]a 
(V2e) 
V3/ Lastf 
V4, V5, V7, V8, V10, 
V11, V13, V14, V16, 
V17, V19, V20, V22, 
V23, V25, V26, V28 
V6f, V9, V12f, 
V15, V18f, V21, 
V24f, V27f 
V29/ET 
V30 
V31 
V32 
Serum Creatinine 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Lixivaptan dispensation 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Lixivaptan compliance and 
reconciliation 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
IRT entry 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Adverse events 
<---------------------> <---------------------------------------------------------------------------------------------------------------------------------------> 
Assess for liver dysfunction 
<---------------------> 
 
<------------------------------------------------------------------------------------------------------------------------> 
Prior and concomitant 
medications 
<---------------------> <--------------------------------------------------------------------------------------------------------------------------------------> 
ECG = electrocardiogram; EoT = End of treatment; ET = Early termination visit; IRT = interactive response technology system; Last = Last re-titration visit; V = Visit; 
WOCBP = women of childbearing potential  
   Shaded assessments (Visit 24, Visit 25, Visit 26) denote PA-ADPKD-303 assessments that will not be included as part of screening and/or baseline values for study 
PA-ADPKD-304 ;[ ] = denotes assessment not part of PA-ADPKD-303 Follow-up Period V27; ( ) = Not all participants will need these visits. 
a Results from assessments completed during the final 4 visits (Visits 24, 25, 26, and 27) of the lead-in study, PA-ADPKD-303 will serve as the Screening/baseline 
values for this study.  Clinical laboratory assessments completed at Visit 24 of the lead-in study will be used for assessment of eligibility criteria at Visit 1 of this 
study with the exception of eGFR, which will be determined from the Visit 26 results. Results for other safety assessments including vital signs, pregnancy testing, 
physical examination and ECG needed for evaluation of eligibility for study PA-ADPKD-304 will be those assessed at Visit 27. 
b Participants who meet all eligibility criteria for enrollment at Visit 1 will be assigned lixivaptan at a dose of 100 mg BID for 1 week to start the re-titration period. At 
Visit 2, the dose of lixivaptan will be increased from 100 mg BID to the final dose taken at the end of the PA-ADPKD-303 Maintenance Period for those participants 


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whose final dose at the end of the lead-in study was greater than 100 mg BID.  Participants will continue on the escalated dose for one week before entering the 
Maintenance Treatment Period.  Participants whose final dose in the lead-in study was 100 mg BID (or lower in exceptional cases), will skip Visit 2 and proceed 
directly to Visit 3/Last Titration Visit and undergo the assessments scheduled for that visit. Dosing will continue for the remainder of the study at this level.  However, 
if there is difficulty with tolerability, the dose may be temporarily reduced.  Dosing reductions for participants on Level 2 (100 mg BID) per Table 2 require prior 
approval from the medical monitor.   
c   During the Follow-up Period, 3 visits will occur to obtain the 3 serum creatinine values for calculation of eGFR.  The first visit (V30) will occur on the 8th day 
(+3 days) after the last dose of lixivaptan treatment and the last visit (V32) will occur on the 28th day (±3 days) after the last dose of lixivaptan treatment.  V31 must 
be scheduled a minimum of 24 hours apart from either V30 or V32 and should occur 12 to 24 days after the last dose of lixivaptan.  At the final visit (V32), additional 
safety and efficacy assessments will be completed as denoted in Table 3. 
d Visits designated as “Laboratory Only” may be completed at the clinic or remotely by a home healthcare clinician or by a designated third-party that will draw and 
process samples for shipment to the central laboratory where available and approved.   
e Visit 2 is a telehealth visit (e.g., telemedicine virtual visit, telephone, or video call (without recording)) with site staff. Visit 2 is only applicable to participants whose 
final dose in the lead-in study was greater than 100 mg BID.  At telehealth Visit 2, lixivaptan treatment compliance will be monitored and lixivaptan reconciliation 
will occur at Visit 3. 
f Study Visits are more extensive than laboratory only or telehealth visits. Study Visits designated as “Clinic or Remote Visits” can be performed either on-site or 
remotely by a Home Health Clinician (HHC).  Visits 3, 6, 12, 18, 24 and 27 are designated as “Clinic or Remote Visits”. All other Study Visits are Clinic Visits. 
g Vital signs after the participant has been sitting for 5 minutes include sitting heart rate and sitting blood pressure. 
h Weight will be measured at Visit 24 (PA-ADPKD-303), Visit 3, Visit 15, Visit 29/ET, and Visit 32.  Weight may be measured at any other visit to assess hydration 
status as necessary. 
i A brief physical examination will be performed at Visit 1 (Visit 27 of lead-in study), Visit 9, Visit 15, Visit 21, and Visit 32.  A full physical examination will be 
completed at Visit 29/ET. Additional physical examinations will be performed only for assessment of signs or symptoms reported by the participant that might require 
further evaluation.   
j Routine pregnancy testing for WOCBP will be performed locally on urine. All positive urine results will be confirmed by a serum pregnancy test at the central lab. 
k Chemistry blood samples will be collected according to the schedule in Table 3: 
• 
A complete chemistry panel includes the following parameters: albumin; blood urea nitrogen (urea); calcium; chloride; carbon dioxide (CO2); creatinine, 
enzymatic; glucose; phosphorous; potassium; protein; sodium; uric acid.  
• 
The liver chemistry panel includes alkaline phosphatase; ALT; AST; bilirubin (total and direct). 
• 
All serum creatinine determinations will be performed by the central laboratory.   
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice per day 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRO 
Contract Research Organization 
CS 
clinically significant 
DILI 
drug induced liver injury 
DILIN 
Drug Induced Liver Injury Network 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HERC 
Hepatic Events Review Committee 
HHC 
home healthcare clinician 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
OTC 
over-the-counter 
PBPK 
physiologically based pharmacokinetic 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
Women of childbearing potential 
 


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1 INTRODUCTION 
1.1 Background 
Lixivaptan (also known as VPA-985, BIIB030, and CL 347,985) is a potent, non-peptide 
selective antagonist for the vasopressin V2 receptor, which is expressed primarily in the 
collecting duct of the nephron (Chan et al, 1998).  Lixivaptan antagonizes the effects of 
vasopressin that are mediated by the V2 receptor, resulting in the pharmacologic effect of 
increased free water excretion, thus decreasing urine osmolality, increasing urine flow, and 
increasing serum osmolality as well as restoring normal levels of intracellular cyclic 
adenosine 3’,5’-monophosphate (Chebib et al, 2015).   
The sponsor (Palladio Biosciences, Inc.) is currently developing lixivaptan for the treatment 
of autosomal dominant polycystic kidney disease (ADPKD).  Lixivaptan had previously been 
under development for the treatment of symptomatic hypervolemic and euvolemic 
hyponatremia associated with heart failure and syndrome of inappropriate anti-diuretic 
hormone secretion.   
Additional background information for lixivaptan including an overview of ADPKD and 
available therapies, the rationale for lixivaptan therapy in ADPKD, summary of non-clinical 
studies, and summary of clinical studies can be found in the Investigator’s Brochure (IB). 
1.2 Study Rationale 
This is a Phase 3, open-label, roll-over study of the Phase 3 PA-ADPKD-303 trial. It is 
designed to assess long-term safety of lixivaptan in eligible participants with autosomal 
dominant polycystic kidney disease (ADPKD) who completed study PA-ADPKD-303: The 
ALERT STUDY. 
ADPKD is the most frequent, inherited cause of end-stage renal failure. Animal models have 
shown that vasopressin activity is necessary for the disease to manifest and progress.  Studies 
of the vasopressin V2 receptor antagonist tolvaptan have shown that it can slow the 
progression of renal function deterioration in patients with ADKD.  However, serious drug 
induced liver injury (DILI) occurs in a certain percentage of patients treated with tolvaptan 
requiring diligent testing of liver chemistry in all participants and discontinuation of the drug 
when the test results are elevated in order to prevent serious outcomes.  The vasopressin V2 
receptor antagonist, lixivaptan, has also been shown to ameliorate polycystic disease 
manifestations in animal models of disease.  Evidence from Quantitative Systems Toxicology 
modeling and initial clinical results suggest that lixivaptan does not have the same potential 
for liver injury.  Thus, lixivaptan may represent a safer alternative to tolvaptan with similar 
efficacy.  This Phase 3, roll-over study will enroll completers of study PA-ADPKD-303, an 
open-label study of lixivaptan in patients who experienced abnormal liver chemistry test 
results on tolvaptan resulting in permanent discontinuation of tolvaptan and is designed to 
provide those participants with continued access to lixivaptan as well as allow for the 
assessment of long-term safety in addition to efficacy of lixivaptan in this population. 
Lixivaptan as a safer alternative to tolvaptan  
Tolvaptan, a vasopressin V2 receptor antagonist, has been approved in many territories, to 
slow the progression of renal function deterioration in patients with autosomal dominant 


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polycystic kidney disease (ADPKD).  However, DILI occurs in a certain percentage of 
patients taking tolvaptan.  Acute liver failure requiring liver transplantation has also been 
reported (Endo et al, 2019).   Patients who are on tolvaptan require frequent testing of liver 
chemistry and discontinuation of the drug when the test results are elevated in order to 
prevent serious outcomes.   
DILI modeling has allowed for the assessment of potential abnormal liver chemistry tests 
prior to conducting large clinical trials (Woodhead et al, 2017a).  This is a Quantitative 
Systems Pharmacology model of drug-induced liver injury (DILIsymTM).  DILIsym 
integrates physiologically based pharmacokinetic (PBPK) and in vitro toxicity data of parent 
compound and its active metabolites.  Specific in vitro data incorporated into the model 
includes drug induced bile acid transporter inhibition, mitochondrial dysfunction, and 
oxidative stress which has been identified as putative mechanisms for DILI. 
DILIsym was employed to model tolvaptan-mediated liver injury (Woodhead et al, 2017b).  
DILIsym was able to successfully recapitulate the observed toxicity.  The frequency of 
predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split 
daily dosing, was 7.9% compared with clinical observations of 4.4-5.6% in ADPKD trials.  
The simulations also demonstrated that the in vivo hepatic exposure to tolvaptan and its 
metabolite, DM-4103, combined with alterations in bile acid disposition and inhibition of 
mitochondrial respiration were sufficient to account for the initiation of tolvaptan-mediated 
liver toxicity.  
This same platform was used to evaluate the potential of lixivaptan to cause liver toxicity 
(Woodhead et al, 2020).  In vitro data relating to reactive oxygen species formation, 
mitochondrial toxicity, and bile acid transporter inhibition for lixivaptan and its major 
metabolites (WAY-138451, WAY-141624, and WAY-138758) were collected in parallel with 
tolvaptan as a positive control.  Using these data, lixivaptan and its metabolites were 
represented in DILIsym.  Proposed ADPKD treatment dosing regimens were simulated and 
the predicted potential for liver enzyme elevations was compared to that previously 
determined for tolvaptan in DILIsym.  Results showed that lixivaptan was not predicted to 
cause liver enzyme elevations in a simulated human population which included variability in 
toxicity susceptibility and pharmacokinetics, while tolvaptan was correctly predicted to cause 
rare liver enzyme elevations in a similar population (Table 4).  Additional information 
regarding the DILIsym evaluation of lixivaptan can be found in the IB.   
Table 4. DILIsym simulations of lixivaptan and tolvaptan 
Drug 
Dose, Duration 
Clinical 
ALT >3 × ULN 
Simulated 
ALT >3 × ULN, n/N 
Lixivaptan 
200/100 mg  
q AM/PM, 12 weeks 
Study not yet 
conducted 
0/285 
Tolvaptan 
90/30 mg 
q AM/PM, 24 weeks 
4.4% 
18/229 
7.86% 
Therefore, compared to tolvaptan, in silico modeling and simulation have demonstrated that 
lixivaptan does not have the same potential for liver injury.   


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A safety assessment of the potential for lixivaptan to be associated with clinical 
hepatotoxicity in the hyponatremia program was included in the Cardiokine NDA.  In the 
healthy volunteer studies, analysis of adverse events and liver-related laboratory tests showed 
no evidence of liver toxicity with lixivaptan.  In the Phase 2 and Phase 3 trials in participants 
with hyponatremia, a population prone to liver chemistry abnormalities, there were small 
mean decreases in ALT, AST, and total bilirubin in the lixivaptan treated participants. 
Furthermore, there were no instances of hepatotoxicity meeting the definition of Hy’s Law 
among participants treated with lixivaptan.  The percentage of participants who had 
concomitant elevations of ALT >3 × upper limit of normal (ULN) and total bilirubin >2 × 
ULN was low and numerically lower in the lixivaptan group compared to the placebo group, 
further suggesting no lixivaptan-related liver toxicity.  Analysis of the Phase 2 ADPKD study 
also did not show any hepatic AEs.  
Recently, Palladio has had the opportunity to test the hypothesis of lixivaptan’s superior liver 
safety in a clinical setting.  An ADPKD patient who experienced disabling kidney pain was 
treated with tolvaptan in 2017 with marked clinical improvement. However, tolvaptan-
associated liver toxicity manifest as ALT elevation required interruption of tolvaptan 
treatment. Two subsequent attempts to re-introduce the drug resulted in rapid recurrence of 
the ALT abnormalities (Figure 2) and the drug was stopped permanently in December 2017.  
The treating physician reached out to Palladio for access to lixivaptan for treatment of the 
recurrent disabling pain. Treatment with lixivaptan in this participant was started in 2019 
under an expanded access protocol.  Pain reduction and improvement in measured quality of 
life occurred as the dose of lixivaptan was up-titrated.  At the time of this writing, there has 
been no evidence of increased ALT values in this participant after 14 months of therapy with 
lixivaptan (Figure 3). 
Figure 2. Time Course of ALT Levels in Relationship to Dosing of Tolvaptan in a 
Patient with Painful ADPKD 
 
 
 
 


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Figure 3. Time Course of ALT Levels in Relationship to Dosing of Lixivaptan in a 
Patient with Painful ADPKD 
 
These results strongly suggest that lixivaptan may represent a safer alternative to tolvaptan 
not only for the general patient population, but also for those participants who experienced 
abnormal liver chemistry test results while receiving tolvaptan.  The intent of the PA-
ADPKD-303 study is to replicate the experience of hepatic safety with lixivaptan in a larger 
number of ADPKD patients previously treated with tolvaptan who discontinued the drug 
permanently because of abnormal liver chemistry test results. This roll-over study (PA-
ADPKD-304) will thus provide additional hepatic safety information over a longer treatment 
experience. 
1.3 Dose Rationale 
The human equivalent exposure range of lixivaptan to be employed for this study has been 
shown to be safe and tolerated in nonclinical animal studies and previous clinical studies 
conducted in healthy participants, in participants with hyponatremia of various etiologies, 
and in the PA-102 study of patients with ADPKD.   
The dose range to be employed for this roll-over study is the same as in the lead-in study PA-
ADPKD-303, i.e., 100 mg BID up to 200 mg BID. However, eligible participants completing 
study PA-ADPKD-303 study will be re-titrated to their final dose from study PA-ADPKD-
303 over a 1-to-2-week Re-titration Period in accordance with Table 1.   
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objectives 
• To assess the hepatic safety of lixivaptan with continued dosing. 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
• To characterize the non-hepatic safety and tolerability of lixivaptan 
• To assess renal function (efficacy) in participants while on lixivaptan using change in 
estimated glomerular filtration rate (eGFR). 
2.2 Study Endpoints 
2.2.1 Primary Endpoint 
Safety: 
• Proportion of participants with serum ALT levels >3 × ULN during Lixivaptan Re-
titration or Maintenance Treatment Periods that were assessed by the independent 
Hepatic Events Review Committee (HERC) to be at least probably related to 
lixivaptan and resulted in discontinuation of lixivaptan treatment. 
2.2.2 Secondary Endpoints 
Safety: 
• Proportion of participants with serum ALT levels >5 × ULN during the Lixivaptan 
Re-titration or Maintenance Treatment Periods that were assessed by the independent 
HERC to be at least probably related to lixivaptan and resulted in discontinuation of 
lixivaptan treatment. 
• Proportion of participants with serum ALT levels >3 × ULN during the Lixivaptan 
Re-titration or Maintenance Treatment Periods that were assessed by the independent 
HERC to be at least probably related to lixivaptan and resulted in dose reduction of 
lixivaptan treatment. 
• Safety and tolerability of lixivaptan assessed through evaluation of AEs, clinical 
laboratory findings (clinical chemistry including additional analyses of liver 
chemistry tests, hematology, and urinalysis), vital signs and 12-lead 
electrocardiograms (ECGs). 
Efficacy: 
• Change in annualized eGFR from baseline (mean of 3 eGFR determinations obtained 
at Visits 25, 26 and 27 of study PA-ADPKD-303) to final assessment (mean of 3 
eGFR determinations obtained during the Follow-up Period). 


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3 INVESTIGATIONAL PLAN 
3.1 Study Design 
3.1.1 Overview of Study Design 
This is a Phase 3, open-label roll-over study to demonstrate the continued hepatic and non-
hepatic safety and renal efficacy of lixivaptan in patients with ADPKD who previously 
experienced abnormal liver chemistry test results while treated with tolvaptan that resulted in 
permanent discontinuation of tolvaptan for that reason and subsequently completed study PA-
ADPKD-303, the open-label lead in study with lixivaptan. Up to 50 participants can be 
enrolled and treated with lixivaptan in study PA-ADPKD-303. All participants completing 
the lead-in study and meeting eligibility criteria for this roll-over study will be able to enroll. 
It is estimated that approximately up to 40 participants will enroll in this study, assuming 
90% of participants complete study PA-ADPKD-303 and 90% meet eligibility and elect to 
enroll. 
There will be a Screening, Re-titration, Maintenance, and Follow-up Period. The Screening 
Period will be 4 weeks in duration. Assessments completed during the final 4 visits (Visits 
24, 25, 26, and 27) of study PA-ADPKD-303 will serve as the screening and baseline 
assessments for this roll-over study. Visit 27 of the lead-in study will be used as Visit 1 of this 
roll-over study. Safety assessments performed during Visits 24, 25, 26 and 27 of the lead-in 
study will also be used for assessment of eligibility and will constitute the baseline values for 
this study. The mean of the eGFR values obtained at Visits 25, 26, and 27 of the lead-in study 
will be used to determine the baseline eGFR value for this study. Evaluation of eligibility will 
be completed at Visit 1 of this study, following signing of the informed consent form (ICF). 
Participants satisfying all study entry criteria at Visit 1 will be considered enrolled following 
completion of all Visit 1 study procedures and will be dispensed lixivaptan treatment in 
accordance with Table 1 to start the Lixivaptan Re-titration Period. 
The Re-titration Period will be 1 to 2 weeks. However, Investigators have the flexibility to 
increase the 2-week period if re-titration needs to go slower or a dose reduction is needed for 
tolerability or safety reasons.  During the 1-to-2-week Lixivaptan Re-titration Period, 
participants whose final dose during the Maintenance Period of the lead-in study was 100 mg 
BID will remain on that dose for one week, complete Visit 3 assessments, and then proceed 
to the Maintenance Treatment Period of the current study with no further up-titration. (Note: 
Eligible participants who completed the lead-in study on 50 mg BID may continue on that 
dose in this study. Those participants will undergo a one-week re-titration, complete Visit 3 
assessments and then proceed to the PA-ADPKD-304 Maintenance Treatment Period). 
Participants on doses greater than 100 mg BID at the end of the Maintenance Period of study 
PA-ADPKD-303 will be directly titrated to their final dose of the lead-in study during the 
second week of the Re-titration Period. Following re-titration, participants will enter the 
Maintenance Treatment Period. Lixivaptan treatment titration and assignment will be 
programmed into the Interactive Response Technology (IRT) system. 
Participants will then continue on lixivaptan treatment for up to 104 weeks during the 
Maintenance Treatment Period and will be assessed at a study visit every 12 weeks where 


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study procedures will include clinical laboratory determinations, including liver chemistry 
tests. In between quarterly study visits, participants will be required to have blood drawn for 
liver chemistry determinations every 4 weeks. Where available and approved, visits 
designated as “laboratory only” may be conducted remotely by a home healthcare clinician 
(HHC) or by a designated third-party that will process samples for shipment to the central 
laboratory. Liver chemistry tests may also be drawn at the clinic if that is convenient. 
At the end of 104 weeks, lixivaptan treatment will be stopped, and participants will enter the 
Follow-up Period during which final assessments of safety and efficacy will be obtained over 
3 visits starting on the 8th day following the last dose of lixivaptan treatment and continuing 
through the 28th day. 
All assessments and the relative timings are listed in the Schedule of Study Procedures (Table 
3).  Study procedures by visit are outlined in Section 6.  A comprehensive description of 
study procedures can be found in Section 7.  Dosing procedures are outlined in Section 5.   
Note that the study or a participant’s involvement in the study may be interrupted at any time 
if safety issues compromise the safety of the participants.  
The study schematic is depicted in Figure 1. 
 
 
3.1.2 Detailed Study Design 
Screening Period:  
The Screening Period will be 4 weeks in duration.  Screening information for assessing 
eligibility for enrollment will be obtained during the final 4 visits (Visits 24, 25, 26 and 27) 
of the lead-in study, PA-ADPK-303.  Evaluation of eligibility will be initiated following 
signing of the ICF for this study at Visit 27 of the lead-in study PA-ADPKD-303 which will 
be Visit 1 of this roll-over study (PA-ADPKD-304).  The mean of the eGFR values obtained 
at Visits 25, 26 and 27 of study PA-ADPKD-303 will be used to determine the baseline eGFR 
value for this study.  Participants satisfying all study entry criteria at Visit 1 will be 
considered enrolled following completion of all Visit 1 study procedures and will be 
dispensed lixivaptan treatment in accordance with Table 1 to start the Lixivaptan Re-titration 
Period.  
Lixivaptan Re-titration Period: 
Re-titration of lixivaptan in enrolled participants will occur over a 1-to-2-week period.  The 
first week of dosing follows the completion of Visit 1.  Participants whose final dose was 100 
mg BID at the end of the PA-ADPKD-303 study Maintenance Period will be titrated over one 
week and then proceed to Visit 3.  NOTE: Eligible participants whose final dose was 50 mg 
BID at the end of study PA-ADPKD-303 can continue on that dose in this study, and will 
also be re-titrated over one week, and then proceed to Visit 3. Following one week of dosing, 
participants whose final dose at the end of study PA-ADPKD-303 was greater than 100 mg 
BID, will have their dose of lixivaptan increased from 100 mg BID to the final dose taken at 


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the end of the Maintenance Period during the second week of the Re-titration Period (see 
Table 1).  
NOTE: Investigators have the option to re-titrate more slowly and/or reduce the dose in the 
event of emerging tolerability or safety issues. In this instance, the Re-titration Period would 
be increased as needed. 
Maintenance Treatment Period: 
Following completion of the Lixivaptan Re-titration Period, participants will continue into 
the open-label Maintenance Treatment Period following completion of Visit 3 assessments 
for up to 104 weeks. Participants will be assessed at study visits scheduled every 12 weeks 
with assessments but will have required liver chemistry testing every 4 weeks at visits 
designated as “laboratory-only visits”. Where available and approved, the laboratory-only 
visits may be conducted remotely by an HHC or by a designated third-party that will process 
samples for shipment to the central laboratory. In addition, the liver chemistry tests may be 
drawn in the clinic if that is more convenient.  Furthermore, certain study visits can be 
performed by an HHC. 
Follow-up Period: 
Three visits will occur over 4 weeks following the last dose of lixivaptan treatment in order 
to obtain final assessments. Starting with the 8th day after the last dose of lixivaptan 
treatment, serum creatinine will be assessed at 3 time points (no less than 24 hours apart 
between each sampling) over a period of up to 28 days post last dose of lixivaptan. Certain 
follow-up visits are designated as laboratory-only visits.  NOTE: If a participant terminates 
the study early (ET), an eGFR determination from serum creatinine obtained at 3 time points 
over a period of up to 28 days post last dose, will be carried out. 
NOTE: The total duration of participation in this roll-over study from the signing of the ICF 
at Visit 1 will be approximately 109 to110 weeks. 
3.2 Rationale for Study Design 
Evidence suggests that lixivaptan may be a safer alternative to tolvaptan with similar efficacy 
in the treatment of patients with ADPKD. This roll-over study of PA-ADPKD-303 is 
designed to provide timely, additional supporting evidence of the overall safety, specifically 
hepatic safety and renal function, of lixivaptan dosing over a 2-year period in these 
participants. 


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4 PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
4.1 Selection of Study Population 
Participants completing study PA-ADPKD-303 will be invited to enroll in this study.  In this 
study, up to approximately 40 participants will be enrolled and treated at approximately 25 
sites in the US.  All participants completing the lead-in study and meeting all the inclusion 
criteria and none of the exclusion criteria for this study will be eligible to enroll.  With the 
approval of the medical monitor and Investigator, participants who fail inclusion/exclusion 
criteria due to temporary or correctable reasons may be re-screened up to 2 times after re-
consenting each time. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
participant safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential. 
4.1.1 Inclusion Criteria 
For entry into the study at Visit 1, each participant must meet the following inclusion criteria: 
1. Male or female participants with ADPKD who completed study PA-ADPKD-303 
2. Female participants must: 
a. not be pregnant, lactating, or breastfeeding   
b. be either postmenopausal (defined as amenorrhea for ≥12 months), surgically 
sterile (defined as having undergone hysterectomy and/or bilateral 
oophorectomy), or if of child-bearing potential (WOCBP) must agree to 
continue to practice appropriate methods of birth control or remain abstinent 
(only if this is the usual and preferred lifestyle of the participant) during the 
full duration of the study and for 30 days after the last dose of lixivaptan 
treatment.  Acceptable forms of contraception include the following: 
• hormonal contraceptives (i.e., oral, intravaginal, transdermal, 
injectable, implantable) 
• intrauterine device (IUD), including progestin-containing intrauterine 
devices 
• intrauterine hormone-releasing system (IUS) 
• male sexual partner who has been vasectomized for at least 3 months 
prior to Screening and who has obtained a follow-up negative sperm 
count and is the sole sexual partner 
• bilateral tubal ligation 
• Essure® procedure (tubal occlusion) 
• male or female condom with spermicide (cream, spray, gel, 
suppository, or polymer film) 
• diaphragm, cervical cap, or contraceptive sponge with spermicide 


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(with or without a male condom) 
3. Male participants must agree to continue to use an acceptable form of birth control 
(see list above) or remain abstinent (only if this is the usual and preferred lifestyle of 
the participant) during the full duration of the trial and for 30 days after the last dose 
of lixivaptan treatment. 
4. Continued control of hypertension without the use of a diuretic in concert with 
KDIGO “Clinical Practice Guideline for the Management of Blood Pressure in 
Chronic Kidney Disease” 
5. Continued adherence to prohibitions on concomitant medications stated in the study 
PA-ADPKD-303 protocol, and in Section 5.7.1.2 of this protocol, including use of 
strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers 
6. Read, understood, and provided written informed consent after the nature of the study 
has been fully explained and must be willing to comply with all study requirements 
and procedures. 
4.1.2 Exclusion Criteria 
Participants meeting any of the following exclusion criteria at Visit 1 are not eligible for 
study enrollment: 
1. Any contraindication to continued treatment with lixivaptan   
2. Clinically significant (CS) incontinence, overactive bladder, or urinary retention 
(e.g., benign prostatic hyperplasia) 
3. New York Heart Association Functional Class 3 or 4 heart failure or other 
significant cardiac or electrocardiogram (ECG) findings that could pose a safety 
risk to the participant 
4. Hypovolemia on physical examination at Screening 
5. The following laboratory results based on serum drawn at Visit 24 of PA-
ADPKD-303: 
a. Serum alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) values >1.5 × upper limit of normal (ULN)  
b. Total bilirubin values >1.5 × ULN 
6. eGFR <20 ml/min/1.73 m2 based on laboratory results from Visit 26 of PA-
ADPKD-303  
7. A finding at Screening that precludes safe participation in the study or participants 
who are likely to be non-compliant with study procedures in the opinion of the 
Investigator or medical monitor. 
4.2 Completion and Withdrawal of Participants from the Study 
4.2.1 Definition of Completed Participants 
A completed treatment participant is one who has completed the procedures beginning with 
Screening through the last Maintenance Treatment Period visit (Visit 29). A completed study 
participant is one who has completed the procedures beginning with Screening through the 


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last Follow-Up Period visit (Visit 32).  The end of the study is defined as the last participant’s 
last visit. 
4.2.2 Screening Failures  
Participants may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the Investigator or at the study site.   
During the Screening Period, participants who withdraw their consent or fail to meet all the 
entry criteria to participate in the study will be designated as “Screen failures”.  Screen 
failure participants will be recorded as such on the electronic Case Report Form (eCRF) and 
do not need to complete an ET Visit or enter the Follow-up Period unless a serious adverse 
event (SAE) is ongoing, in which case they will be scheduled for Visit 32 in 4 weeks.  Screen 
failure participants who do not meet study entry requirements due to temporary or 
correctable reasons may be re-screened up to 2 times with the approval of the medical 
monitor and sponsor. 
4.2.3 Participant Withdrawal Criteria 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
administrative reasons.  
Participants who discontinue or are discontinued after the Screening Period will be 
considered as a withdrawal, regardless of whether they have received lixivaptan treatment.   
All premature discontinuations and their causes must be carefully documented in the eCRF, 
and in the AE form (if applicable).  
Participants not completing the entire study on lixivaptan treatment should be encouraged to 
continue with the visit schedule, a modified visit schedule, or telephone follow-up as agreed 
between the participant and the Investigator.  At a minimum, participants should be 
encouraged to complete the ET Visit (Visit 29) in the clinic within 7 days of lixivaptan 
treatment discontinuation and the Follow-up Visits (Visits 30 to 32) over the 4 weeks after 
the last dose of lixivaptan treatment.  Participants with ongoing SAEs or AEs believed to be 
at least possibly related to study medication will continue to be followed until resolution or 
for 28 days as warranted by the nature of the AE.  If the AE is related to abnormal liver 
chemistry test results, see Section 7.2.7 for additional follow-up requirements.  
4.2.4 Reasons for Withdrawal 
Reasons for withdrawal (participants who refuse to return for any remaining study visits) or 
discontinuation (participants who prematurely stop the treatment) at any time during the 
study may include, but are not limited, to the following: 
1. No longer meet the protocol inclusion or exclusion criteria, e.g., require a prohibited 
concomitant medication. 
2. Noncompliance with the protocol. 
3. Lack of efficacy. 


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4. A serious or intolerable AE that, in the Investigator’s opinion, requires withdrawal 
from the study, including but not limited to laboratory safety assessments that reveal 
CS hematological or biochemical changes from the baseline values, other than 
changes that are expected for vasopressin antagonists, and symptoms of an 
intercurrent illness that justifies withdrawal.  If the AE is related to abnormal liver 
chemistry test results, see Section 7.2.7 for additional follow-up requirements.  Mild 
elevations in serum creatinine or serum sodium are known pharmacodynamic effects 
of vasopressin antagonists like lixivaptan and are transient and reversible.  Therefore, 
participants should not be withdrawn from study participation solely due to mildly 
elevated serum creatinine or serum sodium.  Cases where eGFR has declined by 25% 
or more from baseline should be discussed with the medical monitor and sponsor. 
5. Death. 
6. Lost to follow-up. 
7. Other (e.g., pregnancy, study burden, development of contraindication to use of 
lixivaptan treatment). 
8. Withdrawal of consent (partial or complete). 
9. Investigator’s or sponsor’s decision to discontinue the participant from the study. 
10. Sponsor termination of the study. 
Upon occurrence of an SAE or intolerable AE, the Investigator will confer with the medical 
monitor and sponsor.  If a participant is discontinued from lixivaptan treatment because of an 
AE, the event will be followed until it is resolved or stable or up to 28 days as determined by 
the Investigator.  Any participant may withdraw his or her consent at any time.  Participants’ 
safety will be closely monitored throughout the study, and the study will be conducted 
following Good Clinical Practices (GCP).  The entire study may be stopped at any time at the 
discretion of the sponsor. 
4.2.5 Methods to Prevent Loss to Follow-up 
The Investigator must make every attempt to follow-up participants who have withdrawn 
from the study at any time and for any reason.  When a participant is “lost to follow-up” (i.e., 
fails to return for study visits or complete one or more scheduled remote visits), a reasonable 
effort (3 documented phone calls or 2 phone calls and 2 text messages [if the participant has a 
mobile phone], on separate occasions, and a follow-up letter sent by registered mail) should 
be made to contact him/her to determine a reason for the failure to return or complete remote 
visit(s).  If the participant cannot be reached, he/she should be identified as “lost to follow-
up” in the eCRF. 
4.2.6 Replacements 
Participants who withdraw from the study will not be replaced. 


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4.2.7 Withdrawals Due to Abnormal Liver Chemistry Test Results 
Guidance for management of abnormal liver chemistry test results is provided in 
Section  7.2.7.  In some cases, it will be advisable to discontinue lixivaptan treatment and 
under other circumstances dose reduction might be appropriate.  These actions in response to 
abnormal liver chemistry test results must be discussed with the medical monitor and sponsor 
prior to taking any action (except in an emergency).  If lixivaptan treatment is withdrawn, re-
starting lixivaptan should generally be encouraged after discussion with the medical monitor 
and sponsor, when liver chemistry tests have normalized or stabilized, and in conjunction 
with a plan for increased frequency of liver chemistry test monitoring.  When re-starting 
lixivaptan treatment after an interruption, the need for re-establishment of dose should be 
discussed with the medical monitor.  In certain circumstances described in Section 7.2.7.2, 
restarting lixivaptan treatment should only occur when the HERC believes the relationship 
between the abnormal liver chemistry test results and the lixivaptan treatment is ≤50% 
according to the DILIN criteria, modified, Section 13.2  (Fontana et al, 2009). 
 


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5 LIXIVAPTAN TREATMENT AND CONCOMITANT MEDICATION 
5.1 Lixivaptan Treatment 
5.1.1 Identity of the Investigational Product 
The investigational product, lixivaptan capsule, is formulated as a white, banded, hard gelatin 
capsule containing 50 mg of lixivaptan, and the inactive ingredients listed in Table 5. 
Table 5.  Investigational Product 
 
Lixivaptan 
Strength 
50 mg 
Formulation 
Capsules, packaged 30 per bottle 
Inactive ingredients 
Polyethylene glycol 400, NF/EP; Polyethylene glycol 1000, 
NF/EP; Povidone (K-17), USP/EP; Polysorbate 80, NF/EP; 
Butylated hydroxytoluene NF/EP; Butylated hydroxyanisole 
NF/EP 
 
Manufacturer 
PMRS, Inc. 
202 Precision Road  
Horsham, PA 19044 
Packager 
PCI Pharma Services 
4545 Assembly Drive 
Rockford, IL 61109 
 
5.1.2 Route of Administration 
Lixivaptan (capsules) is intended to be taken orally, i.e., to be swallowed whole with water.  
Lixivaptan can be taken with or without food.  The capsule should NOT be opened.   
5.1.3 Lixivaptan Packaging, Labeling, and Storage 
Lixivaptan capsules will be packaged and labeled by PCI Pharma Services, Rockford, IL, 
USA according to all local legal requirements and will be labeled in accordance with 
applicable regulatory requirements. 
Lixivaptan should be stored at the study site in its original packaging in a secure, locked area 
under the responsibility of the Investigator or other authorized individual.  At the study site, 
lixivaptan should be stored in accordance with the specifications detailed in the study 
pharmacy manual.  Once lixivaptan is dispensed, the participant should be instructed to store 
it in its original packaging and in accordance with lixivaptan treatment labelling at all times 
until ready to take. For study visits conducted remotely (not applicable to laboratory only 
visits), study drug will be dispensed and shipped from the study site to the participant’s 
home, or to an alternate location pre-specified by the participant, via an experienced courier 
approved by the Sponsor.  Participants will be provided with written instructions to securely 


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store the study drug in its original packaging under the conditions described above and not to 
open the package until the HHC arrives. 
5.1.4 Accountability 
The Investigator will maintain accurate records of lixivaptan receipt and disposition.  In 
addition, accurate records will be kept regarding when and how much lixivaptan is dispensed 
and used by each participant in the study.  Reasons for departure from the expected 
dispensing regimen will also be recorded.  At the completion of the study, to satisfy 
regulatory requirements regarding lixivaptan accountability, all unused lixivaptan capsules 
will be reconciled and returned to the sponsor or designee or destroyed according to 
applicable regulations and site’s applicable Standard Operating Procedures. 
5.2 Dose Administered 
During all treatment periods, lixivaptan treatment will be administered BID, with the PM 
dose administered approximately 10 hours after the AM dose.   
Lixivaptan will be dispensed following the completion of Visit 1 to initiate the Lixivaptan 
Re-titration Period in accordance with Table 1. Participants will start the Lixivaptan Re-
titration Period at a dose of 100 mg BID, with the exception of those whose final dose in 
study PA-ADPKD-303 was 50 mg BID.  Those participants will initiate re-titration at 50 mg 
BID and continue on that dose in the current study.  Participants whose final dose in the lead-
in study was greater than 100 mg BID will be directly titrated to a dose equivalent to their 
final dose in PA-ADPKD-303 during week 2 of the Re-titration Period.  
The most common dosing scenarios are presented in Table 2.  With concurrence of the 
medical monitor, participants may be allowed to enter the Maintenance Treatment Period at a 
lower dose (50 mg BID) if tolerability is an issue after trying a higher dose during the Re-
titration Period. 
Throughout the study, participants will continue to adhere to the recommended fluid intake 
regimen outlined in Section 5.8. 
After completing the Re-titration Period (1 to 2 weeks), participants will enter the 
Maintenance Treatment Period and continue at the lixivaptan dose level achieved at the end 
of the Re-titration Period.  During the Maintenance Treatment Period, the dose may be 
adjusted downward at the Investigator’s discretion if needed to manage non-hepatic side 
effects and may also be increased back to the dose achieved at the end of the Re-titration 
Period.  The Investigator may temporarily interrupt lixivaptan treatment, if necessary, to 
manage acute intercurrent illness, tolerability issues, planned or unplanned surgical 
procedures or life situations, e.g., airplane travel, etc.  Participants who require a prolonged 
interruption due to illness, including COVID-19, or other reasons may be able to restart their 
lixivaptan treatment when medically stable and following discussion with the medical 
monitor and sponsor.  Re-titration is required in the event of a prolonged interruption (i.e., >4 
weeks).  Temporary or permanent lixivaptan treatment discontinuation for management of 
abnormal liver chemistry test results is described further in Section 7.2.7. 


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5.3 Method of Assigning Participants to Identification Numbers 
In the lead-in study (PA-ADPKD-303), each Investigator was assigned a unique 5-digit site 
number (XXXXX).  This site number was concatenated with a leading protocol number 
(303) and a following 3-digit participant number to assure that each participant was uniquely 
identified in the clinical database.  Thus, a participant number in PA-ADPKD-303 appeared 
as 303-XXXXX-YYY, i.e., the identification number for the first participant screened at the 
first site activated in the lead-in study was 303-10001-001. 
In this study (PA-ADPKD-304), each participant number will include the 5-digit Investigator 
site number and the 3-digit participant number assigned in the lead-in study, as well as the 
current protocol number (304).  Thus, a participant identification number in PA-ADPKD-304 
will appear as 304-XXXXX-YYY (i.e., if the first participant from site 10001 in PA-
ADPKD-303 enrolled in the current study, the identification number would be 304-10001-
001). 
5.4 Blinding 
This will be an open-label study. 
5.5 Randomization and Treatment Assignment 
This study will not be randomized.  
5.6 Treatment Compliance 
Dispensing of lixivaptan treatment will be done initially at Visit 1.  Subsequently, dispensing 
of lixivaptan treatment and reconciliation will occur at Visit 3 during the Re-titration Period 
and every 12 weeks, at clinic or direct-to-participants in advance of remote visits, during the 
Maintenance Treatment Period.  A final reconciliation will be done by the site once each 
participant completes lixivaptan treatment.  Participant compliance will be monitored by 
capsule counts as lixivaptan treatment is returned. 
The dates of all lixivaptan treatment dosing, including interruptions, missed doses or 
overdose, must be recorded in the eCRF.  If the participant is not ≥80% compliant with the 
prescribed lixivaptan treatment doses during the study, then the period of non-compliance 
should be noted as significant protocol deviation and the sponsor should be notified.  The 
participant should be re-educated regarding the correct lixivaptan treatment doses to be 
administered.  However, if the Investigator, medical monitor, and sponsor have agreed to a 
treatment interruption (Section 5.2), then this period of non-compliance will not be 
considered a protocol deviation.   
5.7 Prior and Concomitant Therapy 
Participants will be allowed to take their medications to treat chronic conditions unless 
excluded by this protocol, per Section 5.7.1.2 and provided that their chronic medication 
therapy meets the conditions outlined in Section 5.7.1.1, including remaining constant 
throughout the duration of the study (unless there is a documented medical reason to change 
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Any concomitant medication deemed necessary for the well-being of the participant during 
the study may be given at the discretion of the Investigator after consideration of the clinical 
situation.  The Investigator is responsible for ensuring that details regarding concomitant 
medication use are recorded in the eCRF.  For each concomitant medication administered the 
following details will be documented and recorded in the participant’s eCRF: name of 
medication, dose administered, dates and time of administration, and reason for medication 
use.  This will include all prescription drugs, herbal products, vitamins, minerals, and over-
the-counter (OTC) medications.  Any changes in concomitant medications will also be 
recorded in the participant’s eCRF. 
Upon entering the study, each participant will be instructed about the importance of not 
taking any medication (including herbal supplements and OTC medications) without 
consulting the Investigator. 
5.7.1.1 Permitted Therapy 
Allowed medications include those typically prescribed to treat ADPKD, chronic kidney 
disease, and their complications such as hypertension.  These include angiotensin II receptor 
blockers (e.g., valsartan, candesartan, telmisartan, irbesartan) and angiotensin-converting 
enzyme inhibitors (e.g., enalapril, lisinopril).  However, certain medications are prohibited, 
as detailed in Section 5.7.1.2.    
Acetaminophen, at doses ≤1 g per day, is permitted for use any time during the study in 
participants who usually take acetaminophen to control episodic pain.  Because of their effect 
on renal function, use of non-steroidal anti-inflammatory drugs should be minimized. 
Non-sedating antihistamines (other than loratadine) and decongestants are permitted on an 
as-needed basis.  Low-dose aspirin (up to 150 mg per day) is permitted.   
Chronic use of other concomitant medications that are required to treat a medical condition 
may be permitted unless otherwise prohibited (see Section 5.7.1.2).  Doses of such 
medications should remain as stable as possible allowing for minor adjustments per the 
standard of care to treat medical conditions.  The stability of certain drugs, such as insulin 
and warfarin, should be based on the standard of care rather than on a stable dose.   
As lixivaptan has the potential to inhibit the metabolism of CYP3A4 and CYP2C8 substrates, 
care should be exercised when administering lixivaptan in combination with these substrates 
(Section 5.7.1.2) due to the potential for drug-drug interactions.  Caution should be exercised 
when concomitantly administering simvastatin or amlodipine with lixivaptan.  In order to 
minimize the potential for AEs, the Investigator should consider potential dose adjustments 
or alternative therapeutic options that are not CYP3A4 or CYP2C8 substrates (e.g., 
rosuvastatin to replace simvastatin) or that have a high therapeutic index.  If participants are 
receiving simvastatin as background medication and it is not possible to replace simvastatin 
with rosuvastatin, the dose of simvastatin should be decreased to ≤10 mg daily.  If 
amlodipine is needed for clinical care, the dose should not exceed 5 mg daily. 
5.7.1.2 Prohibited Therapy 
The following medications are prohibited throughout the study: 
• 
bardoxolone; 


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• 
conivaptan;  
• 
demeclocycline;  
• 
diuretics; 
• 
HIF-PH inhibitors;  
• 
metformin (for ADPKD);  
• mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.);  
• 
nicotinamide (for ADPKD); 
• 
SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.);  
• 
somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.);  
• 
tolvaptan; 
• 
strong or moderate CYP3A4 or CYP2C8 inducers, including barbiturates, bosentan, 
carbamazepine, efavirenz, enzalutamide, etravirine, modafinil, mitotane, nevirapine, 
oxcarbazepine, phenytoin, pioglitazone, rifabutin, rifampin, and St. John’s wort; 
• 
strong or moderate CYP3A4 or CYP2C8 inhibitors, including aprepitant, boceprevir, 
clarithromycin, chloramphenicol (not eye drops), cimetidine, ciprofloxacin, clopidogrel, 
clotrimazole (if used orally), cobicistat and cobicistat-containing products, crizotinib, 
cyclosporine, danazol, deferasirox, diltiazem, dronedarone, erythromycin, fluconazole, 
fluvoxamine, gemfibrozil, HIV protease inhibitors, imatinib, isoniazid, itraconazole, 
josamycin, ketoconazole, nefazodone, posaconazole, quinupristin/dalfopristin, ritonavir 
and ritonavir-containing products, telaprevir, teriflunomide, tofisopam, troleandomycin, 
verapamil, and voriconazole; 
• 
any investigational drug or device;  
• medications that may interfere with the accurate measurement of serum creatinine 
including cimetidine, trimethoprim, pyrimethamine, phenacemide, and aspirin (aspirin 
dose above 150 mg per day); 
• any other drug/treatment including medications, supplements, and herbals with known 
activity on serum creatinine or interference with serum creatinine assays and/or 
vasopressin activity or interference with serum creatinine assays and/or vasopressin 
activity. 
5.8 Diet, Fluid, Activity, and Lifestyle Considerations 
Restriction of excess dietary sodium and cooked meat protein may prove beneficial to 
participants with a history of, or predisposition for, hypertension or kidney disease in general.  
In the absence of alternate regional practices, dietary salt should be restricted to <5g/day and 
dietary cooked meat protein to <1 g/kg/day.  In addition, the amount of meat protein should 
remain stable from day-to-day, and an increased consumption of meat should not occur the 
day before scheduled serum creatinine measurements. 
Participants will refrain from consumption of grapefruit or Seville oranges (or their juices) 
from 7 days prior to the first dose of lixivaptan treatment until after the completion of the 
study.   
Increased fluid intake is encouraged in participants with ADPKD.  Given the potential for 
dehydration with lixivaptan treatment, all participants should be instructed to ingest fluids in 
anticipation of, or at the first sign of, thirst in order to avoid excessive thirst or dehydration.  
At the initiation of the Re-titration Period, all participants should receive the reminder to 
ingest at least 3 to 4 quarts (or liters as an approximation of quarts) of fluid (including in 


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solid, semi-solid, and liquid foods) per day, unless otherwise directed by the Investigator.  
This recommendation should start at the beginning of the Re-titration Period and continue 
through the end of the study.  Additionally, participants should ingest 1 to 2 cups 
(approximately 250-500 mL) of water before bedtime regardless of perceived thirst and 
replenish fluids overnight with each episode of nocturia.  Dehydration can be monitored by 
participant self-assessment of symptoms such as lightheadedness or dizziness.   
Daily activity including exercise should remain stable during the study and participants 
should avoid heavy lifting or intense physical exertion on the day before scheduled serum 
creatinine measurements. 
Consumption of alcohol should be limited to 1 alcoholic drink equivalent per day in women 
and 2 alcoholic drink equivalents per day in men.  An alcoholic drink equivalent is 12 ounces 
(360 ml) of regular beer, or 5 ounces (150 ml) of wine, or 1.5 ounces (45 ml) of distilled 
spirits. 


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6 TIMING OF STUDY PROCEDURES  
The timing of study procedures is presented in Table 3.  Scheduled quarterly visits (except 
for Visits 9, 15 and 21) may occur in the Investigator’s clinic or remotely with an HHC.  
Visits 9, 15 and 21 must occur in the Investigator’s clinic.  Other “Laboratory Only” visits at 
4-week intervals can be completed remotely by an HHC or by an approved designated third-
party. 
6.1 Screening Period 
The evaluation of both eligibility and baseline values for this roll-over study will be 
determined from the final 4 visits (Visits 24, 25, 26, and 27) of study, PA-ADPKD-303. 
Participants with a signed ICF and meeting study inclusion/exclusion criteria will be 
considered enrolled into this roll-over study after completion of all Visit 1 study procedures 
and will begin the Lixivaptan Re-titration Period. 
Participants who screen fail due to correctable or temporary reasons may be re-screened at a 
later time (up to 2 times) with the approval of the medical monitor and sponsor, after new 
informed consents are obtained. 
6.1.1 Visit 1/Visit 27 of PA-ADPKD-303 
For participants electing to enroll in this roll-over study, eligibility criteria will be reviewed 
following the signing of the ICF during Visit 27 of the lead-in study.  Visit 27 of study PA-
ADPKD-303 will also serve as Visit 1 of this study (PA-ADPKD-304).  Assessments 
performed at earlier visits of the lead-in study that will be utilized to determine eligibility 
include:   
• Visit 24 - laboratory assessments (urinalysis, hematology, complete chemistry, and 
liver panel)  
• Visit 26 - eGFR  
• Visit 27  safety assessments (vital signs, pregnancy testing in WOCP, brief physical 
examination, ECG, AEs, and concomitant medications). 
The mean of the eGFR values obtained at Visits 25, 26, and 27 (Follow-up Period) of study 
PA-ADPKD-303 will constitute the baseline eGFR value for this study.  No lixivaptan study 
treatment will be administered during this time. 
After signing the ICF at Visit 1, the following screening procedures will be performed: 
• Determine whether the participant is eligible to participate in the study based on 
meeting all the Inclusion Criteria (Section 4.1.1) and none of the Exclusion Criteria 
(Section 4.1.2) 
o If the participant is not eligible to participate, the site will record the screen failure 
in the IRT and complete the appropriate eCRFs.  No ET or Follow-up Period 
visits are needed unless an SAE is ongoing, in which case Visit 32 should be 
completed. 
o If all study entry criteria are met, contact the IRT to record the participant’s 
completion of Visit 1 and obtain lixivaptan kit number assignments to initiate the 
Re-titration Period.  Participants whose final dose during PA-ADPKD-303 was 
≤100 mg BID should receive sufficient lixivaptan for a 7 + 3-day interval in 


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accordance with Table 2.  Participants whose final dose during PA-ADPKD-303 
was >100 mg BID, should receive sufficient lixivaptan for a 14 + 3-day interval, 
including a dose escalation that will begin following completion of Visit 2, in 
accordance with Table 2.  Proceed as follows: 
 Dispense lixivaptan and have participant take the first dose when 
he/she returns home from the clinic.  Instruct the participant to take 2 
capsules (100 mg) BID approximately 10 hours apart, e.g., 8 AM and 6 
PM.  (Instruct participants whose final dose was 50 mg BID during the 
lead-in study, to take 1 capsule [50 mg] BID) 
 Remind the participant to expect aquaretic effects and to maintain fluid 
intake to prevent dehydration 
• Schedule the participant for Visit 2 to occur in 1 week (NOTE: For participants with 
a final dose of ≤100 mg BID in the lead-in study, omit Visit 2 and schedule Visit 3 in 
1 week).  Provide the participant with an appointment reminder card and any written 
instructions. 
6.2 Re-titration Period 
The Re-titration Period will last from 1 to 2 weeks.  Participants will self-administer 
lixivaptan at home.  Participants whose final dose during the Maintenance Period of the lead-
in study was ≤100 mg BID will remain on that dose for 1 week and then proceed to Visit 3.  
Participants on doses greater than 100 mg BID will be directly titrated to their final dose of 
the lead-in study following completion of the telehealth visit at Visit 2 in the Re-titration 
period and remain on that dose for 1 week, in accordance with Table 1. 
6.2.1.1 Visit 2  
Participants whose final dose at the end of the lead-in study was >100 mg BID will have a 
telehealth visit at Visit 2 of the Re-titration Period.   
 
The following procedures will be performed: 
• Check AEs and SAEs 
• Assess liver dysfunction (symptoms) in accordance with Part 1 of the checklist and 
instructions in Appendix 4 (Section 13.4) 
• Collect and review concomitant medication information 
• Review lixivaptan treatment compliance (capsules to be reconciled during Visit 3) 
• Contact the IRT to record the visit 
• Instruct the participant to increase his/her dose of lixivaptan based on the dose level 
guide in Table 2 
• Schedule the participant for Visit 3 to occur in 1 week and remind the participant to 
take adequate fluids.  Provide the participant with an appointment reminder card and 
any written instructions. 
 


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Participants whose final dose in the lead-in study was ≤100 mg BID will skip Visit 2 and 
proceed directly to Visit 3. 
6.2.1.2 Visit 3/Last Titration Visit 
Participants will either report to the clinic or have a remote visit by an HHC for assessments 
for the last visit of the Re-titration Period.  Dosing will continue for the remainder of the 
study at the level the participant was receiving at the end of the Maintenance Period of the 
lead-in study. 
If there is difficulty with tolerability, the dose may be temporarily reduced, participant may 
then enter the Maintenance Treatment Period and the dose will be readdressed at the next 
clinic visit (Visit 6).  Dosing reductions for participants on Level 2 (100 mg BID or less) will 
require prior approval from the medical monitor. 
Participants should bring any remaining lixivaptan treatment into the clinic if having a site 
visit. If the visit is a remote visit, participant should give any remaining lixivaptan to the 
HHC. 
 
The following procedures will be performed: 
• Check AEs and SAEs 
• Assess clinically for liver dysfunction (symptoms and signs) in accordance with the 
checklist and instructions in Appendix 4 (Section 13.4) 
• Collect and review concomitant medication information 
• Review lixivaptan treatment compliance/reconciliation 
• Check vital signs (sitting blood pressure and heart rate)  
• Collect body weight 
• Collect urine to conduct a pregnancy test in WOCBP  
• Collect blood samples for  
o Complete chemistry panel  
o Liver chemistry panel 
o Hematology 
• Contact the IRT to record the visit and obtain lixivaptan kit number assignments for 
initiation of the Maintenance Treatment Period 
• Dispense 12-week supply of lixivaptan and instruct participant on appropriate dosing 
based on the dose level guide in Table 2 
• Schedule the participant for Visit 4 (laboratory only visit) to occur in 4 weeks and 
remind the participant to take adequate fluids.  Provide the participant with an 
appointment reminder card and any written instructions. 
6.3 Maintenance Treatment Period 
The Maintenance Treatment Period will last 104 weeks (Visit 4 to Visit 29).  Visits 
designated as “laboratory only” may be completed at the clinic or conducted remotely by an 


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HHC or by a designated third-party who will draw and process samples for shipment to the 
central laboratory where available and approved.  Laboratory only visits include Visits 4, 5, 
7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, and 28.  Visits 9, 15, 21 and 29 will be 
completed at the study clinic, while the remaining visits designated as “clinic or remote 
visits” (Visits 6, 12, 18, 24 and 27) may be performed either on-site or remotely by an HHC. 
6.3.1 Visits 4 to 28 
 Study visits will occur every 12 weeks ± 5 days.   Laboratory only visits will occur every 
4 weeks ± 5 days on weeks when there is not a clinic or remote visit. 
6.3.1.1 Visits 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, and 
28/Laboratory Only Visits 
The following procedures will be performed for each laboratory only visit: 
• Collection of a blood sample for liver chemistry panel 
• Site personnel to contact the IRT to register visit 
• Site personnel to schedule the participant for the next visit in 4 weeks; confirm where 
the visit will be performed. Remind the participant to take adequate fluids. 
6.3.1.2 Visits 6, 12, 18, 24, and 27/Clinic or Remote Visits 
Visits 6, 12, 18, 24 and 27 can be performed either on-site or remotely by an HHC. 
 
The following procedures will be performed at each clinic or remote visit: 
• Check AEs and SAEs 
• Assess liver dysfunction (signs and symptoms at clinic visits (Part 1 and Part 2 of the 
checklist); symptoms only at remote visits (Part 1 of the checklist)) in accordance 
with  instructions in Appendix 4 (Section 13.4) 
• Collect and review concomitant medication information 
• Review lixivaptan treatment compliance/reconciliation 
• Check vital signs (sitting blood pressure and heart rate)  
• Collect urine to conduct a pregnancy test in WOCBP 
• Collect blood samples for  
o Complete chemistry panel  
o Liver chemistry panel 
• Contact the IRT at each visit to obtain lixivaptan kit number assignments and 
complete the visit 
• Dispense 12-week supply of lixivaptan and instruct participant to take the appropriate 
dose BID approximately 10 hours apart, e.g., 8 AM and 6 PM  
• Schedule the participant to return in 4 weeks for his/her next laboratory visit (if not 
already scheduled); confirm where the visit will take place.  Also, schedule 
participant for the next clinic or remote visit in 12 weeks.  At each visit, remind the 
participant to take adequate fluids.  Provide the participant with an appointment 


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reminder card(s) and any written instructions.  Note: Visit 29 should be scheduled 
approximately 8 weeks from Visit 27.  Dosing instructions should be tailored 
accordingly. 
6.3.1.3 Visits 9, 15, and 21/Clinic Visits 
Participants should bring any remaining lixivaptan treatment into the clinic. 
 
The following procedures will be performed at each clinic visit: 
• Check AEs and SAEs 
• Assess clinically for liver dysfunction (symptoms) in accordance with the checklist 
and instructions in Appendix 4 (Section 13.4) 
• Collect and review concomitant medication information 
• Review lixivaptan treatment compliance/reconciliation 
• Check vital signs (sitting blood pressure and heart rate)  
• Collect body weight (Visit 15 only) 
• Perform a brief physical examination  
• Perform a 12-lead ECG  
• Collect urine to conduct a pregnancy test in WOCBP 
• Collect urine for urinalysis (Visit 15 only) 
• Collect blood samples for  
o Complete chemistry panel  
o Liver chemistry panel 
o Hematology  
• Contact the IRT at each visit to obtain lixivaptan kit number assignments and 
complete the visit 
• Dispense 12-week supply of lixivaptan and instruct participant to take the appropriate 
dose BID approximately 10 hours apart, e.g., 8 AM and 6 PM 
• Schedule the participant to return in 4 weeks for his/her next laboratory visit (if not 
already scheduled); confirm where the visit will take place.  Also, schedule 
participant for the next clinic or remote visit in 12 weeks.  At each visit, remind the 
participant to take adequate fluids.  Provide the participant with an appointment 
reminder card(s) and any written instructions. 
6.3.2 Visit 29/Early Termination  
Visit 29 will occur at Week 104 ± 5 days.   
Participants will report to the clinic to undergo final Maintenance Treatment Period 
assessments. These procedures will also be conducted on participants that terminate the study 
early (Section 6.4.4).  
Participants should bring any remaining lixivaptan treatment into the clinic. 
The following procedures will be performed: 


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• Check AEs and SAEs 
• Assess clinically for liver dysfunction (symptoms and signs) in accordance with the 
checklist and instructions in Appendix 4 (Section 13.4) 
• Collect and review concomitant medication information 
• Review lixivaptan treatment compliance/reconciliation 
• Check vital signs (sitting blood pressure and heart rate)  
• Collect body weight 
• Perform a full physical examination 
• Perform a 12-lead ECG 
• Collect urine to conduct a pregnancy test in WOCBP 
• Collect urine for urinalysis 
• Collect blood samples for  
o Complete chemistry panel (including serum creatinine for eGFR) 
o Liver chemistry panel 
o Hematology 
• Contact the IRT to register the visit 
• Schedule the participant to return for the first follow-up visit (Visit 30) in 8 days + 3 
days. 
 
6.4 Follow-up Period  
The Follow-up Period will last 28 days and include 3 visits (Visit 30, Visit 31, and Visit 32).  
Visits 30 and 31 are designated as “laboratory only visits” and may be completed at the clinic 
or conducted remotely by an HHC or by a designated third-party who will draw and process 
samples for shipment to the central laboratory where available and approved. 
6.4.1 Visit 30 
Visit 30 will occur no earlier than 8 (+ 3) days after the last dose of lixivaptan treatment.   
 
The following procedures will be performed at Visit 30 (“laboratory only visit”): 
• Collect a blood sample for serum creatinine 
• Site personnel to contact the IRT to register visit 
• Schedule the participant for the next visit (Visit 31), to occur 12 to 24 (± 3) days after 
the last dose of lixivaptan treatment. 
6.4.2 Visit 31 
The following procedures will be performed at Visit 31 (“laboratory only visit”): 
• Collect a blood sample for serum creatinine 
• Site personnel to contact the IRT to register visit 


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• Schedule the participant to return to the clinic for Visit 32 to occur 28 (± 3) days after 
the last dose of lixivaptan treatment. 
6.4.3 Visit 32 (End of Study Visit) 
Visit 32 is the last visit in this study and will occur 28 (± 3) days after the last dose of 
lixivaptan treatment.  The visit will be conducted in the clinic.   
 
The following procedures will be performed at Visit 32: 
• Check AEs and SAEs 
• Assess clinically for liver dysfunction (symptoms and signs) in accordance with the 
checklist and instructions in Appendix 4 (Section 13.4) 
• Collect and review concomitant medication information 
• Check vital signs (sitting blood pressure and heart rate)  
• Collect body weight 
• Perform a brief physical examination 
• Perform a 12-lead ECG 
• Collect urine to conduct a pregnancy test in WOCBP 
• Collect urine for urinalysis 
• Collect blood samples for  
o Complete chemistry panel  
o Liver chemistry panel 
• Contact the IRT to register participant completion in PA-ADPKD-304. 
 
6.4.4 Early Termination Procedures 
Participants who terminate the study during the Screening Period will not have an ET visit 
unless there is an ongoing SAE (see Section 4.2.2). 
Participants who terminate the study during the Re-titration or Maintenance Treatment 
Periods will have ET procedures and follow up procedures performed as described in Section 
4.2.3. 


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7 DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study specific procedures, all potential participants will sign the study 
ICF.  Participants will have the opportunity to have any questions answered before signing 
the ICFs.  The Investigator must address all questions raised by the participant. 
The study assessments to be performed at each visit are specified in the study Schedule of 
Procedures (Table 3).  
Visits may occur in the morning or afternoon.   
7.1 Efficacy Assessments 
7.1.1 eGFR 
The eGFR values reported to Investigators from the central laboratory will be calculated 
according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 
from the serum creatinine concentrations taken at Screening and at the visits specified in the 
Schedule of Procedures (Table 3) when either the complete chemistry panel or serum 
creatinine is listed.  During the Screening Period, serum creatinine assessments from Visits 
25, 26, and 27 of study PA-ADPKD-303 will be used to determine the mean eGFR. The 
mean value will be used as the eGFR baseline.  The eGFR assessment at Visit 1 (Visit 27 of 
the lead-in study) will be carried out on serum creatinine from the complete chemistry 
sample. 
Alteration in the metabolism of creatinine based on changes in meat intake and exercise may 
impact accuracy of serum creatinine and determination of eGFR.  Measures to reduce 
variability are provided in Section 5.8.   
7.2 Safety and Tolerability Assessments 
The safety and tolerability of lixivaptan will be assessed by evaluation of AEs, SAEs, 
physical examinations, vital sign measurements, ECGs, and clinical laboratory parameters 
(hematology, clinical chemistry including liver chemistry tests, and urinalysis).  Additional 
safety assessments may be performed as needed at the discretion of the Investigator.  Safety 
assessments will be performed at Screening and throughout the study as described in the 
study Schedule of Procedures (Table 3).  Assessment windows are presented Table 3. 
7.2.1 Body Height, Weight, and BMI 
At Visit 1, body mass index (BMI) will be calculated automatically by the eCRF 
functionality (BMI [kg/m2] = body weight [kg] / height2 [m2]) using the height recorded in 
study PA-ADPKD-303 and body weight (pounds or kilograms) measured to the nearest tenth 
at Screening (Visit 24 of study PA-ADPKD-303). Body weight will subsequently be 
measured at the timepoints specified in the Schedule of Procedures (Table 3). It is preferable 
to use the same scale at each visit where body weight is measured, and measurements of 
height and weight will be without the participant wearing shoes. 


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7.2.2 Demographics and Medication History  
Demographic data (e.g., age, childbearing potential) and medication history will be updated 
as necessary at Visit 1. 
7.2.3 Physical Examinations  
A brief physical examination will be performed at Visit 1 (Visit 27 of lead-in study), at 
designated clinic visits during the Maintenance Treatment Period and at the final visit (Visit 
32) in the Follow-up Period (Table 3).  A complete physical examination will be conducted at 
Visit 29/ET. Additional physical examinations will be performed only for assessment of signs 
or symptoms reported by the participants which may require further evaluation.  
Complete physical examinations will include, at a minimum, height and weight, general 
appearance, and assessment of the following systems: skin, head, ears, eyes, and throat, 
respiratory system, cardiovascular system, gastrointestinal system, neurologic system, blood 
and lymphatic systems, and the musculoskeletal system.  The physical examination may be 
performed by the Investigator, a sub-Investigator who is a medical doctor, a qualified nurse 
practitioner or a physician’s assistant in accordance with the site’s current practice and local 
requirements, as applicable. 
Brief physical examinations include, at a minimum, weight, and assessment of the following 
systems: chest and heart auscultation, abdominal examination, neurologic condition (i.e., 
alert and oriented x3; not including cranial nerves), and edema and hydration assessment. 
The brief physical examination may be performed by the same individuals who can perform 
a complete physical examination. 
Physical examination findings noted during the Screening will be recorded as AEs as 
appropriate.  New physical examination findings observed after re-initiation of lixivaptan 
treatment will be classified as being in 1 of 3 categories:  normal, abnormal but not clinically 
significant (NCS), or abnormal and CS.  All CS findings will be reported as AEs. 
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator.  Symptom-directed physical examinations will be performed as 
appropriate for participants experiencing AEs. 
7.2.4 Vital Sign Measurements 
Vital sign measurements will include systolic blood pressure, diastolic blood pressure, and 
pulse rate and will be performed at the time-points specified in the study Schedule of 
Procedures (Table 3). Respiratory rate and body temperature will be measured once at 
Screening. 
Participants will remain at rest in a seated position for a minimum of 5 minutes before vital 
signs measurements are obtained.  For all participants, blood pressure and pulse rate will be 
measured once at each specified time using an automated sphygmomanometer.  Blood 
pressure measurements will be taken with the appropriate cuff size and in the same arm 
(whenever possible) for the duration of the study. The arm should be positioned level with 
the heart and the blood pressure cuff applied directly to the skin (not over clothing).  A 
confirmatory repeat vital sign measurement may be performed at the discretion of the 


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Investigator. Although sitting is the standard position for measurement of vital signs, a site 
that uses a different standard of care, e.g., semi-recumbent, may utilize that position as long 
as all measurements at that site are done in the same position.  Other positions to obtain vital 
signs may be used after discussion with the medical monitor.  Any confirmed, clinically 
significant vital sign measurements must be recorded as an AE.  If other procedures are 
scheduled at the same time point, vital signs should be obtained first, before an ECG and/or 
blood draw. 
7.2.5 12-Lead ECGs 
Standard 12-lead ECGs will be performed at the time-points specified in the study Schedule 
of Procedures (Table 3). 
Safety 12-lead ECG intervals will be measured using an ECG machine that automatically 
calculates the HR and measures PR, QRS, QT and QTcF.  The same ECG machine should be 
used for the same participant throughout the study.  
ECGs will be obtained with the participant remaining in a supine or semi-recumbent position 
following 5 minutes of rest.  All ECGs throughout the study for a given participant should be 
measured in the same position, i.e., either all in a supine position or all in a semi-recumbent 
position.  If other procedures are scheduled at the same time-point, the ECG should be 
obtained after vital sign measurements and/or before the scheduled blood draw.   
For all participants, ECGs will be reviewed, signed, and dated by the Investigator or a 
qualified designee.  The ECGs will be classified as being in one of three categories:  normal, 
abnormal but not clinically significant (NCS), or abnormal and CS.  All CS findings will be 
reported as AEs. 
Additional ECGs may be performed if deemed medically appropriate. 
7.2.6 Clinical Laboratory Tests 
Blood and urine specimens will be collected for the clinical laboratory (hematology, clinical 
chemistry, and urinalysis) and pregnancy tests (all female participants of child-bearing 
potential) at the time-points specified in the study Schedule of Procedures (Table 3). Except 
where noted, all laboratory testing will be performed at the central laboratory, which will 
return results with normal ranges to the clinical sites.   A confirmatory assessment through 
the central laboratory should be obtained as soon as possible for any CS abnormal laboratory 
parameter if deemed necessary by the Investigator.  Repeat testing for abnormal liver 
chemistry tests is described in Section 7.2.7.1.  Any other repeat laboratory testing for values 
that are not CS should be discussed first by the Investigator with the medical monitor before 
such tests are ordered.  All routine testing will be conducted in the morning after an overnight 
fasted state (minimum of 8 hours except for water).  Mild elevations in serum creatinine or 
serum sodium are known pharmacodynamic effects of vasopressin antagonists like 
lixivaptan, therefore confirmatory assessments for serum creatinine and serum sodium will 
be at the Investigator's discretion.   
Clinical laboratory parameters for analysis are presented in Table 6. 
Macroscopic urinalysis will be performed via dipstick. Microscopic examination is needed 
only if macroscopic results are positive for blood or protein.   


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Additional liver chemistry tests should be collected if the participant experiences liver 
chemistry test abnormalities of concern or has suspicious symptoms or signs of liver 
dysfunction (Section 7.2.7).  
Table 6. Clinical Laboratory Parameters 
Complete Chemistry Panel 
Hematology 
Urinalysis 
Albumin 
Hematocrit 
pH 
Blood urea nitrogen (urea) 
Hemoglobin 
Protein 
Calcium 
Red blood cell count 
Glucose 
Chloride 
Quantitative platelet count 
Ketones 
CO2 
WBC count with 
Bilirubin 
Creatinine, enzymatic* 
differential (total and %) only if  
Blood 
Glucose 
 WBC count is abnormal: 
Urobilinogen 
Phosphorous 
    Neutrophils 
Leukocytes 
Potassium 
    Lymphocytes 
Nitrite 
Protein 
Sodium 
Uric Acid 
    Monocytes 
    Eosinophils 
    Basophils 
Microscopic examination  
(if positive for  
blood, protein,  
nitrite, or 
 
     
leukocytes) 
Serum Creatinine* 
 
 
Creatinine, enzymatic 
 
 
 
 
 
Liver Chemistry Panel 
Other Tests 
 
Alanine aminotransferase 
Urine or serum pregnancy test 
 
Alkaline phosphatase 
 (WOCBP only) 
 
Aspartate aminotransferase 
 
 
Bilirubin Total and Direct 
 
 
 
 
 
Abbreviations: CO2 = carbon dioxide; WBC = white blood cell; WOCBP = women of childbearing 
potential 
*serum creatinine will be assessed as part of the complete chemistry panel at study visits where a complete 
chemistry panel is required (Table 3) 
 
7.2.6.1 Sample Collections 
Instructions regarding the collection, processing, and shipment of laboratory samples are 
detailed in a separate laboratory manual.  All samples will be given a unique identifier.  The 
sample collection date and time will be entered into the eCRF. 


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7.2.7 Assessment of Liver Symptoms, Signs, or Test Abnormalities 
Testing for hepatic transaminases (ALT/AST), alkaline phosphatase, and total and direct 
bilirubin will be performed at the time-points specified in the Schedule of Procedures (Table 
3). Management of hepatic and liver chemistry test abnormalities is discussed below.   
The appearance of any suspicious symptoms or signs of liver dysfunction as described in 
Appendix 4 (Section 13.4) in a participant at any time during the study should trigger prompt 
testing of liver chemistry tests (i.e., within 48 hours). 
7.2.7.1 Requirements for Additional Liver Chemistry Testing 
To determine when repeat liver chemistry testing is necessary, follow the instructions in 
Table 7. 
Table 7. Additional Liver Chemistry Testing and Other Testing 
Participants with Liver Chemistry 
Values Exceeding Eligibility 
Requirements at Screening 
Participants with Eligible Liver 
Chemistry Values at Screening 
Participants with transaminase 
(ALT/AST) or total bilirubin values above 
the values in the exclusion criteria (>1.5 × 
ULN) during the Screening Period will 
not proceed further in the study.  Any 
required follow up should be part of 
routine clinical care.  However, if 
evaluation indicates a reversible cause of 
liver disease, such participants may be re-
screened in consultation with the medical 
monitor and sponsor when such liver 
chemistry test results return to values 
allowing entry into the study. 
Any transaminase value >3 × ULN or total 
bilirubin >2 × ULN during the Re-titration 
or Maintenance Treatment Periods requires 
immediate retesting within 48 hours.  Local 
laboratory testing is acceptable with 
collection of a concurrent central laboratory 
sample for confirmation whenever possible.  
During the time that values remain elevated, 
testing should be done at least weekly for 
the first month, gradually returning to 
monthly as indicated by the results. 
Individual cases that either resolve quicker 
or slower should be discussed with the 
medical monitor and sponsor.  The medical 
monitor will discuss with the Investigator 
any additional laboratory testing or imaging 
depending on the case circumstances. 
Examples of such testing are shown in 
Appendix 3 (Section 13.3). 
 
7.2.7.2 Changes in Lixivaptan Dosing if Liver Chemistry Test 
Abnormalities Occur During the Titration or Maintenance 
Treatment Periods 
After the Investigator consults with the medical monitor and sponsor, temporary reduction in 
dose or interruption of lixivaptan treatment administration must be instituted if liver 


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transaminase levels >3 × ULN or total bilirubin levels >2 × ULN are observed during the Re-
titration or Maintenance Treatment Periods.  All elevations meeting these thresholds will be 
assessed by the HERC.  In the case of lixivaptan treatment interruption, re-starting lixivaptan 
treatment should be encouraged (see exception below) after discussion with the medical 
monitor and sponsor, when liver chemistry tests have normalized or stabilized, and in 
conjunction with a plan for increased frequency of liver chemistry test monitoring. 
In the presence of such liver chemistry test abnormalities, additional clinical testing 
(examples listed in Appendix 3 (Section 13.3) may be recommended by the medical monitor 
and sponsor and those results reported according to local guidelines. 
Treatment with study drug cannot be resumed in participants when: 
• transaminase levels >8 × ULN at any time, 
• transaminase levels >5 × ULN for more than 2 weeks, or 
• concurrent elevations of transaminase levels >3 × ULN and total bilirubin >2 × ULN 
except under these circumstances: 
Participants with these levels of abnormality may be re-challenged with lixivaptan 
treatment if abnormalities were adjudicated as having a ≤50% likelihood of being 
related to lixivaptan treatment (per DILI Network [DILIN] probability criteria, 
modified), Appendix 2 (Section 13.2) (Fontana et al, 2009) by the HERC, and the 
Investigator, medical monitor, and sponsor agree to an intensive monitoring plan to 
mitigate risk.  The participant must also be willing to comply with these monitoring 
measures, be informed of the potential risks, and consent to lixivaptan treatment re-
challenge. 
Liver chemistry test increases of a lesser extent should be discussed with the medical 
monitor.  They may be related to the underlying variability of such tests in ADPKD 
participants.  Generally, dosing should continue, but the frequency of laboratory testing 
should increase, particularly during the Maintenance Treatment Period.  Slowing of re-
titration may also be considered if the abnormalities occur during the Re-titration Period. 
7.2.7.3 Special Reporting of Liver Events 
A liver dysfunction details eCRF will be utilized during the study.  The type of information 
needed to complete it is provided in Appendix 4 (Section 13.4).  The purpose of the liver 
dysfunction details eCRF and additional testing is to facilitate review of each participant who 
develops liver chemistry test abnormalities and/or signs or symptoms of liver dysfunction 
during the study to determine the probable cause(s) of these abnormalities.  The review will 
be performed by an independent HERC using DILIN probability criteria, modified (0 to 5% 
= unrelated; 6 to 25% = unlikely, 25% to 50% = possibly, 51% to 75% = probably, 76% to 
95% = very likely, >95% = definite) (Fontana et al, 2009).  The HERC will independently 
decide attribution and will communicate in writing with the sponsor. The results of the 
HERC review will be used in assessing the primary and secondary endpoints.  The result of 
these analyses may be presented separately from the final clinical study report (CSR). 
The Investigator must complete the liver dysfunction details eCRF and submit it within 24 
hours of awareness through the SAE reporting pathway (described in Section 7.2.8.3) for any 


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participant who develops an Adverse Event of Special Interest (AESI) related to abnormal 
liver chemistry test results or clinical signs or symptoms. Specifically, any participant who 
• develops any signs or symptoms of hepatic dysfunction (see Appendix 4 [Section 
13.4]) 
• discontinues treatment due to a liver-related AE, 
• reports a serious liver-related AE, 
• develops ALT or AST levels >3 × ULN, 
• develops total bilirubin levels >2 × ULN.  
The AESI report form should be updated as new information becomes available. 
7.2.8 Adverse Events 
7.2.8.1 Definitions of Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to lixivaptan treatment or their clinical significance, as 
outlined in Section 7.2.8.2 below. 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to lixivaptan treatment. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
lixivaptan treatment in this study or any event already present at baseline that worsens in 
either intensity or frequency after exposure to lixivaptan treatment. 
An SAE is defined as any event that results in death, is immediately life threatening, requires 
in-patient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect.  Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered SAEs when, based upon appropriate medical judgment, they may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
Hospitalization does not include admissions for treatment of a pre-existing condition, 
including surgery, not associated with a new AE; respite care; social reasons; administrative 
reasons; skilled nursing care; rehabilitation; hospice; or same-day surgery. 
7.2.8.2 Eliciting and Documenting Adverse Events and Serious Adverse 
Events 
All AEs and SAEs will be recorded from the time the ICF is signed until study completion.   
At every study visit, participants will be asked a standard non-leading question to elicit any 
medically related changes in their well-being.  They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and OTC medications). 


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In addition to participant observations, any abnormal laboratory test results (hematology, 
clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, 
vital sign measurements, physical examination findings), including those that worsen from 
baseline, deemed to be CS in the medical and scientific judgment of the Investigator are to be 
recorded as AEs or SAEs. 
7.2.8.3 Reporting Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
All AEs reported or observed during the study will be recorded on the AE page of the eCRF.  
Information to be collected includes lixivaptan treatment, dose, event term, date of onset, 
Investigator-specified assessment of severity and relationship to lixivaptan treatment, date of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome.  
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported.  All AEs will 
be followed to adequate resolution. 
Any medical condition that is present at the time the participant is screened for eligibility, 
i.e., medical history, but does not deteriorate should not be reported as an AE.  However, if it 
deteriorates at any time during the study, it should be recorded as an AE. 
However, any safety assessments that are associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant’s condition, are 
not to be reported as AEs or SAEs. 
For the purpose of this study, liver events are considered to be AESIs.  Liver events will be 
reported directly from the electronic data capture [EDC] system.  
Pregnancy events will need to be reported on special pregnancy forms to ICON PVSS. 
Any AE that meets SAE or AESI criteria will be reported to ICON Pharmacovigilance & 
Safety Services (PVSS) immediately (i.e., within 24 hours) after site personnel first learn 
about the event.  Investigators should record all SAE/AESI details available, including 
Investigator causality assessment, on the AE eCRF or appropriate AESI form and submit the 
report via the electronic data capture (EDC) system within 24 hours of becoming aware of 
the event.  Notification of SAE/AESI entry will be generated and sent to ICON PVSS via the 
EDC system. Pregnancy events will also be reported to ICON PVSS within 24 hours of 
recognition of the event, but on the special forms provided. 
In the event the EDC system is unavailable, a completed SAE Report Form should be 
submitted to ICON PVSS as an email attachment or by fax to the email address / fax number 
below. The EDC system must be updated with the information on the paper report as soon as 
the EDC is available. The preferred method of reporting on paper is via email: 
ICON PVSS Email Address: ICON-Safety-CentralReceipt@iconplc.com 
or via fax to: 
ICON PVSS Fax: 1-215-616-3096 (within US) 
ICON PVSS Fax: +44 (0)208 100 5005 (outside US) 


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Should the site have questions or concerns regarding SAE report submission, the site may 
elect to call the ICON PVSS SAE Hotline number. The site will be asked to provide the 
following information: protocol number, site number, participant identifiers, event term, 
lixivaptan treatment information, relationship of the event to lixivaptan treatment. 
• ICON PVSS SAE Hotline Number: +1-888-426-8801 (within US) – Toll Free 
Number or +1-281-295-4889 (outside of US) 
In a study-related health emergency, for discussion of urgent protocol medical-related 
questions when the assigned medical monitor for a study cannot be reached, an on-call 
physician can be reached 24 hours per day, 7 days per week via an ICON Call-Center:  
• 
Telephone: +1 857-957-5013  
(a chargeable telephone number allowing a global reach from both landlines and mobile 
phones)  
• https://icophone.iconplc.com/24-7-Medical.pdf (list of country-specific toll-free 
telephone numbers).  
7.2.8.4 Assessment of Severity 
AEs should be graded as mild, moderate, or severe, using the following definitions: 
• Mild: Awareness of signs or symptoms, but easily tolerated and of a minor irritant 
type, causing no loss of time from normal activities.  Symptoms do not require 
therapy or a medical evaluation; signs and symptoms are transient. 
• Moderate: Events introduce a low level of inconvenience or concern to the participant 
and may interfere with daily activities but are usually improved by simple therapeutic 
measures; moderate experiences may cause some interference with functioning. 
• Severe: Events interrupt the participant’s normal daily activities and generally require 
systemic drug therapy or other treatment; they are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed.  AEs characterized as 
intermittent do not require documentation of onset and duration of each episode. 
7.2.8.5 Assessment of Causality 
The Investigator’s assessment of causality must be provided for all AEs.  The causality is the 
determination of whether there exists a reasonable possibility that the lixivaptan treatment 
itself caused or contributed to an AE. 
If the final determination of causality is unknown and the Investigator does not know 
whether the lixivaptan treatment caused the event, then the event will be handled as “possibly 
related to lixivaptan treatment” for reporting purposes.  If the Investigator’s causality is 
“unknown, but not related to lixivaptan treatment”, this should be clearly documented on 
study records. 
The relationship of an AE to the administration of lixivaptan treatment will be assessed and 
recorded on the eCRF.  Terms used to describe the degree of causality between lixivaptan 
treatment and an AE are: definitely, probably, possibly, unlikely, or not related.  The best 


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estimate at the time of reporting of the causal relationship between the experimental 
intervention and an AE and the degree of certainty about causality will be graded using the 
criteria specified in Table 8. 
 
 
 


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Table 8. Guideline for Assessment of Adverse Event Causality 
Relationship to 
Lixivaptan 
Treatment 
Description 
Not Related 
The AE is clearly due to extraneous causes (e.g., underlying disease, environment) or 
exposure to the investigational product has not occurred.  Such events MUST have 
an alternative, definitive etiology documented in the participant's medical record. 
Unlikely Related 
A potential relationship between lixivaptan treatment and the AE could exist (i.e., the 
possibility cannot be excluded), but the AE is most likely explained by causes other 
than the lixivaptan treatment (e.g., could readily have been produced by the 
participant's clinical state or could have been due to environmental or other 
interventions). 
Possibly Related 
The AE and administration of lixivaptan treatment are reasonably related in time 
and/or follow a known pattern of response, and the AE can be explained equally well 
by causes other than lixivaptan treatment (e.g., could readily have been produced by 
the participant's clinical state or could have been due to environmental or other 
interventions). 
Probably Related 
The AE and administration of lixivaptan treatment are reasonably related in time 
and/or follow a known pattern of response, and the AE is more likely explained by 
lixivaptan treatment than other causes. 
Definitely Related 
The AE and administration of lixivaptan treatment are related in time, and a direct 
association can be demonstrated (e.g., disappears or decreases with reduction in dose 
or cessation of lixivaptan treatment/investigational product and recurs with re-
exposure). 
7.2.8.6 Follow-Up of Participants Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page of the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not CS, or until 
the participant is considered to be stable. 
7.2.8.7 Overdose Management 
An overdose is any dose of lixivaptan treatment given to a participant or taken by a 
participant that exceeds the dose described in the protocol.  Any overdose, with or without 
associated AEs, must be promptly reported to the Investigator and also reported to the 
sponsor.  Overdoses without signs or symptoms do not need to be recorded as AEs; in case of 
any AEs associated with the overdose, these should be reported on relevant AE/SAE sections 
in the eCRF.  In the event of suspected overdose, the appropriate supportive clinical care 
including fluid replacement should be instituted at the discretion of the Investigator or as 
dictated by the participant’s clinical status. 
7.2.8.8 Pregnancy 
Pregnancy is not regarded as an AE unless there is a medical/surgical complication.  Any 
pregnancy of a participant or the partner of a participant that occurs during study 
participation must be reported using a clinical study pregnancy reporting form.  To ensure 
participant safety, each pregnancy must be reported through this mechanism to ICON PVSS 
within 24 hours of learning of its occurrence.  


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The pregnancy must be followed up to determine outcome (including spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality) and status of 
mother and child, even if the participant was discontinued from the study.  Pregnancy 
complications and terminations of pregnancy will be reported as an SAE if SAE criteria are 
fulfilled.  Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the Investigator’s attention 
after the participant has completed the study, and considered by the Investigator as possibly 
related to the study treatment, must be promptly reported to ICON PVSS. 
7.2.9 Clinical Laboratory and Other Safety Assessments 
Any abnormal clinical laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital sign measurements), including 
those that worsen from baseline, felt to be CS in the medical and scientific judgment of the 
Investigator are to be recorded as AEs or SAEs. 
However, any safety assessments that are associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant’s condition, are 
not to be reported as AEs or SAEs. 
7.2.10 Hepatic Events Review Committee (HERC) 
The HERC consists of 4 expert hepatologists who will review demographic, medical and 
medication history, safety data and any other relevant data as available on participants who 
develop liver abnormalities of concern during the study.  
This committee will independently determine the probable causality for instances of 
suspected liver dysfunction and liver chemistry test abnormalities of concern (Section 7.2.7) 
and of relatedness to lixivaptan.   
The results of these reviews will be captured on an eCRF and used for analysis of the 
primary and secondary safety endpoints. A full report may be provided separately from the 
clinical study report. 


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8 STATISTICAL AND ANALYTICAL PLAN 
The statistical and analytical plan for this clinical study is summarized below.  Further details 
are provided separately in the Statistical Analysis Plan (SAP). 
8.1 Sample Size 
All participants in the lead-in study (PA-ADPKD-303) who satisfy all eligibility criteria and 
sign the Informed Consent may be enrolled into this roll-over study.  It is estimated that 
approximately 40 participants will be able to enroll assuming approximately 90% of 
participants complete the lead-in study and 90% of those meet all eligibility criteria and elect 
to enroll in this roll-over study. 
NOTE: Up to 50 participants were to be enrolled and treated in the lead-in study (PA-
ADPKD-303).   
8.2 Populations for Analysis 
The following populations will be used for analyzing the data: 
Enrolled Population: The Enrolled Population is defined as all participants who meet all 
eligibility criteria during the Screening Period and complete Visit 1.  All general summaries, 
except safety and efficacy analyses are based on the Enrolled Population, unless specified 
otherwise. 
Safety Population: The Safety Population is a subset of the Enrolled Population defined as 
those participants who received at least 1 dose of lixivaptan.  This population will be utilized 
for all safety analyses. 
Efficacy Population: The Efficacy Population is a subset of the Safety Population defined as 
those participants who have at least 1 eGFR determination during the Screening Period 
(Follow-up Period of study PA-ADPKD-303) and have at least 1 eGFR determination during 
the Follow-up Period.  This population will be used for all efficacy analyses. 
8.3 Analysis of Demographic and Baseline Characteristics 
Descriptive statistics for demographic (e.g., age, race, and sex) and baseline (e.g., eGFR) 
characteristics will be presented for the Enrolled, Safety and Efficacy Populations.  
8.4 Safety Analyses 
8.4.1 Primary Hepatic Safety Analysis 
Descriptive statistics (n, percentage and 95% confidence intervals) will be used to present the 
proportion of participants with serum ALT levels >3 × ULN that were assessed by the 
independent HERC to be at least probably related to lixivaptan and resulted in 
discontinuation of lixivaptan treatment during the Lixivaptan Re-titration or Maintenance 
Treatment Periods.   
8.4.2 Secondary Hepatic Safety Analyses 
Similarly, descriptive statistics (n, percentage and 95% confidence intervals) will be utilized 
to present the 2 secondary endpoints: 1) the proportion of participants with serum ALT levels 
>5 × ULN during the Lixivaptan Re-titration or Maintenance Treatment Periods that were 


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assessed by the independent HERC to be at least probably related to lixivaptan and resulted 
in the discontinuation of lixivaptan treatment; and 2) the proportion of participants with 
serum ALT levels >3 × ULN during the Lixivaptan Re-titration or Maintenance Treatment 
Periods that were assessed by the independent HERC to be at least probably related to 
lixivaptan and resulted in lixivaptan dose reduction 
8.4.3 Additional Hepatic Safety Analyses 
The proportion of participants who develop any of the following abnormalities during the 
Lixivaptan Re-titration or Maintenance Treatment Periods will be tabulated and presented 
descriptively: 
• >3 ×, 5 ×, 10 ×, and 20 × ULN elevations for ALT  
• >3 ×, 5 ×, 10 ×, and 20 × ULN elevations for AST 
• >3 ×, 5 ×, 10 ×, and 20 × ULN elevations for either ALT or AST 
• ALT or AST levels >2 × their baseline 
• Any elevation of total bilirubin >2 × ULN 
• Any elevation of alkaline phosphatase >2 × ULN 
• Elevation of aminotransferase (>3 × ULN) accompanied by elevated bilirubin (>2 × 
ULN) and displayed as evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) 
plots 
• Elevation of aminotransferase in temporal association with nausea, vomiting, 
anorexia, abdominal pain, or fatigue 
• Possible liver-related deaths and liver-related treatment discontinuations. 
8.4.4 Non-hepatic Safety Analyses: Adverse Events 
The number and percentage of participants and the number of events during the Re-titration 
and Maintenance Treatment Periods will be presented for TEAEs, SAEs, treatment-related 
TEAEs, and TEAEs leading to premature withdrawal according to the system organ class 
(SOC) and preferred term (PT) assigned to the event using MedDRA.  In addition, TEAEs 
will also be summarized by SOC, and PT separately by maximum severity and relationship 
to lixivaptan treatment.  Listings of deaths and serious TEAEs will be provided.  Similarly, 
number and percentage of participants will be presented for TEAEs, SAEs, and treatment-
related TEAEs during the Follow-Up Period. 
All AE data will be listed for all participants.  Both the Investigator’s verbatim terms and the 
MedDRA preferred terms will be listed for each participant.  Listings will also include the 
SAEs, start and end time and date of AEs, relationship to lixivaptan treatment, severity, and 
action taken for the AEs.  Adverse events with a relationship to lixivaptan treatment 
considered possibly, probably, or definitely related will be considered related.     
8.4.5 Clinical Laboratory Tests 
Descriptive statistics (n, mean, standard deviation [SD], median, minimum, and maximum) 
for clinical laboratory data and changes from baseline will be presented for each scheduled 
time point. 


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The Baseline value is the last value observed prior to first administration of lixivaptan 
treatment and any information taken after first administration of lixivaptan treatment is 
regarded as post-baseline information.  The change-from-baseline variables will be calculated 
as the postbaseline value minus the value at baseline.  Change from baseline on continuous 
data will be summarized using descriptive statistics at each scheduled time point.  For 
categorical data, change from baseline will be summarized using frequency and percentage at 
each scheduled time-point. 
Individual data listings of clinical laboratory results will be presented for each participant.  
Values outside of the clinical laboratory's reference range (i.e., those with low or high values) 
will be flagged in the clinical laboratory listings. 
For all continuous clinical laboratory variables, a shift table comparing the baseline value 
(normal, low, and high) to last observation on treatment will be presented. 
For urinalysis, a shift table comparing the baseline value to the maximum value will be 
presented (using number of participants with results of negative, trace, or positive). 
8.4.6 ECGs 
Observed values and changes from baseline for continuous ECG parameters including heart 
rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), and QTcF 
interval will be summarized over each scheduled time-point in terms of absolute values using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  In addition, a 
summary shift table comparing baseline interpretation (normal, abnormal - NCS, abnormal - 
CS) to the Investigator interpretation at each time point will also be presented. 
A listing will be provided for Investigator-identified ECG abnormalities from safety ECGs.  
Overall evaluation of safety ECGs will be summarized using frequency counts and 
percentage of participants as normal or abnormal, and the relevance of the abnormality will 
be summarized by CS or NCS. 
8.4.7 Vital Signs 
Changes from baseline in vital signs at each scheduled time-point will be summarized using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  The baseline value is 
defined as the last value observed prior to first administration of lixivaptan treatment.  The 
change from baseline is defined as the postbaseline value minus the baseline value.   
8.5 Efficacy Analysis 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented for 
observed values at baseline and end of study (Follow-up Period), as well as the annualized 
change from baseline in eGFR at the end of the study (Follow-up Period).  Baseline eGFR is 
defined as the mean of the 3 eGFR assessments obtained during the Screening Period (Visits 
25, 26, and 27 of study PA-ADPKD-303).  However, if any values are missing, the remaining 
values will be used to determine the baseline eGFR.  The endpoint eGFR is defined as the 
mean of 3 eGFR assessments obtained during the Follow-up Period of this study.  However, 
if any values are missing, the remaining values will be used to determine the endpoint eGFR. 
To compensate for the effect of subjects prematurely discontinuing from treatment, the 
changes from baseline will be annualized by multiplying each participant’s change from 


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baseline by 365.25 days divided by the duration from the median of the baseline eGFR 
assessments to the median of the 3 eGFR assessments made during the post-treatment, 
follow-up assessments in days.   
8.6 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS® software Version 9.4 or higher.  All 
continuous variables will be summarized using the following descriptive statistics: number of 
non-missing observations (n), mean, SD, median, minimum, and maximum.  Categorical 
variables will be summarized using the following descriptive statistics: frequency counts and 
percentages and 95% confidence intervals for the primary and secondary safety endpoints.  
All data will be listed in data listings. 
Further details of the statistical analyses, methods, and data conventions are described in the 
SAP.  The SAP may modify the plans outlined in the protocol; however, any major 
modifications of the primary analysis will also be reflected in a protocol amendment.  
Additional statistical analyses other than those described in this section may be performed if 
deemed appropriate in the plan. 
8.7 Data Quality Assurance 
Standard operating procedures are available for all activities performed at the study sites 
relevant to the quality of this study.  Designated study site personnel will be responsible for 
maintaining quality assurance and quality control to ensure that the study conduct as well as 
data collection and documentation are performed in compliance with the study protocol, GCP 
requirements, and applicable regulatory requirements. 
All clinical data will undergo source document verification by the Clinical Research 
Associate (CRA) and data review by Data Management prior to database lock.  Programmed 
edit checks are also implemented to check for missing data, data inconsistencies, data ranges, 
etc.  Corrections are made prior to database lock.  Electronic CRFs can be printed directly 
from the database.  Each eCRF will be reviewed and signed electronically by the 
Investigator. 
8.7.1 Data Management 
An eCRF is required and should be completed for each included participant. The completed 
original eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of the sponsor or appropriate 
regulatory authorities, without written permission from the sponsor. 
As part of the responsibilities assumed in conducting the study, the Investigator agrees to 
maintain adequate case histories for the participants treated as part of the research under this 
protocol.  The Investigator has ultimate responsibility for the accuracy, authenticity, and 
timely collection and reporting of all clinical, safety, laboratory data entered on the eCRFs 
and any other data collection forms. The eCRFs must be signed by the Investigator to attest 
that the data contained on the eCRFs are true. Any corrections to entries made on the eCRFs 
must be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. 
In most cases, the source documents are the hospital's or the physician's participant chart. In 


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these cases, data collected on the eCRFs must match the data in those charts.  
In some cases, the eCRF, or part of the eCRF, may also serve as source documents. In these 
cases, a document should be available at the Investigator’s site as well as at the sponsor and 
clearly identify those data that will be recorded on the eCRF, and for which the eCRF will 
stand as the source document. 
The Investigator agrees to maintain accurate eCRFs and source documentation as part of the 
case histories.  These source documents may include laboratory reports, ECGs, etc. 
Investigative site personnel will enter participant data into eCRFs using the EDC system 
designated by the sponsor.  The analysis data sets will be a combination of these data and 
data from other sources (e.g., laboratory data) and follow Clinical Data Interchange 
Standards Consortium (CDISC) standards. 
Clinical data management will be performed in accordance with applicable standards and 
data cleaning procedures of the contract research organization (CRO) to ensure the integrity 
of the data, e.g., removing errors and inconsistencies in the data.  Adverse events and 
concomitant medication terms will be coded using the MedDRA and World Health 
Organization Drug Dictionaries, respectively. 
After database lock, each study site will receive all site-specific eCRF data for the study, 
including full discrepancy and audit history.  Additionally, a copy of all the study site’s data 
from the study will be created and sent to the sponsor for storage.  The CRO will maintain a 
duplicate copy for their records.  In all cases, participant’s initials will not be collected or 
transmitted to the sponsor. 


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9 ETHICS 
9.1 Institutional Review Board (IRB)/Ethics Committee (EC) 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, ICFs, and other relevant documents, e.g., written participant 
instructions, recruitment advertisements, if applicable, from the Institutional Review 
Board/Ethics Committee (IRB)/(EC) before involvement of human participants in research 
studies.  All correspondence with the IRB/EC should be retained in the Investigator Site File.  
Copies of IRB/EC approvals should be forwarded to the sponsor. 
All IRB/EC approvals should be signed by the IRB/EC chairperson or designee and must 
identify the IRB/EC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/EC.  The 
Investigator must promptly supply the sponsor or its designee, the IRB/EC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to participants. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and all applicable regulations.  In addition, the study will be 
conducted in accordance with the protocol, the International Conference on Harmonisation 
(ICH) tripartite guideline E6 (R2), GCP, and applicable local regulatory requirements and 
laws. 
9.3 Participant Information and Consent 
Written informed consents in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each participant before entering the study, upon re-
screening, and when performing any unusual or non-routine procedure that involves risk to 
the participant.  Informed consent templates may be provided by the sponsor to investigative 
sites.  If any institution-specific modifications to study-related procedures are proposed or 
made by the site, the consents should be reviewed by the sponsor or its designee or both 
before IRB/EC submission.  Once reviewed, the consents will be submitted by the 
Investigator to his or her IRB/EC for review and approval before the start of the study.  If the 
ICF is revised during the course of the study, all active participants must sign the revised 
form. 
Before recruitment and enrollment, each prospective participant or his or her legal guardian 
will be given a full explanation of the study and be allowed to read the approved ICF.  Once 
the Investigator is assured that the participant /legal guardian understands the implications of 
participating in the study, the participant / legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 


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form to the participant or legal guardian. 
10 INVESTIGATOR’S OBLIGATIONS AND STUDY PERSONNEL 
The study will be conducted by qualified Investigators under the sponsorship of Palladio 
Biosciences, Inc. (the sponsor). 
The contact information for the sponsor’s Chief Medical Officer and the CRO’s medical 
monitor are listed on the cover page of this protocol.  Contact information for other sponsor 
personnel, ICON Clinical Research Limited, the designated CRO, and other vendors are 
listed in the Investigator Site File provided to each site. 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines.  Changes will be reported to the IRB 
but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participants’ confidentiality.  All records will be kept in a secure 
storage area with limited access.  Clinical information will not be released without 
participants’ (or legal guardians’) written permission, except as necessary for monitoring and 
auditing by the sponsor, its designee, the Food and Drug Administration (FDA), or the 
IRB/EC. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study.  Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators 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 must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor sponsor’s representatives 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 sponsor’s 
representatives is financially responsible for further treatment of the participant’s disease. 
10.3 Investigator Documentation 
Before beginning the study, the Investigator will be asked to comply with ICH E6 (R2) 
Section 10.4 and Title 21 of the CFR by providing the following essential documents, 
including but not limited to: 


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• IRB/EC written approval and any other local approval, as appropriate 
• Original signed Investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 
1572 
• Curriculum vitae for the Investigator and each Sub-Investigator listed on Form 
FDA 1572 
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54.  In addition, 
the Investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB/EC-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the participant or legal guardian, and 
• Laboratory certifications and normal ranges for any local laboratories used by the 
site, in accordance with 42 CFR 493. 
10.4 Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of ICH 
E6 (R2).  The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations.  Study information from this protocol will be 
posted on publicly available clinical trial registers before enrollment of participants begins. 
10.5 Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 (R2) and all applicable guidelines and regulations. 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the Investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in the protocol.  In addition, the Investigator agrees to 
submit annual reports to the study site IRB as appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution; the Investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authority with any reports required. 
10.8 Records Retention 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the 
Investigator agrees to keep records, including the identity of all participants (sufficient 


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information to link records, e.g., eCRFs and hospital records), all original signed ICFs, 
copies of all eCRFs, SAE forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports).  The records should be retained by the Investigator 
according to ICH, local regulations, or as specified in the Clinical Study Agreement, 
whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), the sponsor should be prospectively notified.  
The study records must be transferred to a designee acceptable to the sponsor, such as 
another Investigator, another institution, or to the sponsor.  The Investigator must obtain the 
sponsor's written permission before disposing of any records, even if retention requirements 
have been met. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study treatment.  These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor.  It is the responsibility of the sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal.  In these cases, the sponsor will be 
responsible for these activities and will work with the Investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues.  The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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11 STUDY MANAGEMENT 
11.1 Monitoring 
11.1.1 Monitoring of the Study 
The CRA and/or designee, as a representative of the sponsor, has the obligation to follow the 
study closely.  In doing so, the CRA will visit the Investigator and study site at periodic 
intervals, or conduct central or remote monitoring, in addition to maintaining necessary 
telephone, email and letter contact.  The CRA will maintain current personal knowledge of 
the study through observation, review of study records and source documentation, and 
discussion of the conduct of the study with the Investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.2 Inspection of Records and Quality Assurance 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/EC review, and regulatory inspections by providing direct access to all study 
records.  In the event of an audit or inspection, the Investigator agrees to allow the sponsor, 
representatives of the sponsor, or a regulatory agency (e.g., FDA or other regulatory agency) 
access to all study records. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits, or inspections and that sufficient time is devoted to the 
process. 
The Investigator should promptly notify the sponsor and/or its designee of any inspections 
scheduled by any regulatory authorities and promptly forward copies of any related reports 
received to the sponsor. 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the participant, must be reviewed and approved by the sponsor or its 
designee.  Amendments to the protocol must be submitted in writing to the Investigator’s 
IRB/EC for approval before participant can be enrolled into an amended protocol, and before 
the changes can be implemented. 
11.2.2 Protocol Deviations 
The Investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol.  The Investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
participants without prior IRB/EC approval.  As soon as possible after such an occurrence, 
the implemented deviation or change, the reasons for it, and any proposed protocol 


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amendments should be submitted to the IRB/EC for review and approval, to the sponsor for 
agreement, and to the regulatory authorities, if required. 
A protocol deviation is defined as an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB and agreed to by the 
Investigator.  A major deviation occurs when there is not adherence to the protocol by the 
participant or Investigator that results in a significant, additional risk to the participant.  
Major deviations can include not adhering to inclusion or exclusion criteria, enrollment of the 
participant without prior sponsor approval, or not adhering to FDA regulations or ICH GCP 
guidelines, and may lead to the participant being withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the Clinical Monitor throughout the course of 
monitoring visits.  Investigators will be notified in writing by the monitor of deviations.  The 
IRB/EC should be notified of all protocol deviations in a timely manner. 
11.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last participant completes the final 
end of study assessment. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
CSR is prepared and provided to the regulatory agency as required by the applicable 
regulatory requirement(s).  The sponsor will also ensure that the CSR in marketing 
applications meet the standards of the ICH harmonized tripartite guideline E3: Structure and 
content of CSRs. 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the CSR.  The Investigator will be provided reasonable access 
to statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, the sponsor will provide the Investigator with the full summary 
of the study results.  The Investigator is encouraged to share the summary results with the 
study participants, as appropriate.  The study results will be posted on publicly available 
clinical trial registers. 


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12  REFERENCE LIST 
1. Chan PS, Coupet J, Park HC, Lai F, Hartupee, D, Cervoni P, Dusza JP, Albright JD, 
Ru X, Mazandarani H, Tanikella T, Shepherd C, Ochalski L, Bailey T, Lock YYW, 
Ning X, Taylor JR, Spinelli W. 1998. VPA-985, a nonpeptide orally active and 
selective vasopressin V2 receptor antagonist. Adv Exp Med Biol. 449:439-443. 
2. Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE. 2015. Vasopressin and 
disruption of calcium signaling in polycystic kidney disease. Nat Rev Nephrol. 
11(8):451-464. 
3. Endo M, Katayama K, Matsuo H, et al. 2019. Role of liver transplantation in 
tolvaptan-associated acute liver failure. Kidney Int Rep. 4:1653-57. 
4. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon 
J; DILIN Study Group. 2009. Drug-Induced Liver Injury Network (DILIN) 
prospective study: rationale, design and conduct. Drug Saf. 32(1):55-68. 
5. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek 
JW, Eggers P, Van Lente F, Greene T, Coresh J. 2009. A new equation to estimate 
glomerular filtration rate. Ann Intern Med. 150:604-612. 
6. Woodhead JL, Brock WJ, Roth SE, et al. 2017b. Application of a Mechanistic Model 
to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and 
Identify Patient Susceptibility Factors. Toxicological Sciences 155:61-74. 
7. Woodhead JL, Pellegrini L, Shoda LKM, Howell BA. 2020. Comparison of the 
Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic 
Kidney Disease Using Quantitative Systems Toxicology Modeling. Pharm Res. 
6;37(2):24.  
8. Woodhead JL, Watkins PB, Howell BA, Siler SQ, Shoda LKM. 2017a. The role of 
quantitative systems pharmacology modeling in the prediction and explanation of 
idiosyncratic drug-induced liver injury. Drug Metabolism Pharmacokinetics. 
32(1):40-45. 
 


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13 APPENDICES 
13.1 Appendix 1: Chronic Kidney Disease Classification Criteria 
This study uses the 2009 CKD-EPI creatinine equation (Levey et al, 2009) which is 
recommended by the KDIGO Clinical Practice Guidelines for Management of Chronic 
Kidney Disease. 
The CKD-EPI equation is: 
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 141 ×  𝑚𝑚𝑚𝑚𝑚𝑚൬𝑆𝑆𝑆𝑆𝑆𝑆
κ , 1൰
α
× max ൬𝑆𝑆𝑆𝑆𝑆𝑆
κ , 1൰
−1.209
× 0.993Age × 1.018 (if female) × 1.159 (if black),   
where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females 
and -0.411 for males, age is in years, min indicates the minimum of Scr/κ or 1, and max 
indicates the maximum of Scr/κ or 1. 
 


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13.2 Appendix 2: DILI Network Causality Criteria, modified 
Causality assessment scoring in the Drug-Induced Liver Injury Network (DILIN) prospective 
study, modified (Fontana et al, 2009)  
Causality score 
Likelihood 
(%) 
Description 
1 = definite 
>95 
Liver injury is typical for drug or herbal product 
(‘signature’ or pattern of injury, timing of onset, 
recovery). 
The evidence for causality is “beyond a reasonable 
doubt”. 
2 = highly likely 
75-95 
The evidence for causality is ‘clear and convincing’ but 
not definite. 
3 = probable 
50-74 
The causality is supported by ‘the preponderance of 
evidence’ as implicating the drug but the evidence cannot 
be considered definite or highly likely. 
4 = possible 
25-49 
The causality is not supported by ‘the preponderance of 
evidence’; however, one cannot definitely exclude the 
possibility. 
5 = unlikely 
6-24 
The evidence for causality is ‘highly unlikely’ based 
upon the available information. 
6 = unrelated 
0-5 
An alternate cause was clearly established. 
7 = insufficient data 
Not 
applicable 
Key elements of the drug exposure history, initial 
presentation, alternative diagnoses and/or diagnostic 
evaluation prevent one from determining a causality 
score. 
 
 
 


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13.3 Appendix 3: Additional Potential Hepatic Testing if Liver Chemistry 
Abnormalities Occur 
The medical monitor may request the following additional testing if liver chemistry test 
abnormalities occur: 
• Hematology/coagulation:  
o CBC with Diff  
o International normalized ratio (INR) 
• Clinical chemistry 
o Glutamate dehydrogenase (GLDH) 
• Viral hepatitis serology:  
o Hepatitis A immunoglobulin M (IgM) antibody  
o Hepatitis B surface antigen  
o Hepatitis B core antibody  
o Hepatitis C RNA  
o Hepatitis E IgM antibody (hepatitis E RNA, if available) 
o Epstein-Barr viral capsid antigen IgM antibody 
o Cytomegalovirus IgM antibody 
•  Autoimmune serology:  
o Total serum immunoglobulin G  
o Anti-nuclear antibody  
o Anti-smooth muscle antibody 
• Ultrasound of the liver and gallbladder 
 
 
 


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13.4 Appendix 4: Liver Dysfunction Checklist 
The following items will be included in a checklist to be completed by the HHC for remote 
visits (Part 1 only) and by the site for clinic visits (Part 1 and Part 2) when directed by the 
protocol.  For remote visits where there are findings on Part 1 of the checklist, telehealth will 
be utilized to determine if a clinic visit is needed to complete Part 2.   
 
Part 1 - Symptoms 
Did the participant develop the following symptoms since the last visit? 
 
Symptom 
Fatigue 
Weakness 
Malaise 
Loss of appetite 
Nausea 
Vomiting 
Pain in the right upper part of the abdomen 
Urine darker than usual 
Itching 
Yellowing of skin 
Yellowing of eyes 
Fever 
Rash 
 
Part 2 - Signs 
Did the participant develop the following signs since the last visit? 
 
Sign 
Jaundice 
Ascites 
Rash 
Fever 
Right upper quadrant tenderness or liver 
enlargement 
Encephalopathy 
 
Any symptoms, signs, or an associated diagnosis deemed clinically significant based on 
information entered in Part 1 or Part 2 during either a remote visit or a clinic visit will be 
entered in the eCRF by the site as adverse events. The Investigator will determine whether a 
constellation of symptoms and signs in the context of all available information including 


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laboratory data indicate the potential presence of liver dysfunction.  Otherwise, individual 
symptoms and signs need to be recorded as other AEs or as an alternative diagnosis.  For 
example, fatigue alone may be a non-specific AE with no clear cause.  As another example, 
fatigue, weakness, and vomiting occurring together may indicate a gastroenteritis. Liver 
dysfunction should only be considered when the totality of the evidence makes that a 
plausible diagnosis. 
  
If liver dysfunction is suspected, the Investigator will communicate with the medical monitor 
and additional testing detailed in Section 7.2.7.1 may be recommended.  Those tests are listed 
in Appendix 3 (Section 13.3).  Additionally, the following supplemental information to 
complete the liver dysfunction eCRF will be collected by the site: 
 
• Was there evidence of a concomitant viral illness? 
• Did the participant’s alcohol intake increase since the previous visit?  If so, 
o on what date did it start?;  
o on what date did it end?; 
o what type of alcohol was ingested?; and 
o what was the total daily alcohol intake during this time? 
• Did the participant start any new medications or increase any concomitant 
medications including herbal medications, prescribed medications, or over-the-
counter medications? 
• Was any AE related to liver dysfunction serious? 
• Did any AE related to liver dysfunction result in discontinuation of lixivaptan 
treatment, either temporarily or permanently? 
• What is the participant’s country of birth?  
 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
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Study PA-ADPKD-304:  
Clinical Study Protocol Version 2.0, Dated May 20 2022 
Summary of Changes 
This Summary of Changes document reflects revisions incorporated into Protocol Amendment 1, Version 2.0 of the protocol. It 
should be used in conjunction with the tracked-changes version of the clinical study protocol amendment. Page numbers reported 
herein refer to the tracked-changes version. Revisions in Version 2.0 are shown in Track Changes.  Minor editorial and document 
formatting revisions have not been summarized. 
 
The main reasons for majority of the changes in this amendment are to reduce participant burden. With even longer follow up in 
this roll-over study, relative to the lead-in study, and stable treatment, monitoring can be less intense. 
 
Administrative Changes 
This section lists administrative changes, including changes of names or roles of companies or personnel and/or contact 
information. No changes listed here affect clinical decision making or consent.  
 
Page 
Section 
Version 1.0, Dated 01 September 2021 
Version 2.0; Dated 20 May 2022 
Explanation 
1 
Title Page 
Medical Monitor: 
David Frid, MD 
ICON Clinical Research 
Direct: (215) 616-2504 (including urgent 
medical issues) 
Fax: +1 (215) 699-6288 
Email: David.Frid@iconplc.com  
 
Medical Monitor: 
David FridJoyce Johnsrud, MD 
ICON Clinical Research 
Direct: (215) 616-2504 (including urgent medical 
issues) 
Fax: +1 (215) 699-6288 
Email: 
David.Frid@iconplc.comJoyce.Johnsrud@iconpl
c.com 
Updated contact information 
entered due to change in 
Medical monitor 
 


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Text Clarifications 
This section lists corrections of typos, text changes for consistency or other clarifications. These changes do not affect 
clinical decision- making or consent. 
 
Page 
Section 
Version 1.0, Dated 01 September 2021 
Version 2.0; Dated 20 May 2022 
Explanation 
11 
SYNOPSIS 
 
During the 1-to-2-week Lixivaptan Re-
titration Period, participants whose final 
dose during the Maintenance Period of the 
lead-in study was 100 mg BID will remain on 
that dose for one week and then proceed to 
the Maintenance Treatment Period.  
Participants on doses greater than 100 mg 
BID will be directly titrated to their final dose 
of the lead-in study during a second week in 
the re-titration period (See Table 1).  
Lixivaptan treatment titration and 
assignment will be programmed into the 
Interactive Response Technology (IRT) 
system. 
During the 1-to-2-week Lixivaptan Re-titration 
Period, participants whose final dose during the 
Maintenance Period of the lead-in study was 
100 mg BID or less will remain on that dose for 
one week and then proceed to the Maintenance 
Treatment Period.  Participants on doses greater 
than 100 mg BID will be directly titrated to their 
final dose of the lead-in study during a second 
week in the re-titration period (See Table 1).  
Lixivaptan treatment titration and assignment 
will be programmed into the Interactive 
Response Technology (IRT) system. 
Text revised to reflect that 
final Lixivaptan dose may be 
100 mg BID or less. 
18 
SYNOPSIS 
Table 3 Schedule of 
Procedures 
 
Assessments 
Vital signse 
Body weightf 
Physical examinationg 
Pregnancy test (WOCBP only)h 
Chemistry Blood Samplei 
Assessments 
Vital signseg 
Body weightfh 
Physical examinationgi 
Pregnancy test (WOCBP only)hj 
Chemistry Blood Sampleik 
Footnote numbering has been 
updated to reflect the 
additional footnotes added in 
this amendment in Table 3. 
18 
SYNOPSIS 
Table 3 Schedule of 
Procedures 
 
Screening Perioda 
PA-ADPKD-303 Study Visits 
Screening Perioda 
PA-ADPKD-303 Study Visits 
Deleted 'Visits' from 'PA-
ADPKD-303 Study Visits' 
header to avoid potential 
misunderstanding that V1 
Study visit listed in that 
column is from 'PA-ADPKD-
303 Study. The V1 refers to 
the 'PA-ADPKD-304 Study 


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Explanation 
Visit. 
20 
SYNOPSIS 
Footnotes of Table 3 
Schedule of Procedures 
 
d 
Visits designated as “Laboratory Only” 
may be completed at the clinic or remotely 
by a home healthcare clinician or by a 
designated third-party that will draw and 
process samples for shipment to the central 
laboratory where available and approved.  
Otherwise, the visits will be completed at the 
study clinic.   
d 
Visits designated as “Laboratory Only” 
may be completed at the clinic or remotely by a 
home healthcare clinician or by a designated 
third-party that will draw and process samples 
for shipment to the central laboratory where 
available and approved.  Otherwise, the visits 
will be completed at the study clinic.   
Footnote text revised to 
remove redundant language. 
 
34 
4.2.5 Methods to 
Prevent Loss to Follow-
up 
The Investigator must make every attempt 
to follow-up participants who have 
withdrawn from the study at any time and 
for any reason.  When a participant is “lost 
to follow-up” (i.e., fails to return for study 
visits or complete one or more scheduled 
remote site visits), a reasonable effort (3 
documented phone calls or 2 phone calls and 
2 text messages [if the participant has a 
mobile phone], on separate occasions, and a 
follow-up letter sent by registered mail) 
should be made to contact him/her to 
determine a reason for the failure to return 
or complete remote visit(s).  If the 
participant cannot be reached, he/she 
should be identified as “lost to follow-up” in 
the eCRF. 
The Investigator must make every attempt to 
follow-up participants who have withdrawn 
from the study at any time and for any reason.  
When a participant is “lost to follow-up” (i.e., 
fails to return for study visits or complete one or 
more scheduled remote site visits), a reasonable 
effort (3 documented phone calls or 2 phone 
calls and 2 text messages [if the participant has 
a mobile phone], on separate occasions, and a 
follow-up letter sent by registered mail) should 
be made to contact him/her to determine a 
reason for the failure to return or complete 
remote visit(s).  If the participant cannot be 
reached, he/she should be identified as “lost to 
follow-up” in the eCRF. 
Revised remote site visits to 
remote visits for consistency. 
77 
13.4 Appendix 4: Liver 
Dysfunction Checklist 
The following items will be included in a 
checklist to be completed by the HHC for 
remote visits (Part 1 only) and by the site for 
clinic visits (Part 1 and Part 2) when directed 
by the protocol.  For remote visits where 
there are findings on Part 1 of the checklist, 
telemedicine will be utilized to determine if a 
clinic visit is needed to complete Part 2. 
The following items will be included in a 
checklist to be completed by the HHC for 
remote visits (Part 1 only) and by the site for 
clinic visits (Part 1 and Part 2) when directed by 
the protocol.  For remote visits where there are 
findings on Part 1 of the checklist, 
telehealthmedicine will be utilized to determine 
if a clinic visit is needed to complete Part 2. 
“Telemedicine” replaced with 
“telehealth” usage for 
consistency. 
Multiple 
Global 
In-clinic visit 
In-Clinic visit 
“In-Clinic visit” replaced with 


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Explanation 
‘Clinic visit’ throughout the 
protocol for consistency. 
Multiple 
Global 
home healthcare clinician 
home healthcare clinician HHC 
‘home healthcare clinician’ 
abbreviated to HHC 
throughout the protocol for 
consistency. 
 
Clinically-relevant Changes 
This section describes changes that affect safety or study conduct. 
 
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Rationale 
13  
SYNOPSIS 
Study Period Description 
and Estimated Duration: 
Maintenance Treatment Period: 
Following completion of the Lixivaptan 
Re-titration Period, participants will 
continue into the open-label 
Maintenance Treatment Period 
following completion of Visit 3 
assessments for up to 104 weeks.  
Participants will be assessed at study 
visits scheduled every 12 weeks but will 
have required liver chemistry testing 
every 4 weeks; those visits occurring 
between the 12-week study visits    are 
designated as “laboratory-only visits”.  
Where available and approved, the 
laboratory-only visits may be conducted 
remotely by a home healthcare clinician 
or by a designated third-party that will 
process samples for shipment to the 
central laboratory. In addition, liver 
chemistry tests may be drawn in the 
Maintenance Treatment Period: Following 
completion of the Lixivaptan Re-titration 
Period, participants will continue into the 
open-label Maintenance Treatment Period 
following completion of Visit 3 
assessments for up to 104 weeks.  
Participants will be assessed at study visits 
scheduled every 12 weeks but will have 
required liver chemistry testing every 4 
weeks; those visits occurring between the 
12-week study visits    are designated as 
“laboratory-only visits”.  Where available 
and approved, the laboratory-only visits 
may be conducted remotely by a Hhome 
Hhealthcare Cclinician (HHC) or by a 
designated third-party that will process 
samples for shipment to the central 
laboratory. In addition, liver chemistry 
tests may be drawn in the clinic if that is 
more convenient for the participant.  The 
Categorized V6, V12, V18, and V24 
(Weeks 12, 36, 60, and 84, 
respectively) visits as Clinic or 
Remote Visits (can be performed 
either on-site or remotely by a 
Home Health Clinician (HHC)) to 
reduce participant burden. 


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clinic if that is more convenient for the 
participant. 
12 -week study visits at Weeks 12, 36, 60, 
and 84 can be performed either on-site or 
remotely by an HHC, if available and 
approved. 
18 
SYNOPSIS 
Table 3 Schedule of 
Procedures 
 
Follow-up Period (Up to 4 weeks ± 3 
days) 
Day 8 + 3 days after last dose (V30) 
Day 12 to 24 days after last dose (V31) 
Day 28 ± 3 days after last dose (V32) 
 
Follow-up Period (Up to 4 weeks ± 3 days) 
“Laboratory Only Visitsd”-  
Day 8 + 3 days after last dose (V30) 
Day 12 to 24 days after last dose (V31) 
“Study Visits”-  
Day 28 ± 3 days after last dose (V32) 
Categorized 2 follow-up visits (V30 
and V31) to Laboratory Only Visits 
to reduce participant burden. 
 
Lixivaptan Re-titration Periodb  
 
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V2 
Lixivaptan Re-titration Periodb  
Telehealth Visite  
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V2e 
Categorized V2 visit as a Telehealth 
Visit (with site staff) to reduce 
participant burden.  
Lixivaptan Re-titration Periodb  
 
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V3/Last  
Lixivaptan Re-titration Periodb  
Clinic or Remote Visitf  
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V3/Lastf 
Categorized V3/ Last visit as Clinic 
or Remote Visit (can be performed 
either on-site or remotely by a 
Home Health Clinician (HHC)) to 
reduce participant burden. 
Weeks 12, 24, 36, 48, 60, 72, 84, 96 
Weeks 12f, 24, 36f, 48, 60f, 72, 84f, 96f 
Categorized Weeks 12, 36, 60, 84 
and 96 as Clinic or Remote Visits 
(can be performed either on-site or 
remotely by a Home Health 
Clinician (HHC)) to reduce 
participant burden. 
V6, V9, V12, V15, V18, V21, V24, V27 
V6f, V9, V12f , V15, V18f, V21, V24f, V27f 
Categorized V6, V12, V18, V24 and 
V27 visits as Clinic or Remote Visits 
(can be performed either on-site or 
remotely by a Home Health 


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Rationale 
Clinician (HHC)) to reduce 
participant burden. 
Lixivaptan Re-titration Periodb  
 
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V2 
X (Vital Signse) 
Lixivaptan Re-titration Periodb  
 
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V2e 
X (Vital Signseg) 
The safety assessment (Vital Signs) 
during Visit 2 was removed to 
reduce participant burden. 
Study Visits  
(every 12 weeks ± 5 days) 
 
V9, V15, V21, V27 (Physical Examinationf 
and ECG) 
Study Visits  
(every 12 weeks ± 5 days) 
 
V9, V15, V21, V27 (Physical Examinationfh 
and ECG) 
During the visit 27, physical 
examination and ECG safety 
assessments were removed. 
Assessments made at V21 and V32 
(32 weeks apart) are considered 
sufficient to assess these 
parameters. 
19 
Lixivaptan Re-titration Periodb  
 
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V2 
X (Lixivaptan dispensation) 
Lixivaptan Re-titration Periodb  
 
(1 to 2 weeks ± 3 days) 
(Week -1 to Week 0) 
 
V2e 
X (Lixivaptan dispensation) 
The activity (Lixivaptan 
dispensation) during Visit 2 was 
removed as Visit 2 will now be via 
telehealth visit, the drug dispensed 
at Visit 1 will be sufficient to cover 
the full Lixivaptan Re-titration 
Period.   
 
20 
SYNOPSIS 
Footnotes of Table 3 
Schedule of Procedures 
 
e 
Vital signs after the participant 
has been sitting for 5 minutes include 
sitting heart rate and sitting blood 
pressure. 
f 
Weight will be measured at Visit 
24 (PA-ADPKD-303), Visit 3, Visit 15, 
Visit 29/ET, and Visit 32.  Weight may 
be measured at any other visit to assess 
e 
Visit 2 is a telehealth visit (e.g., 
telemedicine virtual visit, telephone or 
video call (without recording)) with site 
staff. Visit 2 is only applicable to 
participants whose final dose in the lead-
in study was greater than 100 mg BID. At 
telehealth Visit 2, lixivaptan treatment 
compliance will be monitored and 
lixivaptan reconciliation will occur at Visit 
3.  
Footnote text has been updated to 
make consistent with revisions in 
Visit Designations in Table. 
• 
Categorized visit 2 as a 
Telehealth Visit (with site staff) 
to reduce participant burden. 
• 
Categorized V3, V6, V12, V18, 
V24, and V27 visits as Clinic or 


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hydration status as necessary. 
g 
A brief physical examination will 
be performed at Visit 1 (Visit 27 of lead-
in study), Visit 9, Visit 15, Visit 21, Visit 
27, and Visit 32.  A full physical 
examination will be completed at Visit 
29/ET. Additional physical examinations 
will be performed only for assessment 
of signs or symptoms reported by the 
participant that might require further 
evaluation.   
h 
Routine pregnancy testing for 
WOCBP will be performed locally on 
urine. All positive urine results will be 
confirmed by a serum pregnancy test at 
the central lab. 
i 
Chemistry blood samples will be 
collected according to the schedule in 
Table 3: 
• A complete chemistry panel 
includes the following parameters: 
albumin; blood urea nitrogen 
(urea); calcium; chloride; carbon 
dioxide (CO2); creatinine, 
enzymatic; glucose; phosphorous; 
potassium; protein; sodium; uric 
acid.  
• The liver chemistry panel 
includes alkaline phosphatase; ALT; 
AST; bilirubin (total and direct). 
• All serum creatinine 
determinations will be performed 
by the central laboratory.   
 
f 
Study Visits are more extensive 
than laboratory only or telehealth visits. 
Study Visits designated as “Clinic or 
Remote Visits” can be performed either 
on-site or remotely by a Home Health 
Clinician (HHC).  Visits 3, 6, 12, 18, 24 and 
27 are designated as “Clinic or Remote 
Visits”. All other Study Visits are Clinic 
Visits. 
eg 
Vital signs after the participant has 
been sitting for 5 minutes include sitting 
heart rate and sitting blood pressure. 
hf 
Weight will be measured at Visit 24 
(PA-ADPKD-303), Visit 3, Visit 15, Visit 
29/ET, and Visit 32.  Weight may be 
measured at any other visit to assess 
hydration status as necessary. 
gi 
A brief physical examination will be 
performed at Visit 1 (Visit 27 of lead-in 
study), Visit 9, Visit 15, Visit 21, Visit 27, 
and Visit 32.  A full physical examination 
will be completed at Visit 29/ET. 
Additional physical examinations will be 
performed only for assessment of signs or 
symptoms reported by the participant 
that might require further evaluation.   
hj 
Routine pregnancy testing for 
WOCBP will be performed locally on 
urine. All positive urine results will be 
confirmed by a serum pregnancy test at 
the central lab. 
ik 
Chemistry blood samples will be 
collected according to the schedule in 
Table 3: 
• A complete chemistry panel 
includes the following parameters: 
Remote Visits (can be 
performed either on-site or 
remotely by a Home Health 
Clinician (HHC)) to reduce 
participant burden. 
• 
During the visit 27, physical 
examination and ECG safety 
assessments were removed. 
Assessments made at V21 and 
V32 (32 weeks apart) are 
considered sufficient to assess 
these parameters. 
• 
Numbering of subsequent 
footnotes has been updated. 


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albumin; blood urea nitrogen (urea); 
calcium; chloride; carbon dioxide 
(CO2); creatinine, enzymatic; glucose; 
phosphorous; potassium; protein; 
sodium; uric acid.  
• The liver chemistry panel includes 
alkaline phosphatase; ALT; AST; 
bilirubin (total and direct). 
• All serum creatinine 
determinations will be performed by 
the central laboratory.   
 
30 
3.1.2 Detailed Study 
Design 
Maintenance Treatment Period:  
Following completion of the Lixivaptan 
Re-titration Period, participants will 
continue into the open-label 
Maintenance Treatment Period 
following completion of Visit 3 
assessments for up to 104 weeks. 
Participants will be assessed at study 
visits scheduled every 12 weeks with 
assessments but will have required liver 
chemistry testing every 4 weeks at visits 
designated as “laboratory-only visits”. 
Where available and approved, the 
laboratory-only visits may be conducted 
remotely by a home healthcare clinician 
or by a designated third-party that will 
process samples for shipment to the 
central laboratory. In addition, the liver 
chemistry tests may be drawn in the 
clinic if that is more convenient. 
Follow-up Period:  
Three visits will occur over 4 weeks 
Maintenance Treatment Period:  
Following completion of the Lixivaptan 
Re-titration Period, participants will 
continue into the open-label 
Maintenance Treatment Period following 
completion of Visit 3 assessments for up 
to 104 weeks. Participants will be 
assessed at study visits scheduled every 
12 weeks with assessments but will have 
required liver chemistry testing every 4 
weeks at visits designated as “laboratory-
only visits”. Where available and 
approved, the laboratory-only visits may 
be conducted remotely by an HHC home 
healthcare clinician or by a designated 
third-party that will process samples for 
shipment to the central laboratory. In 
addition, the liver chemistry tests may be 
drawn in the clinic if that is more 
convenient.  Furthermore, certain study 
Text modified as some visits are 
now categorized as “Clinic or 
Remote Visits” or as “laboratory 
only” visits to reduce participant 
burden. 


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following the last dose of lixivaptan 
treatment in order to obtain final 
assessments. Starting with the 8th day 
after the last dose of lixivaptan 
treatment, serum creatinine will be 
assessed at 3 time points (no less than 
24 hours apart between each sampling) 
over a period of up to 28 days post last 
dose of lixivaptan.  NOTE: If a 
participant terminates the study early 
(ET), an eGFR determination from 
serum creatinine obtained at 3 time 
points over a period of up to 28 days 
post last dose, will be carried out. 
visits can be performed by an HHC. 
Follow-up Period:  
Three visits will occur over 4 weeks 
following the last dose of lixivaptan 
treatment in order to obtain final 
assessments. Starting with the 8th day 
after the last dose of lixivaptan 
treatment, serum creatinine will be 
assessed at 3 time points (no less than 24 
hours apart between each sampling) over 
a period of up to 28 days post last dose of 
lixivaptan.  Certain follow-up visits are 
designated as laboratory-only visits.  
NOTE: If a participant terminates the 
study early (ET), an eGFR determination 
from serum creatinine obtained at 3 time 
points over a period of up to 28 days post 
last dose, will be carried out. 
36 
5.1.3 Lixivaptan Packaging, 
Labeling, and Storage 
Lixivaptan should be stored at the study 
site in its original packaging in a secure, 
locked area under the responsibility of 
the Investigator or other authorized 
individual.  At the study site, lixivaptan 
should be stored in accordance with the 
specifications detailed in the study 
pharmacy manual.  Once lixivaptan is 
dispensed, the participant should be 
instructed to store it in its original 
packaging and in accordance with 
lixivaptan treatment labelling at all times 
until ready to take. 
Lixivaptan should be stored at the study 
site in its original packaging in a secure, 
locked area under the responsibility of the 
Investigator or other authorized individual. 
At the study site, lixivaptan should be 
stored in accordance with the 
specifications detailed in the study 
pharmacy manual.  Once lixivaptan is 
dispensed, the participant should be 
instructed to store it in its original 
packaging and in accordance with 
lixivaptan treatment labelling at all times 
until ready to take. For study visits 
conducted remotely (not applicable to 
laboratory only visits), study drug will be 
dispensed and shipped from the study site 
to the participant’s home, or to an 
Text has been added to reflect 
Lixivaptan dispensing procedure 
during remote visits; remote visits 
were added to reduce patient 
burden.  


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alternate location pre-specified by the 
participant, via an experienced courier 
approved by the Sponsor.  Participants will 
be provided with written instructions to 
securely store the study drug in its original 
packaging under the conditions described 
above and not to open the package until 
the HHC arrives. 
38 
5.6 Treatment Compliance 
Dispensing of lixivaptan treatment will 
be done initially at Visit 1.  Subsequently, 
dispensing of lixivaptan treatment and 
reconciliation will occur at Visit 2 (if 
applicable) and Visit 3 during the Re-
titration Period and every 12 weeks, at 
in-clinic visits, during the Maintenance 
Treatment Period.   
Dispensing of lixivaptan treatment will be 
done initially at Visit 1.  Subsequently, 
dispensing of lixivaptan treatment and 
reconciliation will occur at Visit 2 (if 
applicable) and Visit 3 during the Re-
titration Period and every 12 weeks, at in-
clinic or direct-to-participants in advance 
of remote visits, during the Maintenance 
Treatment Period.   
Text has been revised to reflect 
Lixivaptan dispensing procedure 
during remote visits to reduce 
participant burden 
42 
6 TIMING OF STUDY 
PROCEDURES  
The timing of study procedures is 
presented in Table 3.  Scheduled 
quarterly visits must occur in the 
Investigator’s clinic while other 
“Laboratory Only” visits at 4-week 
intervals can be completed remotely by 
an HHC or by an approved designated 
third-party. 
The timing of study procedures is 
presented in Table 3.  Scheduled quarterly 
visits (except for Visits 9, 15 and 21) must 
may occur in the Investigator’s clinic or 
remotely with an HHC.  Visits 9, 15 and 21 
must occur in the Investigator’s clinic.  
while oOther “Laboratory Only” visits at 4-
week intervals can be completed remotely 
by an HHC or by an approved designated 
third-party. 
Text has been added to reflect 
remote visits, which have been 
added to reduce participant 
burden. 
42 and 43 
6.1.1. Visit 1/Visit 27 of PA-
ADPKD-303 
o 
If all study entry criteria are met, 
contact the IRT to record the 
participant’s completion of Visit 1 and 
obtain a lixivaptan kit number 
assignment to initiate the Re-titration 
Period and proceed as follows: 
▪ 
Dispense lixivaptan and have 
participant take the first dose 
o 
If all study entry criteria are met, 
contact the IRT to record the 
participant’s completion of Visit 1 and 
obtain a lixivaptan kit number 
assignments to initiate the Re-titration 
Period.  Participants whose final dose 
during PA-ADPKD-303 was ≤100mg BID 
should receive sufficient lixivaptan for a 
Text has been added to reflect 
Lixivaptan dispensing procedure 
during remote visits, which have 
been added to reduce participant 
burden. 


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when he/she returns home from 
the clinic.  Instruct the 
participant to take 2 capsules 
(100 mg) BID approximately 10 
hours apart, e.g., 8 AM and 6 PM. 
(Instruct participants whose final 
dose was 50 mg BID during the 
lead-in study, to take 1 capsule 
[50 mg] BID) 
▪ 
Remind the participant to expect 
aquaretic effects and to maintain 
fluid intake to prevent 
dehydration 
7 + 3-day interval in accordance with 
Table 2.  Participants whose final dose 
during PA-ADPKD-303 was >100mg BID, 
should receive sufficient lixivaptan for a 
14 + 3-day interval, including a dose 
escalation that will begin following 
completion of Visit 2, in accordance 
with Table 2.  P and proceed as follows: 
▪ 
Dispense lixivaptan and have 
participant take the first dose 
when he/she returns home from 
the clinic.  Instruct the participant 
to take 2 capsules (100 mg) BID 
approximately 10 hours apart, e.g., 
8 AM and 6 PM.  (Instruct 
participants whose final dose was 
50 mg BID during the lead-in study, 
to take 1 capsule [50 mg] BID) 
▪ 
Remind the participant to expect 
aquaretic effects and to maintain 
fluid intake to prevent dehydration 
43 
6.2 Re-titration Period 
o 
The Re-titration Period will last from 
1 to 2 weeks.  Participants will self-
administer lixivaptan at home.  
Participants whose final dose during 
the Maintenance Period of the lead-in 
study was ≤100 mg BID will remain on 
that dose for 1 week and then 
proceed to Visit 3.  Participants on 
doses greater than 100 mg BID will be 
directly titrated to their final dose of 
the lead-in study at Visit 2 in the Re-
titration period, in accordance with 
Table 1. 
o 
The Re-titration Period will last from 1 
to 2 weeks.  Participants will self-
administer lixivaptan at home.  
Participants whose final dose during 
the Maintenance Period of the lead-in 
study was ≤100 mg BID will remain on 
that dose for 1 week and then proceed 
to Visit 3.  Participants on doses greater 
than 100 mg BID will be directly titrated 
to their final dose of the lead-in study 
following completion of the telehealth 
visit at Visit 2 in the Re-titration period 
and remain on that dose for 1 week, in 
accordance with Table 1. 
Text has been added to reflect 
Lixivaptan dispensing procedure 
during remote visits, which have 
been added to reduce participant 
burden.  


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 12 of 19 
Page 
Section 
Version 1.0, Dated 01 September 
2021 
Version 2.0; Dated 20 May 2022 
Rationale 
43 
6.2.1.1 Visit 2 
Participants whose final dose at the end 
of the lead-in study was >100 mg BID will 
report to the clinic for Visit 2 of the Re-
titration Period.   
Participants should bring any remaining 
lixivaptan treatment into the clinic. 
The following procedures will be 
performed: 
o 
Check AEs and SAEs 
o 
Assess clinically for liver dysfunction 
(symptoms and signs) in accordance 
with the checklist and instructions in 
Appendix 4 (Section 13.4) 
o 
Collect and review concomitant 
medication information 
o 
Review lixivaptan treatment 
compliance/reconciliation 
o 
Check vital signs (sitting blood 
pressure and heart rate)  
o 
Contact the IRT to record the visit and 
obtain a lixivaptan kit number 
assignment for week 2 of the Re-
titration Period 
o 
Dispense lixivaptan and instruct 
participant on appropriate dose 
based on the dose level guide in Table 
2 
o 
Schedule the participant for Visit 3 to 
occur in 1 week and remind the 
participant to take adequate fluids.  
Provide the participant with an 
appointment reminder card and any 
written instructions. 
Participants whose final dose at the end of 
the lead-in study was >100 mg BID will have 
a telehealth visit report to the clinic for at 
Visit 2 of the Re-titration Period.   
Participants should bring any remaining 
lixivaptan treatment into the clinic. 
The following procedures will be 
performed: 
o 
Check AEs and SAEs 
o 
Assess clinically for liver dysfunction 
(symptoms and signs) in accordance 
with Part 1 of the checklist and 
instructions in Appendix 4 (Section 
13.4) 
o 
Collect and review concomitant 
medication information 
o 
Review lixivaptan treatment 
compliance (capsules to be reconciled 
during Visit 3)/reconciliation 
o 
Check vital signs (sitting blood pressure 
and heart rate)  
o 
Contact the IRT to record the visit and 
obtain a lixivaptan kit number 
assignment for week 2 of the Re-
titration Period 
o 
Dispense lixivaptan and iInstruct the 
participant to increase his/her dose of 
lixivaptan on appropriate dose based 
on the dose level guide in Table 2 
o 
Schedule the participant for Visit 3 to 
occur in 1 week and remind the 
participant to take adequate fluids.  
Provide the participant with an 
Text has been revised to reflect 
Lixivaptan dispensing procedure 
during remote visits, which have 
been added to reduce participant 
burden.  


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 13 of 19 
Page 
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Version 1.0, Dated 01 September 
2021 
Version 2.0; Dated 20 May 2022 
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appointment reminder card and any 
written instructions. 
44 
6.2.1.2 Visit 3/Last Titration 
Visit 
Participants will report to the clinic for 
assessments for the last visit of the Re-
titration Period.  Dosing will continue for 
the remainder of the study at the level the 
participant was receiving at the end of the 
Maintenance Period of the lead-in study. 
If there is difficulty with tolerability, the 
dose may be temporarily reduced, 
participant may then enter the 
Maintenance Treatment Period and the 
dose will be readdressed at the next clinic 
visit (Visit 6).  Dosing reductions for 
participants on Level 2 (100 mg BID or 
less) will require prior approval from the 
medical monitor. 
Participants should bring any remaining 
lixivaptan treatment into the clinic. 
Participants will either report to the clinic or 
have a remote visit by an HHC for 
assessments for the last visit of the Re-
titration Period.  Dosing will continue for 
the remainder of the study at the level the 
participant was receiving at the end of the 
Maintenance Period of the lead-in study. 
If there is difficulty with tolerability, the 
dose may be temporarily reduced, 
participant may then enter the 
Maintenance Treatment Period and the 
dose will be readdressed at the next clinic 
visit (Visit 6).  Dosing reductions for 
participants on Level 2 (100 mg BID or less) 
will require prior approval from the medical 
monitor. 
Participants should bring any remaining 
lixivaptan treatment into the clinic if having 
a site visit. If the visit is a remote visit, 
participant should give any remaining 
lixivaptan to the HHC. 
Revised this section to indicate that 
V3 is a remote visit, which have 
been added to reduce participant 
burden.  
45 
6.3 Maintenance Treatment 
Period 
The Maintenance Treatment Period will 
last 104 weeks (Visit 4 to Visit 29).  Visits 
designated as “laboratory only” may be 
completed at the clinic or conducted 
remotely by an HHC or by a designated 
third-party who will draw and process 
samples for shipment to the central 
laboratory where available and approved. 
Laboratory only visits include Visits 4, 5, 7, 
8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 
The Maintenance Treatment Period will last 
104 weeks (Visit 4 to Visit 29).  Visits 
designated as “laboratory only” may be 
completed at the clinic or conducted 
remotely by an HHC or by a designated 
third-party who will draw and process 
samples for shipment to the central 
laboratory where available and approved.  
Laboratory only visits include Visits 4, 5, 7, 
8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 
26, and 28.  The remaining Vvisits 9, 15, 21 
Revised to indicate that V6, V12, 
V18, V24 and V27 are now 
designated as Remote visits, which 
have been added to reduce 
participant burden.  


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 14 of 19 
Page 
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Version 1.0, Dated 01 September 
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26, and 28.  The remaining visits will be 
completed at the study clinic. 
and 29 will be completed at the study 
clinic., while the remaining visits designated 
as “clinic or remote visits” (Visits 6, 12, 18, 
24 and 27) may be performed either on-site 
or remotely by an HHC. 
45 
6.3.1 Visits 4 to 28   
In-clinic study visits will occur every 12 
weeks ± 5 days.  Laboratory only visits will 
occur every 4 weeks ± 5 days on weeks 
when there is not an in-clinic visit. 
In-clinic sStudy visits will occur every 12 
weeks ± 5 days.  Laboratory only visits will 
occur every 4 weeks ± 5 days on weeks 
when there is not an in-clinic or remote 
visit. 
Clarification text added to indicate 
visits that are now designated as 
Clinic or Remote visits, which have 
been added to reduce participant 
burden. 
45 
6.3.1 Visits 4 to 28   
6.3.1.2 Visits 6, 9, 12, 15, 18, 21, 24, and 
27/In-clinic visits  
6.3.1.23 Visits 6, 9, 12, 15, 18,and  21, 24, 
and 27/ In-Cclinic Vvisits 
The visits 6, 12, 18, 24 and 27 are 
now categorized as Remote Visits 
(can be performed either on-site or 
remotely by a Home Health 
Clinician (HHC)) to reduce 
participant burden. Converted the 
clinic visits as Section 6.3.1.3 and 
added the Remote visits as Section 
6.3.1.2. 
45 
6.3.1.2 Visits 6, 9, 12, 18, 21, 
and 24/Remote visits   
6.3.1.2 Visits 6, 12, 18, 24, and 27/Clinic or 
Remote Visits   
Visits 6, 12, 18, 24 and 27 can be performed 
either on-site or remotely by an HHC. 
The following procedures will be performed 
at each clinic or remote visit: 
• 
Check AEs and SAEs 
• 
Assess liver dysfunction (signs and 
symptoms at clinic visits (Part 1 
and Part 2 of the checklist); 
symptoms only at remote visits 
(Part 1 of the checklist)) in 
Added Remote Visits as Section 
6.3.1.2 to distinguish the clinic and 
remote visits and list of procedures 
added.  
Removed safety assessments 
during V9 and V21 to reduce 
patient burden; safety assessments 
obtained at a maximum time 
period of every 24-32 months are 
considered sufficient to monitor 
those safety parameters  


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 15 of 19 
Page 
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accordance with  instructions in 
Appendix 4 (Section 13.4) 
• 
Collect and review concomitant 
medication information 
• 
Review lixivaptan treatment 
compliance/reconciliation 
• 
Check vital signs (sitting blood 
pressure and heart rate)  
• 
Collect urine to conduct a 
pregnancy test in WOCBP 
• 
Collect blood samples for  
o 
Complete chemistry panel 
o 
Liver chemistry panel 
• 
Contact the IRT at each visit to 
obtain lixivaptan kit number 
assignments and complete the visit 
• 
Dispense 12-week supply of 
lixivaptan and instruct participant 
to take the appropriate dose BID 
approximately 10 hours apart, e.g., 
8 AM and 6 PM 
• 
Schedule the participant to return 
in 4 weeks for his/her next 
laboratory visit (if not already 
scheduled); confirm where the visit 
will take place.  Also, schedule 
participant for the next clinic or 
remote visit in 12 weeks.  At each 
visit, remind the participant to take 
adequate fluids.  Provide the 
participant with an appointment 
reminder card(s) and any written 
instructions.  Note: Visit 29 should 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 16 of 19 
Page 
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Version 1.0, Dated 01 September 
2021 
Version 2.0; Dated 20 May 2022 
Rationale 
be scheduled approximately 8 
weeks from Visit 27.  Dosing 
instructions should be tailored 
accordingly. 
46 
6.3.1.2 Visits 6, 9, 12, 15, 18, 
21, 24, and 27/In-clinic visits 
Section 6.3.1.2  Visits 6, 9, 12, 15, 18, 21, 
24, and 27/In-clinic visits 
Participants should bring any remaining 
lixivaptan treatment into the clinic. 
The following procedures will be 
performed at each in-clinic visit: 
• 
Check AEs and SAEs 
• 
Assess clinically for liver 
dysfunction (symptoms) in 
accordance with the checklist 
and instructions in Appendix 4 
(Section 13.4) 
• 
Collect and review concomitant 
medication information 
• 
Review lixivaptan treatment 
compliance/reconciliation 
• 
Check vital signs (sitting blood 
pressure and heart rate)  
• 
Collect body weight (Visit 15 
only) 
• 
Perform a brief physical 
examination (Visits 9, 15, 21, and 
27 only) 
• 
Perform a 12-lead ECG (Visits 9, 
15, 21, and 27 only) 
• 
Collect urine to conduct a 
pregnancy test in WOCBP 
Section 6.3.1.32  Visits 6, 9, 12, 15, 18,and  
21, 24, and 27/In-Cclinic Vvisits 
Participants should bring any remaining 
lixivaptan treatment into the clinic. 
The following procedures will be performed 
at each in-clinic visit: 
• 
Check AEs and SAEs 
• 
Assess clinically for liver 
dysfunction (symptoms) in 
accordance with the checklist and 
instructions in Appendix 4 (Section 
13.4) 
• 
Collect and review concomitant 
medication information 
• 
Review lixivaptan treatment 
compliance/reconciliation 
• 
Check vital signs (sitting blood 
pressure and heart rate)  
• 
Collect body weight (Visit 15 only) 
• 
Perform a brief physical 
examination (Visits 9, 15, 21, and 
27 only) 
• 
Perform a 12-lead ECG (Visits 9, 15, 
21, and 27 only) 
• 
Collect urine to conduct a 
pregnancy test in WOCBP 
Revised Section 6.3.1.2 as 6.3.1.3 
to distinguish clinic visits (V9, V15 
and V21) from remote visits (V6, 
V12, V18, V24 and V27 visits) and 
revised list of procedures. Remote 
visits have been introduced to 
reduce patient burden. 
 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 17 of 19 
Page 
Section 
Version 1.0, Dated 01 September 
2021 
Version 2.0; Dated 20 May 2022 
Rationale 
• 
Collect urine for urinalysis (Visit 
15 only) 
• 
Collect blood samples for  
o 
Complete chemistry 
panel  
o 
Liver chemistry panel 
o 
Hematology (Visits 9, 15 
and 21 only) 
• 
Dispense 12-week supply of 
lixivaptan and instruct participant 
to take the appropriate dose BID 
approximately 10 hours apart, 
e.g., 8 AM and 6 PM 
• 
Schedule the participant to 
return in 4 weeks for his/her next 
laboratory visit (if not already 
scheduled); confirm where the 
visit will take place.  Also, 
schedule participant for the next 
in-clinic visit in 12 weeks.  At 
each visit, remind the participant 
to take adequate fluids.  Provide 
the participant with an 
appointment reminder card(s) 
and any written instructions. 
• 
Collect urine for urinalysis (Visit 15 
only) 
• 
Collect blood samples for  
o 
Complete chemistry panel 
o 
Liver chemistry panel 
o 
Hematology (Visits 9, 15 
and 21 only) 
• 
Contact the IRT at each visit to 
obtain lixivaptan kit number 
assignments and complete the visit 
• 
Dispense 12-week supply of 
lixivaptan and instruct participant 
to take the appropriate dose BID 
approximately 10 hours apart, e.g., 
8 AM and 6 PM 
• 
Schedule the participant to return 
in 4 weeks for his/her next 
laboratory visit (if not already 
scheduled); confirm where the visit 
will take place.  Also, schedule 
participant for the next in-clinic or 
remote visit in 12 weeks.  At each 
visit, remind the participant to take 
adequate fluids.  Provide the 
participant with an appointment 
reminder card(s) and any written 
instructions. 
47 
6.4 Follow-up Period  
The Follow-up Period will last 28 days and 
include 3 visits (Visit 30, Visit 31, and Visit 
32).  
The Follow-up Period will last 28 days and 
include 3 visits (Visit 30, Visit 31, and Visit 
32). Visits 30 and 31 are designated as 
“laboratory only visits” and may be 
completed at the clinic or conducted 
remotely by an HHC or by a designated 
third-party who will draw and process 
Updated this section to indicate 
that Visit 30 and 31 are Laboratory 
Only Visit; these Laboratory Only 
visits will reduce patient burden. 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 18 of 19 
Page 
Section 
Version 1.0, Dated 01 September 
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Version 2.0; Dated 20 May 2022 
Rationale 
samples for shipment to the central 
laboratory where available and approved. 
47 
6.4.1 Visit 30 
The following procedures will be 
performed at Visit 30: 
• 
Check AEs and SAEs 
• 
Assess clinically for liver 
dysfunction (symptoms and 
signs) in accordance with the 
checklist and instructions in 
Appendix 4 (Section 13.4) 
• 
Collect and review concomitant 
medication information 
• 
Collect a blood sample for serum 
creatinine 
Schedule the participant to return to the 
clinic for Visit 31, in 12 to 24 (± 3) days 
after the last dose of lixivaptan treatment. 
The following procedures will be performed 
at Visit 30 (“laboratory only” visit): 
• 
Check AEs and SAEs 
• 
Assess clinically for liver 
dysfunction (symptoms and signs) 
in accordance with the checklist 
and instructions in Appendix 4 
(Section 13.4) 
• 
Collect and review concomitant 
medication information 
• 
Collect a blood sample for serum 
creatinine 
• 
Site personnel to contact the IRT to 
register visit 
• 
Schedule the participant for the 
next visit to return to the clinic for 
(Visit 31) to occur , in 12 to 24 (± 3) 
days after the last dose of 
lixivaptan treatment. 
Updated this section to indicate 
that Visit 30 is Laboratory Only 
Visit. This Laboratory Only visit will 
reduce patient burden. 
Revised the list of procedures and 
added IRT information to align with 
“laboratory only procedures” 
48 
6.4.2 Visit 31 
The following procedures will be 
performed at Visit 31: 
• 
Check AEs and SAEs 
• 
Assess clinically for liver 
dysfunction (symptoms and 
signs) in accordance with the 
checklist and instructions in 
Appendix 4 (Section 13.4) 
• 
Collect and review concomitant 
medication information 
The following procedures will be performed 
at Visit 31 (“laboratory only” visit): 
• 
Check AEs and SAEs 
• 
Assess clinically for liver 
dysfunction (symptoms and signs) 
in accordance with the checklist 
and instructions in Appendix 4 
(Section 13.4) 
• 
Collect and review concomitant 
medication information 
Updated this section to indicate 
that Visit 31 is Laboratory Only 
Visit. This Laboratory Only visit will 
reduce patient burden. 
Revised the list of procedures and 
added IRT information to align with 
“laboratory only procedures” 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 20 May 2022 
Palladio Biosciences 
 
PA-ADPKD-304 
 
20-MAY-2022 
Confidential Information 
Page 19 of 19 
Page 
Section 
Version 1.0, Dated 01 September 
2021 
Version 2.0; Dated 20 May 2022 
Rationale 
• 
Collect a blood sample for serum 
creatinine 
Schedule the participant to return to the 
clinic for Visit 32, in 28 (± 3) days after the 
last dose of lixivaptan treatment. 
• 
Collect a blood sample for serum 
creatinine 
• 
Site personnel to contact the IRT to 
register visit 
• 
Schedule the participant to return 
to the clinic for Visit 32 to occur, in 
28 (± 3) days after the last dose of 
lixivaptan treatment. 
 

SAP_001.pdf: 
Study Title: PA-ADPKD-304: A Phase 3, Open-label, Roll-over Study to Assess Long-term 
Safety of Lixivaptan in Participants With Autosomal Dominant Polycystic Kidney Disease 
Who Completed Study PA-ADPKD-303: The ALERT Study 
 
ClinicalTrials.gov ID: NCT05208866 
 
 
 
Statistical Analysis Plan Version 2.0, dated 24-Sep-2022 
 
Note: a summary of changes implemented from Version 1.0 (dated 03-Aug-2022) is provided in 
the Revision History.   


 
 
 Page 1 of 17 
 
   Statistical Analysis Plan 
Title 
Statistical Analysis Plan 
Protocol Title: 
A Phase 3, Open-label, Roll-over Study to Assess Long-term 
Safety of Lixivaptan in Participants with Autosomal Dominant 
Polycystic Kidney Disease Who Completed Study PA-ADPKD-
303: The ALERT Study 
Protocol Number: 
PA-ADPKD-304 
Sponsor: 
Palladio Biosciences, Inc 
Document Version: 
Final Version 2.0 
Document Date:  
24-September-2022 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality: Information contained in this document is the property of Palladio Biosciences, 
Inc and is confidential. The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons without written 
authorization from Palladio Biosciences, Inc. 
 
 
DocuSign Envelope ID: 2053D060-C99F-46FE-9F9A-84F5EDF8DD4C


 
Statistical Analysis Plan,  
 
Palladio Biosciences  
 
Protocol Number PA-ADPKD-304 
 
 Page 2 of 17 
Approvals 
Role 
Signatures 
Biostatistician 
 
Genzhou Liu, PhD 
Head of Biometrics 
and Data 
Management 
Print Name: Genzhou Liu, PhD 
Sign Name: 
 
 
 
 
 
Clinical 
Representative 
 
Neil H. 
Shusterman, MD 
Chief Medical 
Officer 
Print Name: Neil H. Shusterman, MD 
Sign Name: 
 
 
 
 
 
 
 
DocuSign Envelope ID: 2053D060-C99F-46FE-9F9A-84F5EDF8DD4C
9/24/2022
9/25/2022


 
Statistical Analysis Plan,  
 
Palladio Biosciences  
 
Protocol Number PA-ADPKD-304 
 
 Page 3 of 17 
Revision History 
 
 
Version/Date 
Version name 
Section 
Changes implemented 
Version 1.0/03Aug2022 Final V1.0 
NA 
NA 
Version 2.0/24Sep2022 
Final V2.0 
7.2 
Added the section for potentially 
clinically Important criteria for 
laboratory values, vital signs, and 
electrocardiograms. 
DocuSign Envelope ID: 2053D060-C99F-46FE-9F9A-84F5EDF8DD4C


 
Statistical Analysis Plan,  
 
Palladio Biosciences  
 
Protocol Number PA-ADPKD-304 
 
 Page 4 of 17 
List of Abbreviations 
Abbreviation 
Definition 
ADPKD 
autosomal dominant polycystic kidney disease  
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
CSR 
clinical study report 
ECG 
electrocardiogram 
eDISH 
evaluation of drug-induced serious hepatotoxicity 
eGFR 
estimated glomerular filtration rate 
EoT 
end of treatment 
ET 
early termination 
HERC 
hepatic events review committee 
HHC 
home healthcare clinician 
ICF 
informed consent form 
IRT 
interactive response technology 
SAP 
statistical analysis plan 
TFLs 
tables, figures and listings 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
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Statistical Analysis Plan,  
 
Palladio Biosciences  
 
Protocol Number PA-ADPKD-304 
 
 Page 5 of 17 
Table of Contents 
Approvals ........................................................................................................................................ 2 
Revision History ............................................................................................................................. 3 
List of Abbreviations ...................................................................................................................... 4 
Table of Contents ............................................................................................................................ 5 
1. 
Introduction ......................................................................................................................... 6 
2. 
Study Objectives ................................................................................................................. 6 
2.1. 
Primary Objective ......................................................................................................... 6 
2.2. 
Secondary Objectives.................................................................................................... 6 
3. 
Study Design ....................................................................................................................... 6 
3.1. 
General Study Design ................................................................................................... 6 
3.2. 
Randomization and Blinding ........................................................................................ 7 
3.3. 
Study Treatments and Assessment................................................................................ 7 
4. 
Study Endpoints ................................................................................................................ 12 
4.1. 
Primary Endpoint ........................................................................................................ 12 
4.2. 
Secondary Endpoints .................................................................................................. 12 
5. 
Sample Size and Power ..................................................................................................... 12 
6. 
Analysis Populations ......................................................................................................... 12 
6.1. 
Enrolled Population .................................................................................................... 12 
6.2. 
Safety Population ........................................................................................................ 13 
6.3. 
Efficacy Population ..................................................................................................... 13 
7. 
Statistical Considerations and Analyses ........................................................................... 13 
7.1. 
Planned Analyses ........................................................................................................ 13 
7.2. 
Potentially Clinically Important Results of Laboratory Values, Vital signs and 
Electrocardiograms ..................................................................................................... 14 
7.3. 
Study Early Termination and Data Presentations ....................................................... 16 
 
 
 
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Statistical Analysis Plan,  
 
Palladio Biosciences  
 
Protocol Number PA-ADPKD-304 
 
 Page 6 of 17 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol PA-ADPKD-304 
Version 2.0 “A Phase 3, Open-label, Roll-over Study to Assess Long-term Safety of Lixivaptan 
in Participants with Autosomal Dominant Polycystic Kidney Disease Who Completed Study PA-
ADPKD-303: The ALERT Study” dated 20May2020 for final analysis. 
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
All data analyses and generation of TFLs will be performed using SAS version 9.4® or higher. 
2. 
Study Objectives 
2.1. 
Primary Objective 
To assess the hepatic safety of lixivaptan with continued dosing. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
 To characterize the non-hepatic safety and tolerability of lixivaptan 
 To assess renal function (efficacy) in participants while on lixivaptan using change in 
estimated glomerular filtration rate (eGFR). 
3. 
Study Design 
3.1. 
General Study Design 
This is a Phase 3, open-label roll-over study to demonstrate the continued hepatic and non-
hepatic safety and renal efficacy of lixivaptan in patients with ADPKD who previously 
experienced abnormal liver chemistry test results while treated with tolvaptan that resulted in 
permanent discontinuation of tolvaptan for that reason and subsequently completed study PA-
ADPKD-303, the open-label lead in study with lixivaptan. Up to 50 participants can be enrolled 
and treated with lixivaptan in study PA-ADPKD-303. All participants completing the lead-in 
study and meeting eligibility criteria for this roll-over study will be able to enroll. It is estimated 
that approximately up to 40 participants will enroll in this study, assuming 90% of participants 
complete study PA-ADPKD-303 and 90% meet eligibility and elect to enroll. 
There will be a Screening, Re-titration, Maintenance, and Follow-up Period. The Screening 
Period will be 4 weeks in duration. Assessments completed during the final 4 visits (Visits 24, 
25, 26, and 27) of study PA-ADPKD-303 will serve as the screening and baseline assessments 
for this roll-over study. Visit 27 of the lead-in study will be used as Visit 1 of this roll-over 
study. Safety assessments performed during Visits 24, 25, 26 and 27 of the lead-in study will 
also be used for assessment of eligibility and will constitute the baseline values for this study. 
The mean of the eGFR values obtained at Visits 25, 26, and 27 of the lead-in study will be used 
to determine the baseline eGFR value for this study. Evaluation of eligibility will be completed 
at Visit 1 of this study, following signing of the informed consent form (ICF). Participants 
satisfying all study entry criteria at Visit 1 will be considered enrolled following completion of 
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Statistical Analysis Plan,  
 
Palladio Biosciences  
 
Protocol Number PA-ADPKD-304 
 
 Page 7 of 17 
all Visit 1 study procedures and will be dispensed lixivaptan treatment to start the Lixivaptan Re-
titration Period. 
The Re-titration Period will be 1 to 2 weeks. However, Investigators have the flexibility to 
increase the 2-week period if re-titration needs to go slower or a dose reduction is needed for 
tolerability or safety reasons. During the 1-to-2-week Lixivaptan Re-titration Period, participants 
whose final dose during the Maintenance Period of the lead-in study was 100 mg BID will 
remain on that dose for one week, complete Visit 3 assessments, and then proceed to the 
Maintenance Treatment Period of the current study with no further up-titration. (Note: Eligible 
participants who completed the lead-in study on 50 mg BID may continue on that dose in this 
study. Those participants will undergo a one-week re-titration, complete Visit 3 assessments and 
then proceed to the PA-ADPKD-304 Maintenance Treatment Period). Participants on doses 
greater than 100 mg BID at the end of the Maintenance Period of study PA-ADPKD-303 will be 
directly titrated to their final dose of the lead-in study during the second week of the Re-titration 
Period. Following re-titration, participants will enter the Maintenance Treatment Period. 
Lixivaptan treatment titration and assignment will be programmed into the Interactive Response 
Technology (IRT) system. 
Participants will then continue on lixivaptan treatment for up to 104 weeks during the 
Maintenance Treatment Period and will be assessed at a study visit every 12 weeks where study 
procedures will include clinical laboratory determinations, including liver chemistry tests. In 
between quarterly study visits, participants will be required to have blood drawn for liver 
chemistry determinations every 4 weeks. Where available and approved, visits designated as 
“laboratory only” may be conducted remotely by a home healthcare clinician (HHC) or by a 
designated third-party that will process samples for shipment to the central laboratory. Liver 
chemistry tests may also be drawn at the clinic if that is convenient. 
At the end of 104 weeks, lixivaptan treatment will be stopped, and participants will enter the 
Follow-up Period during which final assessments of safety and efficacy will be obtained over 3 
visits starting on the 8th day following the last dose of lixivaptan treatment and continuing 
through the 28th day. 
3.2. 
Randomization and Blinding 
The study will not be randomized and will be an open-label study. 
3.3. 
Study Treatments and Assessment 
The investigational product, lixivaptan capsule, is formulated as a white hard gelatin capsule 
with a clear band (without markings) containing 50 mg of lixivaptan. 
The study drug (lixivaptan capsule) is intended to be taken orally, i.e., to be swallowed whole 
with water. The capsule should NOT be opened. 
During all treatment periods, study drug will be administered BID, with the PM dose 
administered approximately 10 hours after the AM dose. During the Lixivaptan Re-titration 
Period, lixivaptan will be started at 100 mg BID for 1 week followed by the final dose taken at 
the end of the Maintenance Period for another week to access lixivaptan tolerability. Participants 
whose final dose was 100 mg BID or less in study PA-ADPKD-303, will proceed directly to 
Visit 3 following one week of re-titration. 
Subjects who tolerate their optimized dose will then enter the Maintenance Period during which 
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time they will continue at the lixivaptan dose level achieved at the end of the Titration Period. 
During the Maintenance Period, the dose may be adjusted downward at the Investigator’s 
discretion if needed to manage non-hepatic side effects and may also be increased back to the 
dose achieved at the end of the Titration Period. The Investigator may instruct the subject to hold 
the study drug for up to 7 days, if necessary, to manage acute intercurrent illness, tolerability 
issues, surgical procedures or life situations, e.g., airplane travel, etc. Additionally, subjects who 
have a longer interruption due to illness, including COVID-19, or other reasons may be able to 
re-start study drug when medically stable after discussion with the medical monitor and sponsor. 
Temporary or permanent study drug discontinuation for management of abnormal liver 
chemistry test results is allowed. 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in Table 1. 
 
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Table 1. Schedule of Procedures 
Assessment 
Screening Perioda 
Lixivaptan 
Re-titration Periodb 
Maintenance Treatment Period 
Follow-up 
Periodc 
 
(4 weeks + days) 
 
Telehealth 
Visite 
Clinic or 
Remote 
Visitf 
Laboratory Only 
Visitsd 
(every 4 weeks ± 5 
days) 
Study Visits 
(every 12 weeks 
± 5 days) 
EoT/ ET 
Visit  
(Week 104 
± 5 Days) 
Laboratory 
Only 
Visitsd 
Study 
Visits 
(1 to 2 weeks  
days) 
(104 weeks ± 3 days) 
(Up to 4 weeks ± 3 
days) 
Study Week 
(Week -6 to Week -2) 
(Week -1 to Week 0) 
Weeks 4, 8, 16, 20, 
28, 32, 40, 44, 52, 56, 
64, 68, 76, 80, 88, 92, 
100 
Weeks 12f, 24, 
36f, 48, 60f, 72, 
84f, 96f  
Week 104 
Day 8 
+ 3 
days 
after 
last 
dose 
Day 
12 to 
24 
days 
after 
last 
dose 
Day 28 
± 3 
days 
after 
last 
dose 
PA-ADPKD-303 
Study 
Visit Number  
V24 V25 
V26 
V27/  
[V1]a 
(V2e) 
V3/ Lastf 
V4, V5, V7, V8, V10, 
V11, V13, V14, V16, 
V17, V19, V20, V22, 
V23, V25, V26, V28 
V6f, V9, V12f, 
V15, V18f, V21, 
V24f, V27f 
V29/ET 
V30 
V31 
V32 
Informed consent 
 
 
 
[X] 
 
 
 
 
 
 
 
 
Review eligibility 
(Inclusion/Exclusion) 
 
 
 
[X] 
 
 
 
 
 
 
 
 
Vital signsg 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Body weighth 
X 
 
 
 
 
X 
 
V15 
X 
 
 
X 
Physical examinationi 
X 
 
 
X 
 
 
 
V9, V15,  
V21  
X 
 
 
X 
ECG 
X 
 
 
X 
 
 
 
V9, V15,  
V21 
X 
 
 
X 
Pregnancy test (WOCBP only)j 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
X 
 
 
 
V15 
X 
 
 
X 
Hematology 
X 
 
 
X 
 
X 
 
V9, V15, V21 
X 
 
 
 
Chemistry Blood Samplek 
X 
 
 
X 
 
 
 
 
 
 
 
 
Complete Chemistry Panel 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
Liver Chemistry Panel 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
X 
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Assessment 
Screening Perioda 
Lixivaptan 
Re-titration Periodb 
Maintenance Treatment Period 
Follow-up 
Periodc 
 
(4 weeks + days) 
 
Telehealth 
Visite 
Clinic or 
Remote 
Visitf 
Laboratory Only 
Visitsd 
(every 4 weeks ± 5 
days) 
Study Visits 
(every 12 weeks 
± 5 days) 
EoT/ ET 
Visit  
(Week 104 
± 5 Days) 
Laboratory 
Only 
Visitsd 
Study 
Visits 
(1 to 2 weeks  
days) 
(104 weeks ± 3 days) 
(Up to 4 weeks ± 3 
days) 
Study Week 
(Week -6 to Week -2) 
(Week -1 to Week 0) 
Weeks 4, 8, 16, 20, 
28, 32, 40, 44, 52, 56, 
64, 68, 76, 80, 88, 92, 
100 
Weeks 12f, 24, 
36f, 48, 60f, 72, 
84f, 96f  
Week 104 
Day 8 
+ 3 
days 
after 
last 
dose 
Day 
12 to 
24 
days 
after 
last 
dose 
Day 28 
± 3 
days 
after 
last 
dose 
PA-ADPKD-303 
Study 
Visit Number  
V24 V25 
V26 
V27/  
[V1]a 
(V2e) 
V3/ Lastf 
V4, V5, V7, V8, V10, 
V11, V13, V14, V16, 
V17, V19, V20, V22, 
V23, V25, V26, V28 
V6f, V9, V12f, 
V15, V18f, V21, 
V24f, V27f 
V29/ET 
V30 
V31 
V32 
Serum Creatinine 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Lixivaptan dispensation 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Lixivaptan compliance and 
reconciliation 
 
 
 
 
X 
X 
 
X 
X 
 
 
 
IRT entry 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
Adverse events 
<---------------------> <---------------------------------------------------------------------------------------------------------------------------------------> 
Assess for liver dysfunction 
<---------------------> 
 
<------------------------------------------------------------------------------------------------------------------------> 
Prior and concomitant 
medications 
<---------------------> <--------------------------------------------------------------------------------------------------------------------------------------> 
ECG = electrocardiogram; EoT = End of treatment; ET = Early termination visit; IRT = interactive response technology system; Last = Last re-titration visit; V = Visit; 
WOCBP = women of childbearing potential  
   Shaded assessments (Visit 24, Visit 25, Visit 26) denote PA-ADPKD-303 assessments that will not be included as part of screening and/or baseline values for study PA-
ADPKD-304 ;[ ] = denotes assessment not part of PA-ADPKD-303 Follow-up Period V27; ( ) = Not all participants will need these visits. 
a Results from assessments completed during the final 4 visits (Visits 24, 25, 26, and 27) of the lead-in study, PA-ADPKD-303 will serve as the Screening/baseline 
values for this study.  Clinical laboratory assessments completed at Visit 24 of the lead-in study will be used for assessment of eligibility criteria at Visit 1 of this study 
with the exception of eGFR, which will be determined from the Visit 26 results. Results for other safety assessments including vital signs, pregnancy testing, physical 
examination and ECG needed for evaluation of eligibility for study PA-ADPKD-304 will be those assessed at Visit 27. 
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b Participants who meet all eligibility criteria for enrollment at Visit 1 will be assigned lixivaptan at a dose of 100 mg BID for 1 week to start the re-titration period. At 
Visit 2, the dose of lixivaptan will be increased from 100 mg BID to the final dose taken at the end of the PA-ADPKD-303 Maintenance Period for those participants 
whose final dose at the end of the lead-in study was greater than 100 mg BID.  Participants will continue on the escalated dose for one week before entering the 
Maintenance Treatment Period.  Participants whose final dose in the lead-in study was 100 mg BID (or lower in exceptional cases), will skip Visit 2 and proceed 
directly to Visit 3/Last Titration Visit and undergo the assessments scheduled for that visit. Dosing will continue for the remainder of the study at this level.  However, 
if there is difficulty with tolerability, the dose may be temporarily reduced.  Dosing reductions for participants on Level 2 (100 mg BID) require prior approval from the 
medical monitor.   
c   During the Follow-up Period, 3 visits will occur to obtain the 3 serum creatinine values for calculation of eGFR.  The first visit (V30) will occur on the 8th day 
(+3 days) after the last dose of lixivaptan treatment and the last visit (V32) will occur on the 28th day (±3 days) after the last dose of lixivaptan treatment.  V31 must be 
scheduled a minimum of 24 hours apart from either V30 or V32 and should occur 12 to 24 days after the last dose of lixivaptan.  At the final visit (V32), additional 
safety and efficacy assessments will be completed as denoted in Table 1. 
d Visits designated as “Laboratory Only” may be completed at the clinic or remotely by a home healthcare clinician or by a designated third-party that will draw and 
process samples for shipment to the central laboratory where available and approved.   
e Visit 2 is a telehealth visit (e.g., telemedicine virtual visit, telephone, or video call (without recording)) with site staff. Visit 2 is only applicable to participants whose 
final dose in the lead-in study was greater than 100 mg BID.  At telehealth Visit 2, lixivaptan treatment compliance will be monitored and lixivaptan reconciliation will 
occur at Visit 3. 
f Study Visits are more extensive than laboratory only or telehealth visits. Study Visits designated as “Clinic or Remote Visits” can be performed either on-site or 
remotely by a Home Health Clinician (HHC).  Visits 3, 6, 12, 18, 24 and 27 are designated as “Clinic or Remote Visits”. All other Study Visits are Clinic Visits. 
g Vital signs after the participant has been sitting for 5 minutes include sitting heart rate and sitting blood pressure. 
h Weight will be measured at Visit 24 (PA-ADPKD-303), Visit 3, Visit 15, Visit 29/ET, and Visit 32.  Weight may be measured at any other visit to assess hydration 
status as necessary. 
i A brief physical examination will be performed at Visit 1 (Visit 27 of lead-in study), Visit 9, Visit 15, Visit 21, and Visit 32.  A full physical examination will be 
completed at Visit 29/ET. Additional physical examinations will be performed only for assessment of signs or symptoms reported by the participant that might require 
further evaluation.   
j Routine pregnancy testing for WOCBP will be performed locally on urine. All positive urine results will be confirmed by a serum pregnancy test at the central lab. 
k Chemistry blood samples will be collected according to the schedule in Table 1: 
 
A complete chemistry panel includes the following parameters: albumin; blood urea nitrogen (urea); calcium; chloride; carbon dioxide (CO2); creatinine, 
enzymatic; glucose; phosphorous; potassium; protein; sodium; uric acid.  
 
The liver chemistry panel includes alkaline phosphatase; ALT; AST; bilirubin (total and direct). 
 
All serum creatinine determinations will be performed by the central laboratory.  
 
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4. 
Study Endpoints 
4.1. 
Primary Endpoint 
Safety: 
 Proportion of participants with serum ALT levels >3 × ULN during Lixivaptan Re-
titration or Maintenance Treatment Periods that were assessed by the independent 
Hepatic Events Review Committee (HERC) to be at least probably related to lixivaptan 
and resulted in discontinuation of lixivaptan treatment. 
4.2. 
Secondary Endpoints 
Safety: 
 Proportion of participants with serum ALT levels >5 × ULN during the Lixivaptan Re-
titration or Maintenance Treatment Periods that were assessed by the independent HERC 
to be at least probably related to lixivaptan and resulted in discontinuation of lixivaptan 
treatment. 
 Proportion of participants with serum ALT levels >3 × ULN during the Lixivaptan Re-
titration or Maintenance Treatment Periods that were assessed by the independent HERC 
to be at least probably related to lixivaptan and resulted in dose reduction of lixivaptan 
treatment. 
 Safety and tolerability of lixivaptan assessed through evaluation of AEs, clinical 
laboratory findings (clinical chemistry including additional analyses of liver chemistry 
tests, hematology, and urinalysis), vital signs and 12-lead electrocardiograms (ECGs). 
Efficacy: 
 Change in annualized eGFR from baseline (mean of 3 eGFR determinations obtained at 
Visits 25, 26 and 27 of study PA-ADPKD-303) to final assessment (mean of 3 eGFR 
determinations obtained during the Follow-up Period). 
5. 
Sample Size and Power 
All participants in the lead-in study (PA-ADPKD-303) who satisfy all eligibility criteria and sign 
the Informed Consent may be enrolled into this roll-over study. It is estimated that approximately 
40 participants will be able to enroll assuming approximately 90% of participants complete the 
lead-in study and 90% of those meet all eligibility criteria and elect to enroll in this roll-over 
study. 
6. 
Analysis Populations 
6.1. 
Enrolled Population 
The Enrolled Population is defined as all participants who meet all eligibility criteria during the 
Screening Period and complete Visit 1. All general summaries, except safety and efficacy 
analyses are based on the Enrolled Population, unless specified otherwise. 
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6.2. 
Safety Population 
The Safety Population is a subset of the Enrolled Population defined as those participants who 
received at least 1 dose of lixivaptan. This population will be utilized for all safety analyses. 
6.3. 
Efficacy Population 
The Efficacy Population is a subset of the Safety Population defined as those participants who 
have at least 1 eGFR determination during the Screening Period (Follow-up Period of study PA-
ADPKD-303) and have at least 1 eGFR determination during the Follow-up Period. This 
population will be used for all efficacy analyses. 
7. 
Statistical Considerations and Analyses 
7.1. 
Planned Analyses 
Primary Hepatic Safety Analysis: 
Descriptive statistics (n, percentage and 95% confidence intervals) will be used to present the 
proportion of participants with serum ALT levels >3 × ULN that was assessed by the 
independent HERC to be at least probably related to lixivaptan and resulted in discontinuation of 
lixivaptan treatment during the Lixivaptan Re-titration or Maintenance Treatment Periods. 
Secondary Hepatic Safety Analyses:  
Similarly, descriptive statistics (n, percentage and 95% confidence intervals) will be utilized to 
present the 2 secondary endpoints: 1) the proportion of participants with serum ALT levels >5 × 
ULN during the Lixivaptan Re-titration or Maintenance Treatment Periods that were assessed by 
the independent HERC to be at least probably related to lixivaptan and resulted in the 
discontinuation of lixivaptan treatment; and 2) the proportion of participants with serum ALT 
levels >3 × ULN during the Lixivaptan Re-titration or Maintenance Treatment Periods that were 
assessed by the independent HERC to be at least probably related to lixivaptan and resulted in 
lixivaptan dose reduction. 
Additional Hepatic Safety Analyses: 
Proportion of participants who develop any of the following abnormalities during the Lixivaptan 
Re-titration or Maintenance Treatment Periods: 
 >3 ×, 5 ×, 10 ×, and 20 × ULN elevations for ALT 
 >3 ×, 5 ×, 10 ×, and 20 × ULN elevations for AST 
 >3 ×, 5 ×, 10 ×, and 20 × ULN elevations for either ALT or AST 
 ALT or AST levels >2 × their baseline 
 Any elevation of total bilirubin >2 × ULN 
 Any elevation of alkaline phosphatase >2 × ULN 
 Elevation of aminotransferase (>3 × ULN) accompanied by elevated bilirubin (>2 × 
ULN) and displayed as evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plots 
 Elevation of aminotransferase in temporal association with nausea, vomiting, anorexia, 
abdominal pain, or fatigue 
 Possible liver-related deaths and liver-related treatment discontinuations. 
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Additional Non-hepatic Safety Analyses:  
The following safety variables will be summarized using appropriate descriptive statistics:  
Treatment-emergent adverse events, clinical laboratory data, vital signs, and 12-lead ECGs. 
Potentially clinically significant results in certain clinical laboratory tests, 12-lead ECGs, and 
vital signs identified using prospectively defined criteria will be also summarized descriptively.  
Efficacy Analysis: 
Baseline eGFR is defined as the mean of the 3 eGFR assessments obtained during the Screening 
Period (Visits 25, 26, and 27 of study PA-ADPKD-303.) The endpoint eGFR is defined as the 
mean of 3 eGFR assessments obtained during the Follow-up Period of this study. Descriptive 
statistics (n, mean, standard deviation, median, minimum, and maximum) will be presented for 
the change from baseline in annualized eGFR at endpoint. 
7.2. 
Potentially Clinically Important Results of Laboratory Values, Vital signs and 
Electrocardiograms 
The sponsor-defined criteria for potentially clinically important results of clinical laboratory 
evaluations are given  
 
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Table 2. 
 
 
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Table 2: Potentially Clinically Important Criteria (PCI): Laboratory 
Lab Test Category   PCI Criteria 
Chemistry 
Sodium: <132 mmol/L 
Sodium: >149 mmol/L 
Potassium:<2.5 mmol/L 
Potassium: >6.5 mmol/L 
Calcium: <1.62 mmol/L 
Calcium:>3.49 mmol/L 
Uric acid:>715 µmol/L 
Albumin: <25 g/L 
eGFR: Decrease from baseline of ≥25%  
Glucose: ≤2.5 mmol/L 
Glucose: ≥14.0 mmol/L 
Hematology 
Leukocytes: ≤ 2.5 x 109/L 
Leukocytes: ≥ 15.0 x 109/L 
Neutrophils: ≤ 1.5 x 109/L 
Platelets: ≤ 50.0 x 109/L 
Hemoglobin: Decrease from baseline of ≥ 20 g/L 
Hematocrit: Decrease from baseline of ≥ 10% (absolute change) 
Urinalysis 
Glucose: ≥2+ or ≥500 mg/dL 
RBC/HPF: >10 
Protein: >2+ or >100 mg/dL 
Ketones: > 2 + or >40 mg/dL 
Leukocytes/HPF: >10 
Abbreviations: RBC=Red Blood Cell; HPF=high power field. 
The sponsor-defined criteria for potentially clinically important results of vital signs are given in 
Table 3. 
Table 3: Potentially Clinically Important Criteria (PCI): Vital Signs 
Heart Rate Decrease of ≥20 beats/min or ≤ 40 beats/min 
Heart Rate Increase of ≥20 beats/min or ≥ 120 beats/min 
Diastolic Blood Pressure Decrease of ≥ 20 mmHg or ≤ 50 mmHg 
Diastolic Blood Pressure Increase of ≥ 20 mmHg or ≥ 105 mmHg 
Systolic Blood Pressure Decrease of ≥ 25 mmHg or ≤ 90 mmHg 
Systolic Blood Pressure Increase of ≥ 25 mmHg or ≥ 180 mmHg 
Weight Decrease of ≥ 10% 
Weight Increase of ≥ 10% 
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The sponsor-defined criterion for potentially clinically important (PCI) results of 
electrocardiograms (ECG) is defined as QTcF value ≥450 msec. 
7.3. 
Study Early Termination and Data Presentations 
This study has been early terminated by Sponsor. Due to only a single male participant being 
enrolled and prematurely terminated in the study, no statistical analyses will be performed and 
no summary tables will be generated. The following data listings, if applicable, will be produced 
for the study report: 
 Subject Disposition 
 Demographic Characteristics 
 Baseline Characteristics – eGFR 
 Baseline Characteristics - ALT, AST and Total Bilirubin 
 Medical History 
 Concomitant Procedures 
 Prior and Concomitant Medications 
 Drug Accountability 
 Drug Tolerability/Modification 
 Listing of Serum Creatinine and estimated Glomerular Filtration Rate (eGFR) 
 Liver Dysfunction Details 
 Additional Potential Hepatic Events 
 Adverse Events 
 Laboratory Test Results – Hematology 
 Laboratory Test Results – Chemistry 
 Laboratory Test Results - Liver Chemistry 
 Laboratory Test Results – Urinalysis 
 Additional Potential Hepatic Testing 
 Vital Signs Results 
 Electrocardiogram (ECG) Results 
 
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