Clinical trial NCT04064346
Conditions: Autosomal Dominant Polycystic Kidney ADPKD
Sponsor: Palladio Biosciences
Start date: 2021-10-28; Completion date: 2022-08-03
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 trial consisting of a 2-arm, double-blind, placebo-controlled, randomized phase (Part 1) followed by a single-arm open-label phase (Part 2) to demonstrate the efficacy and safety of lixivaptan in participants with autosomal dominant polycystic kidney disease (ADPKD). Part 1 of the trial is designed to demonstrate the efficacy of lixivaptan in slowing the decline in kidney function as measured by the difference in estimated glomerular filtration rate (eGFR) between the lixivaptan-treated and placebo-treated participants. Part 2 of the study is designed to provide confirmation of the durability of this effect. Additionally, both parts of the study will contribute to understanding the safety of lixivaptan, particularly any effects on liver chemistry tests.

Detailed description:
Part 1: Approximately 2250 participants with ADPKD will be screened in order to qualify the 1350 individuals who will proceed through the Placebo Run-in Period, the Lixivaptan Titration Period, and then be randomized to receive lixivaptan or placebo in the Double-blind, Randomized Treatment Period. Throughout Part 1 the study drug will look identical regardless of whether it is placebo or lixivaptan.

After meeting entry criteria during screening, participants will enter a 1-week single-blind, Placebo Run-in Period to obtain select baseline measurements. This will be followed by a 5- to 6-week single-blind dose titration period during which lixivaptan administered twice daily (BID) will be titrated to the highest tolerated dose (the Lixivaptan Titration Period). The starting dose (Level 1) will be 50 mg BID) and this will be increased weekly through Levels 2 (100 mg BID), 3 (150mg BID), and 4 (200 mg BID). The minimum dose to enter the next period, the Double-blind, Randomized Treatment Period, is Level 2 (100 mg BID). Those participants successfully titrated and tolerating the drug will then be randomized (each participant has a 2/3 chance of receiving lixivaptan and a 1/3 chance of receiving placebo) to either continue receiving lixivaptan or switch immediately to matching placebo in a double-blind manner. All dosing throughout the study will be 4 capsules BID. Depending on the study period, treatment arm to which the participant is randomized, and current dose level, the set of 4 capsules may be all placebo, all active or a combination of active and placebo. Double-blind treatment will continue for 52 weeks after which study drug will be held, and final assessments obtained off-treatment over 3 visits starting on the 8th day after the last dose of double-blind study drug through the 28th day after the last dose of study drug.

For Part 1 summaries after randomization, the analysis results will be presented by 2 treatment groups: lixivaptan and placebo.

Part 2: All participants entering Part 1, who have not discontinued due to an adverse event or withdrawn consent, will continue into Part 2 of the study, and will proceed through the Lixivaptan Re-titration Period and a Maintenance Treatment Period.

The Lixivaptan Re-titration Period will be a 2- to 4-week period during which dosing with lixivaptan will start at Level 1 (50 mg BID) for all participants and will be increased weekly until the dose level of lixivaptan, or the inferred lixivaptan dose level for participants randomized to placebo treatment, taken at the end of the Double-blind, Randomized Treatment Period in Part 1 is achieved. Lixivaptan treatment will continue for 52 weeks during the Maintenance Treatment Period after which study drug will be held, and final assessments obtained off-treatment over 3 visits starting on the 8th day after the last dose of lixivaptan through the 28th day after the last dose of lixivaptan.

Since all participants in Part 2 are treated with lixivaptan, the summaries for Part 2 will be presented in the following treatment cohorts and overall (treatment cohorts combined):

* Part1/Part2 - placebo/lixivaptan: all participants in Part 2 who were randomized into the placebo treatment group in Part 1.
* Part1/Part2 - lixivaptan/lixivaptan: all participants in Part 2 who were randomized into the lixivaptan treatment group in Part 1.

Arms: arm 1: Lixivaptan capsules, 100-200 mg twice a day (BID) arm 2: Matching placebo capsules BID
Interventions: intervention 1: Lixivaptan intervention 2: Placebo
Intervention descriptions: intervention 1: Oral vasopressin V2 receptor antagonist intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 
Study Title: A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with 
Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, 
Placebo-controlled, Randomized Phase and a 1-year Open-label Phase: The ACTION 
Study 
ClinicalTrials.gov ID: NCT04064346 
Clinical Study Protocol Version 3.0, dated 14-Feb-2022 
Overview of Changes in the Conduct of the Study  
Clinical Study Protocol Version 3.0, dated 14-Feb-2022, Summary of Changes 
Clinical Study Protocol Version 2.0, dated 01-Feb-2022, Summary of Changes 


 
14 FEB 2022 
Confidential Information 
Version 3.0 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants 
with Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year 
Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-
Label Phase: The ACTION Study 
Protocol Number: PA-ADPKD-301 
 
Sponsor: 
Palladio Biosciences, Inc.  
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
Sponsor Contact: 
Neil Shusterman, MD FACP 
Chief Medical Officer 
Palladio Biosciences, Inc.  
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
 
Regulatory Agency 
Identifying No. 
 
Medical Monitor: 
 
 
Emergency Telephone 
Numbers 
IND number 136,419; EudraCT number 2021-003062-12 
 
 
Refer to the Study Contacts List in the Investigator Site File 
or Trial Master File 
 
North America: +1 510 722 8910 
South America: +54 911 5479 8678 
Europe and Middle East Region: +44 118 936 4096 
Australia, New Zealand: +61 3921 39875 
Version of Protocol: 
 
Original Protocol Date: 
Protocol Version 2 Date: 
Protocol Version 3 Date: 
 
3.0  
 
30 JUN 2021 
01 FEB 2022 
14 FEB 2022 
 
 
 
 


Palladio Biosciences PA-ADPKD-301                            
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CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Palladio Biosciences, 
Inc. (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.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Palladio Biosciences PA-ADPKD-301                            
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PROTOCOL APPROVAL - SPONSOR SIGNATURE 
Protocol Title 
A Phase 3 Study of the Efficacy and Safety of Lixivaptan in 
Participants with Autosomal Dominant Polycystic Kidney Disease 
Consisting of a 1-year Double-blind, Placebo-controlled, Randomized 
Phase and a 1-year Open-label Phase: The ACTION Study 
Protocol Number 
PA-ADPKD-301 
Protocol Version 
3.0 
Protocol Version Date 
14 FEB 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 
 
 
 
 
 
 
14Feb2022_________________________ 
 Signature   
 
 
 
 
Date 


Palladio Biosciences PA-ADPKD-301                            
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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol titled “A Phase 3 Double-blind, Placebo-
controlled, Randomized Study of the Efficacy and Safety of Lixivaptan in Participants with 
Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-
controlled, Randomized Phase and a 1-year Open-label Phase: The ACTION Study”. 
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 
Practices (GCP), including 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 
 
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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TABLE OF CONTENTS 
CONFIDENTIAL .................................................................................................................... 2 
PROTOCOL APPROVAL - SPONSOR SIGNATURE ........................................................ 3 
DECLARATION OF INVESTIGATOR ................................................................................ 4 
TABLE OF CONTENTS ......................................................................................................... 5 
LIST OF TABLES .................................................................................................................. 12 
LIST OF FIGURES ............................................................................................................... 12 
PROTOCOL SYNOPSIS ...................................................................................................... 13 
TABLE 3. SCHEDULE OF PROCEDURES – PART 1 ..................................................... 32 
TABLE 4. SCHEDULE OF PROCEDURES – PART 2 ..................................................... 36 
LIST OF ABBREVIATIONS ................................................................................................ 39 
1 
INTRODUCTION .......................................................................................................... 42 
1.1 
Background ............................................................................................................. 42 
1.2 
Overview of ADPKD .............................................................................................. 42 
1.3 
Overview of Available Therapies for ADPKD ....................................................... 43 
1.4 
Rationale for Lixivaptan Therapy for ADPKD ....................................................... 43 
1.5 
Summary of Nonclinical Studies ............................................................................ 46 
1.6 
Summary of Clinical Studies .................................................................................. 47 
1.7 
Study Rationale ....................................................................................................... 48 
1.8 
Dose Rationale ........................................................................................................ 48 
1.9 
Benefit/Risk Assessment ......................................................................................... 49 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 50 
2.1 
Study Objectives ..................................................................................................... 50 
2.1.1 
Objectives of the Double-blind Phase (Part 1/Year 1) ............................. 50 
2.1.2 
Objectives of the Open-label Phase (Part 2/Year 2) ................................ 51 
2.2 
Study Endpoints ...................................................................................................... 52 
2.2.1 
Part 1/Year 1 ............................................................................................ 52 
2.2.1.1 
Primary Efficacy Endpoint ...................................................................... 52 
2.2.1.2 
Key Safety Endpoint ................................................................................ 52 
2.2.1.3 
Secondary Efficacy Endpoints ................................................................. 52 
2.2.1.4 
Secondary Safety Endpoints .................................................................... 52 


Palladio Biosciences PA-ADPKD-301                                                                                   
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2.2.1.5 
Health Outcome Endpoints ...................................................................... 52 
2.2.1.6 
Population Pharmacokinetics Endpoints ................................................. 53 
2.2.1.7 
Exploratory Endpoints ............................................................................. 53 
2.2.2 
Part 2/Year 2 ............................................................................................ 53 
2.2.2.1 
Key Comparison Endpoint ...................................................................... 53 
2.2.2.2 
Key Safety Endpoint ................................................................................ 53 
2.2.2.3 
Other Comparison Endpoints .................................................................. 53 
2.2.2.4 
Secondary Safety Endpoints .................................................................... 53 
2.2.2.5 
Health Outcome Endpoints ...................................................................... 54 
2.2.2.6 
Population Pharmacokinetics ................................................................... 54 
2.2.2.7 
Exploratory Endpoints ............................................................................. 54 
3 
INVESTIGATIONAL PLAN ........................................................................................ 55 
3.1 
Study Design ........................................................................................................... 55 
3.1.1 
Overview of Study Design ....................................................................... 55 
3.1.2 
Detailed Study Design ............................................................................. 56 
3.2 
Rationale for Study Design ..................................................................................... 60 
4 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA ........................... 61 
4.1 
Selection of Study Population ................................................................................. 61 
4.1.1 
Inclusion Criteria ..................................................................................... 61 
4.1.2 
Exclusion Criteria .................................................................................... 63 
4.2 
Completion and Withdrawal of Participants from the Study .................................. 64 
4.2.1 
Definition of Completed Participants ...................................................... 64 
4.2.2 
Screening and Placebo Run-in/Lixivaptan Titration Failures .................. 65 
4.2.3 
Treatment Interruption ............................................................................. 65 
4.2.4 
Treatment Discontinuation ....................................................................... 67 
4.2.5 
Reasons for Treatment/Study Discontinuation ........................................ 68 
4.2.6 
Study Termination .................................................................................... 69 
4.2.7 
Methods to Prevent Loss to Follow Up ................................................... 69 
4.2.8 
Withdrawal of Consent ............................................................................ 69 
4.2.9 
Replacements ........................................................................................... 70 
5 
STUDY DRUG AND CONCOMITANT MEDICATION ........................................... 71 
5.1 
Study drug ............................................................................................................... 71 
5.1.1 
Identity of the Investigational Product..................................................... 71 
5.1.2 
Identity of Placebo ................................................................................... 71 
5.1.3 
Route of Administration .......................................................................... 71 
5.1.4 
Study Drug Packaging, Labeling, and Storage ........................................ 71 


Palladio Biosciences PA-ADPKD-301                                                                                   
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5.1.5 
Accountability .......................................................................................... 72 
5.2 
Dose Administered .................................................................................................. 72 
5.3 
Method of Assigning Participants to Treatment Groups ......................................... 73 
5.4 
Treatment Compliance ............................................................................................ 74 
5.5 
Prior and Concomitant Therapy .............................................................................. 74 
5.5.1.1 
Permitted Therapy .................................................................................... 75 
5.5.1.2 
Prohibited Therapy .................................................................................. 75 
5.6 
Diet, Fluid, and Activity Control ............................................................................ 76 
6 
TIMING OF STUDY PROCEDURES ......................................................................... 78 
6.1 
Screening Period ..................................................................................................... 78 
6.1.1 
Visit 1a ..................................................................................................... 79 
6.1.2 
Visit 1b ..................................................................................................... 80 
6.1.3 
Visit 2 ....................................................................................................... 81 
6.2 
Placebo Run-in Period and Visit 3 .......................................................................... 82 
6.3 
Lixivaptan Titration Period ..................................................................................... 83 
6.3.1 
Visits 4 to 8 (Lixivaptan Titration Period) ............................................... 84 
6.3.2 
Visit 9/Last Titration Visit ........................................................................ 86 
6.4 
Double-blind, Randomized Treatment Period ........................................................ 87 
6.4.1 
Visits 10 to 21 .......................................................................................... 87 
6.4.2 
Visit 22/Early Termination ....................................................................... 89 
6.5 
Follow-up Period I .................................................................................................. 90 
6.5.1 
Visit 23 and Visit 24 ................................................................................. 90 
6.5.2 
Visit 25 ..................................................................................................... 91 
6.6 
Lixivaptan Re-titration Period – Part 2 ................................................................... 92 
6.6.1 
Visits 26 to 28 .......................................................................................... 93 
6.6.2 
Visit 29/Last Re-titration Visit ................................................................. 93 
6.7 
Maintenance Treatment Period ............................................................................... 94 
6.7.1 
Visits 30 to 41 .......................................................................................... 95 
6.7.2 
Visit 42/Early Termination (Part 2) .......................................................... 96 
6.8 
Follow-up Period II ................................................................................................. 97 
6.8.1 
Visit 43 and Visit 44 ................................................................................. 97 
6.8.2 
Visit 45 ..................................................................................................... 98 
6.9 
Early Termination Procedures ................................................................................. 99 
7 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES .................... 101 
7.1 
Efficacy Assessments ............................................................................................ 101 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.1.1 
eGFR Determination .............................................................................. 101 
7.1.2 
MRI Assessment .................................................................................... 101 
7.1.3 
Urine Osmolality ................................................................................... 102 
7.2 
Health Outcomes Assessments ............................................................................. 102 
7.2.1 
Medical Resource Utilization ................................................................ 102 
7.2.2 
ADPKD- Impact Scale .......................................................................... 103 
7.2.3 
ADPKD- Pain and Discomfort Scale .................................................... 103 
7.2.4 
ADPKD- Urinary Impact Scale ............................................................. 103 
7.3 
Safety and Tolerability Assessments ..................................................................... 104 
7.3.1 
Body Height, Weight, and BMI ............................................................. 104 
7.3.2 
Physical Examinations and Medical History ......................................... 104 
7.3.3 
Vital Sign Measurements ....................................................................... 105 
7.3.4 
12-Lead ECGs ....................................................................................... 105 
7.3.5 
Clinical Laboratory Tests ....................................................................... 106 
7.3.5.1 
Sample Collections ................................................................................ 107 
7.3.6 
Assessment of Tolerability During Placebo Run-in and Lixivaptan Titration 
Period ..................................................................................................... 108 
7.3.7 
Assessment of Liver Symptoms, Signs, or Test Abnormalities ............. 108 
7.3.7.1 
Management of Liver Chemistry Test Abnormalities and Signs or 
Symptoms of Liver Dysfunction Occurring During Study Treatment .. 108 
7.3.7.1.1 
Repeat Liver Testing in Participants with Abnormal Values at 
Screening .................................................................................... 109 
7.3.7.1.2 
Liver Test Abnormalities during the Placebo Run-in and/or 
Lixivaptan Titration Period ........................................................ 110 
7.3.7.2 
Hepatic Events Review Committee (HERC) – Special Reporting of Liver 
Events .................................................................................................... 110 
7.3.8 
Adverse Events ....................................................................................... 111 
7.3.8.1 
Definitions of Adverse Events ................................................................ 111 
7.3.8.2 
Eliciting and Documenting Adverse Events and Serious Adverse Events
 ................................................................................................................ 111 
7.3.8.3 
Reporting Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest ....................................................................................... 112 
7.3.8.4 
Assessment of Severity .......................................................................... 113 
7.3.8.5 
Assessment of Causality ........................................................................ 114 
7.3.8.6 
Procedure for Breaking the Blind .......................................................... 115 
7.3.8.7 
Follow-Up of Participants Reporting Adverse Events ........................... 115 
7.3.8.8 
Overdose Management .......................................................................... 116 
7.3.8.9 
AE/SAEs Experienced by Nonparticipants Exposed to Study Treatment116 
7.3.8.10 Pregnancy .............................................................................................. 116 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.9 
Clinical Laboratory and Other Safety Assessments ............................... 117 
7.3.10 
Independent Data Monitoring Committee ............................................. 117 
7.4 
Population Pharmacokinetic Assessments ............................................................ 117 
7.4.1 
Pharmacokinetic Blood Sampling ......................................................... 117 
8 
STATISTICAL PROCEDURES ................................................................................. 119 
8.1 
Sample Size ........................................................................................................... 119 
8.2 
Blinded Sample Size Re-estimation ..................................................................... 119 
8.3 
Populations for Analysis ....................................................................................... 120 
8.4 
Primary Efficacy Analysis .................................................................................... 120 
8.4.1 
Primary Endpoint Analysis .................................................................... 120 
8.4.2 
Sensitivity Analysis of the Primary Efficacy Analysis .......................... 121 
8.5 
Secondary Efficacy Analyses. ............................................................................... 121 
8.5.1 
Annualized Rate of Change (Slope) in eGFR on Treatment ................. 121 
8.5.2 
Annualized Change in TKV .................................................................. 122 
8.6 
Key Comparison Analysis .................................................................................... 122 
8.6.1 
Key Comparison Endpoint Analysis ...................................................... 122 
8.6.2 
Sensitivity Analysis of the Key Comparison Analysis .......................... 123 
8.7 
Other Comparison Analyses ................................................................................. 123 
8.7.1 
Annualized Rate of Change (Slope) in eGFR on Treatment ................. 123 
8.7.2 
Annualized Change in TKV .................................................................. 123 
8.8 
Population Pharmacokinetics Analyses ................................................................ 123 
8.9 
Health Outcomes Analyses ................................................................................... 123 
8.9.1 
Medical Resource Utilization ................................................................ 123 
8.9.2 
ADPKD-IS, ADPKD-PDS, and ADPKD-UIS ...................................... 123 
8.10 Exploratory Analyses ............................................................................................ 124 
8.10.1 
Annualized Change in LV ...................................................................... 124 
8.10.2 
Urinary Osmolality ................................................................................ 124 
8.10.3 
Annualized Change in eGFR Assessed by Serum Creatinine and Cystatin-
C (CKD-EPIcr-cys_R) ........................................................................... 124 
8.11 Subgroup Analyses ............................................................................................... 124 
8.12 Analysis of Demographic and Baseline Characteristics ....................................... 124 
8.13 Safety Analyses ..................................................................................................... 125 
8.13.1 
Liver Safety Analyses ............................................................................ 125 
8.13.1.1 Liver Safety Analysis for Key Safety Endpoint..................................... 125 
8.13.1.2 Additional Liver Safety Analyses .......................................................... 125 
8.13.2 
Adverse Events ...................................................................................... 125 


Palladio Biosciences PA-ADPKD-301                                                                                   
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8.13.3 
Clinical Laboratory Tests ....................................................................... 126 
8.13.4 
ECGs ...................................................................................................... 127 
8.13.5 
Body Height, Weight and BMI .............................................................. 127 
8.13.6 
Vital Signs .............................................................................................. 128 
8.14 Statistical Analysis Methodology ......................................................................... 128 
8.15 Data Quality Assurance......................................................................................... 128 
8.15.1 
Data Management .................................................................................. 128 
9 
ETHICS ......................................................................................................................... 130 
9.1 
Institutional Review Board (IRB)/Ethics Committee (EC) .................................. 130 
9.2 
Ethical Conduct of the Study ................................................................................ 130 
9.3 
Participant Information and Consent .................................................................... 130 
10 INVESTIGATOR’S OBLIGATIONS AND STUDY PERSONNEL ....................... 132 
10.1 Confidentiality ...................................................................................................... 132 
10.2 Financial Disclosure and Obligations ................................................................... 132 
10.3 Investigator Documentation .................................................................................. 132 
10.4 Study Conduct ....................................................................................................... 133 
10.5 Adherence to Protocol .......................................................................................... 133 
10.6 Adverse Events and Study Report Requirements ................................................. 133 
10.7 Investigator’s Final Report ................................................................................... 133 
10.8 Records Retention ................................................................................................. 133 
10.9 Publications ........................................................................................................... 134 
11 STUDY MANAGEMENT ........................................................................................... 135 
11.1 Monitoring ............................................................................................................ 135 
11.1.1 
Monitoring of the Study ......................................................................... 135 
11.1.2 
Inspection of Records and Quality Assurance ....................................... 135 
11.2 Management of Protocol Amendments and Deviations........................................ 135 
11.2.1 
Modification of the Protocol .................................................................. 135 
11.3 Protocol Deviations ............................................................................................... 135 
11.4 Management of Study Termination ....................................................................... 136 
12 REFERENCE LIST ..................................................................................................... 137 
13 APPENDICES .............................................................................................................. 140 
13.1 Appendix 1: Chronic Kidney Disease Classification Criteria .............................. 140 
13.2 Appendix 2: Liver Dysfunction Checklist ............................................................ 142 


Palladio Biosciences PA-ADPKD-301                                                                                   
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13.3 Appendix 3: Additional Potential Hepatic Testing if Liver Chemistry Abnormalities 
Occur ............................................................................................................. 144 
13.4 Appendix 4: DILI Network Causality Criteria, modified ..................................... 145 
13.5 Appendix 5: Minimization of Missing Data: Study and Study Treatment 
Modification .................................................................................................. 146 
13.6 Appendix 6: Procedures to Prevent Loss to Follow-up ........................................ 147 
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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LIST OF TABLES 
Table 1. Dosing Levels during the Titration Period ................................................................... 24 
Table 2. Dose Titration (Part 2) Based on Dose Level Achieved at End of Double-blind 
Randomized Treatment Period in Part 1 for Participants Assigned to Lixivaptan 
or Placebo in Part 1 ............................................................................................ 26 
Table 3. Schedule of Procedures – Part 1 .................................................................................. 32 
Table 4. Schedule of Procedures – Part 2 .................................................................................. 36 
Table 5. DILIsym Simulations of Lixivaptan and Tolvaptan ..................................................... 46 
Table 6. Dose Re-establishment Following a Prolonged (> 4-week) Study Drug Interruption . 67 
Table 7. Investigational Product ................................................................................................ 71 
Table 8. Clinical Laboratory Parameters ................................................................................. 107 
Table 9. Guideline for Assessment of Adverse Event Causality .............................................. 115 
LIST OF FIGURES 
Figure 1. Part 1 Study Schematic ............................................................................................... 30 
Figure 2. Part 2 Study Schematic ............................................................................................... 30 
Figure 3. Lixivaptan Titration Period (Part 1) — Lixivaptan Titration Flowchart .................... 31 
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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PROTOCOL SYNOPSIS 
Protocol Number: 
PA-ADPKD-301 
Protocol Title: 
A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with 
Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year 
Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-label 
Phase: The ACTION Study 
Sponsor: 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
Name of Active 
Ingredient: 
Lixivaptan 
Indication: 
Autosomal Dominant Polycystic Kidney Disease (ADPKD) 
Phase of 
Development: 
Phase 3 
Number of 
Participants 
(Planned) 
1350 randomized, Part 1 (estimated 1215 will continue into Part 2) 
Study Sites: 
Approximately 250 sites worldwide 
Study Duration 
123 to 131 weeks (Part 1: 65 to 71 weeks; Part 2: 58 to 60 weeks) 
Principal/Lead 
Investigator 
Vicente E. Torres, MD, PhD 
Rationale: 
 
 
 
 
 
 
ADPKD is the most frequent inherited cause of end-stage kidney 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 kidney 
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 the disease.  
Evidence from quantitative systems toxicology modeling and simulation has 
demonstrated that lixivaptan does not have the same potential for liver injury 
as tolvaptan.  In a patient with ADPKD who developed DILI while receiving 
tolvaptan, treatment with lixivaptan in an expanded access study was 
administered for 14 months without any alteration in liver chemistry tests.  
Thus, lixivaptan may represent a safer alternative to tolvaptan with similar 
efficacy.  
In the ongoing lixivaptan study, PA-ADPKD-303, the hepatic and non-hepatic 
safety as well as the efficacy of lixivaptan is being evaluated in participants 
who permanently discontinued treatment with tolvaptan as a result of 
abnormal liver chemistries.   


Palladio Biosciences PA-ADPKD-301                                                                                   
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This Phase 3 trial will assess the efficacy and safety of lixivaptan in a broad 
population of adult participants with ADPKD. 
Objectives: 
 
 
 
 
 
 
 
 
Part 1 (Year 1): 
The primary efficacy objective of Part 1 is: 
• 
To demonstrate the efficacy of lixivaptan compared to placebo in the 
slowing of deterioration in kidney function in participants with 
ADPKD as demonstrated by the annualized change from baseline in 
estimated glomerular filtration rate (eGFR). 
The key safety objective of Part 1 is: 
• 
To compare the incidences of liver chemistry test elevations in 
participants randomized to lixivaptan with participants randomized to 
placebo.  
The secondary efficacy objectives of Part 1 are: 
• 
To compare the rate of change (slope) in on-treatment eGFR in 
participants treated with lixivaptan to participants treated with 
placebo. 
• 
To assess the effect of lixivaptan on total kidney volume (TKV) as 
measured by magnetic resonance imaging (MRI) compared to 
placebo. 
The secondary safety objective of Part 1 is: 
• 
To assess the non-hepatic safety and tolerability of lixivaptan. 
The health outcomes-related objectives of Part 1 are: 
• 
To evaluate medical resource utilization (e.g., medication 
use/changes; unplanned office visit; urgent care and emergency 
department usage; and hospitalizations) resulting from clinical events 
in participants randomized to lixivaptan compared with those on 
placebo and assess which events are driving any observed differences 
in medical resource utilization between lixivaptan and placebo. 
• 
To evaluate the change from baseline in domain scores of the ADPKD 
Impact Scale (ADPKD-IS), ADPKD Pain and Discomfort Scale 
(ADPKD-PDS), and ADPKD Urinary Impact Scale (ADPKD-UIS) in 
participants treated with lixivaptan compared with participants treated 
with placebo. 
The population pharmacokinetics (PopPK) objective of Part 1 is: 
• 
To characterize the pharmacokinetic (PK) profile of lixivaptan 
utilizing population PK (PopPK) based on sparse plasma sampling.  
The exploratory objectives of Part 1 are: 
• 
To assess the effect of lixivaptan on liver volume (LV) as measured 
by MRI compared to placebo. 
• 
To evaluate the change from baseline in urine osmolality in 
participants treated with lixivaptan compared with participants treated 
with placebo. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• 
To evaluate the effect of lixivaptan on kidney function as assessed by 
eGFR using a novel serum creatinine and serum cystatin C-based 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation refit without race variable (CKD-EPIcr-cys_R) compared 
with placebo. 
Part 2 (Year 2): 
The key objective of Part 2 is: 
• 
To demonstrate the continued efficacy of lixivaptan in the slowing of 
deterioration in kidney function in participants randomized to 
lixivaptan in the double-blind phase (Part 1) as measured by the 
annualized change from baseline (Part 2) in eGFR at the end of the 
open-label phase (Part 2). 
The key safety objective of Part 2 is: 
• 
To assess the incidence of liver chemistry test abnormalities during 
the open-label phase. 
The secondary objectives of Part 2 are: 
 
• 
To assess the rate of change (slope) in on-treatment eGFR in Part 2 in 
participants treated with lixivaptan in Part 1 and Part 2. 
• 
To assess the effect of lixivaptan on TKV as measured by MRI in Part 
2 in participants treated with lixivaptan in Part 1 and Part 2. 
The secondary safety objective of Part 2 is: 
• 
To assess the non-hepatic safety and tolerability of lixivaptan. 
The health outcomes-related objectives of Part 2 are: 
• 
To evaluate medical resource utilization (e.g., medication 
use/changes; unplanned office visits; urgent care and emergency 
department usage; and hospitalizations) resulting from clinical events 
in participants on lixivaptan.  
• 
To evaluate the change in domain scores of the ADPKD-IS, ADPKD-
PDS, and ADPKD-UIS. 
The PopPK objective of Part 2 is: 
• 
To further characterize the PK profile of lixivaptan utilizing PopPK 
based on sparse plasma sampling.  
The exploratory objectives of Part 2 are: 
• 
To assess the effect of lixivaptan on LV as measured by MRI 
following 52 weeks of open-label treatment.   
• 
To evaluate the change in urine osmolality. 
• 
To evaluate the effect of lixivaptan on kidney function as assessed by 
eGFR using the CKD-EPIcr-cys_R equation following 52 weeks of 
open-label treatment. 
Study Population: 
Eligibility criteria are to be assessed at Visits 1a, 1b (if required) and 2.  Note: 
On or prior to Visit 3, eligibility based on mean eGFR (Inclusion criterion #4) 
from Visit 1a and 2 or Visit 1b and 2 (if Visit 1b is required) and liver 
chemistry tests (Exclusion criterion #9) from Visit 2 must be re-confirmed.) 
The following are requirements for entry into the study: 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Inclusion criteria: 
1. Male or female, between 18 and 60 years of age (inclusive) at the time 
of Screening (Visit 1a).  
2. Diagnosis of ADPKD by modified Pei criteria: 
• 
For participants with family history of ADPKD, by 
ultrasound: 
• 18-39 years: ≥3 cysts, unilateral or bilateral;   
• 40-59 years: ≥2 cysts in each kidney; 
• 60 years: ≥4 cysts in each kidney; or 
• 
For participants with family history of ADPKD, by 
computerized tomography (CT) or MRI: 
• 18-40 years: ≥10 cysts in both kidneys; or 
• 
For participants without family history of ADPKD 
• a minimum of 10 cysts per kidney by any radiologic 
method and exclusion of other cystic kidney diseases 
(multiple simple kidney cysts, renal tubular acidosis, 
cystic dysplasia of the kidney, multicystic kidney, 
multilocular cysts of the kidney, medullary cystic 
kidney and acquired cystic disease of the kidney); or 
• genetic diagnosis of ADPKD. 
3. At risk for rapid progression of ADPKD as based on the Mayo Clinic 
ADPKD Image Classification of 1C, 1D, or 1E based on age and 
height-adjusted total kidney volume (TKV) as determined by kidney 
MRI obtained during Screening, where class (class 1 [typical] versus 
class 2 [atypical]) and TKV are determined by a central imaging 
vendor. 
4. eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m2 based on the 
mean of 2 eGFR determinations (Visits 1a and 2 or Visits 1b and 2, if 
Visit 1b is required) calculated by the 2021 Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) eGFR creatinine equation 
refit without the race variable (CKD-EPIcr_R) from serum creatinine 
values obtained during Screening. Note: This criterion will 
preliminarily be reviewed at Visit 2 based on Visit 1a or Visit 1b 
results (if Visit 1b is required).  The criterion must be re-evaluated no 
later than Visit 3 when results for Visits 1a and 2 or Visits 1b and 2 
are available to confirm that the participant remains eligible for 
participation.  
5. Appropriate control of hypertension for a minimum of 3 weeks 
including the use of an angiotensin converting enzyme inhibitor or 
angiotensin receptor blocker at a stable dose (unless not considered 
appropriate for the participant) as suggested by the 2021 Kidney 
Disease Improving Global Outcomes (KDIGO) “Clinical Practice 
Guideline for the Management of Blood Pressure in Chronic Kidney 
Disease,” without the use of a diuretic. 
6. Body mass index (BMI) between 18 and 40 kg/m2 (inclusive) at the 
time of Screening. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7. 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), agree to practice acceptable 
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 trial and for 30 days after the last dose of study 
drug.  Birth control methods that can be used during the study 
include the following: 
• hormonal contraceptives: combined (estrogen and 
progestogen containing) hormonal contraception 
associated with inhibition of ovulation (i.e., oral, 
intravaginal, transdermal); progestogen-only 
hormonal contraception (i.e., oral, injectable, 
implantable). Note: in women with severe polycystic 
liver disease, contraceptives containing estrogen (and 
hormone replacement therapy) may be involved in 
the development and growth of liver cysts and 
polycystic liver disease progression; the supplemental 
risk of initiating or continuing estrogen treatment, as 
well as potential alternative contraceptives for 
WOCBP will be discussed with the potential 
participant 
• 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 male condom). 
8. Male participants must agree 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 study drug. 
9. Have read, understood, and provided written informed consent after 
the nature of the study has been fully explained and must be willing to 
comply with protocol requirements and study-related procedures. 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Exclusion criteria: 
1. Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, 
and/or glycosuria by dipstick, significant proteinuria [>300 mcg 
albumin/mg creatinine]), other significant kidney disease, kidney 
cancer, transplanted kidney, single kidney, kidney surgery within the 
past 6 months (including cyst drainage or fenestration) or acute 
kidney injury within 6 months prior to Screening. 
2. Clinically significant 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. History of infection with human immunodeficiency virus (HIV) 
unless the participant is clinically stable and doing well on a non-CYP 
interacting anti-retroviral therapy (ART) regimen and the participant 
has not required more than 2 changes in their ART regimen since 
treatment inception. 
5. History of clinically significant drug or alcohol abuse in the 2 years 
prior to Screening Visit 1a. 
6. Contraindications to or interference with MRI assessments (e.g., 
ferromagnetic metal prostheses, aneurysm clips, severe 
claustrophobia, or large abdominal/back tattoos).  Investigator should 
seek MRI safety guidance from the local MRI facility. 
7. Any malignancy within 5 years prior to Screening except for basal 
cell carcinoma successfully treated with local therapy or malignancies 
that are considered by the Investigator not to affect participant 
survival (after discussion with the medical monitor). 
8. Medical history or findings that preclude safe participation in the trial 
or participants who are likely to be non-compliant with trial 
procedures in the opinion of the Investigator or medical monitor. 
9. Clinically significant liver disease or impairment or alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin values >1.2 x ULN during Screening. Note: This criterion 
will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 
1b results (if Visit 1b is required).  The criterion must be re-evaluated 
no later than Visit 3 when results for Visit 2 are available. 
10. Requirement for ongoing diuretic use. 
11. Participants who are currently taking, or are expected to be taking, 
strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers 
including regular use of grapefruit juice, Seville oranges, or St. John’s 
wort.  If applicable, there should be a 14-day washout of these 
treatments prior to Visit 2. 
12. Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., 
canagliflozin, dapagliflozin, empagliflozin, etc.) within the 2 months 
prior to Screening Visit 1a or expected need for initiation of treatment 
with a SGLT2 inhibitor during the study. 
13. Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) 
inhibitor within the 2 months prior to Screening Visit 1a or expected 


Palladio Biosciences PA-ADPKD-301                                                                                   
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need for initiation of treatment with a HIF-PH inhibitor during the 
study. 
14. Simvastatin at a total daily dose >10 mg or amlodipine at a total daily 
dose >5 mg. 
15. Prior use of tolvaptan or lixivaptan within the 2 months prior to 
Screening Visit 1a. 
16. Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, 
pasireotide, octreotide, etc.), metformin (except for diabetes), 
nicotinamide, bardoxolone, demeclocycline, mTOR kinase inhibitors 
(e.g., everolimus, sirolimus, etc.), or KetoCitra™ or any beta-
hydroxybutyrate (BHB) containing supplements within the 2 months 
prior to Screening Visit 1a. 
17. Participants who have taken any investigational drug or used an 
investigational device within 30 days, or 5 half-lives, whichever is 
longer, prior to Screening Visit 1a or plan to participate in an 
interventional trial during the study. 
18. Hypovolemia on physical examination at Screening.  
19. Abnormal serum sodium concentration at Screening. 
20. Positive test results for hepatitis B surface antigen (HBsAg). 
21. Positive test results for hepatitis C (HCV) antibody (Anti-HCV), with 
the exception of participants for whom the reflex HCV RNA titer test 
is negative. 
22. Known sensitivity or idiosyncratic reaction to lixivaptan and/or its 
excipients.  
Study Design: 
This is a Phase 3 trial consisting of a 2-arm, double-blind, placebo-controlled, 
randomized phase (Part 1) followed by a single-arm open-label phase (Part 2) 
to demonstrate the efficacy and safety of lixivaptan in participants with 
ADPKD.  Part 1 of the trial is designed to demonstrate the efficacy of 
lixivaptan in slowing the decline in kidney function as measured by the 
difference in change from baseline of eGFR between the lixivaptan-treated 
and placebo-treated participants. Part 2 of the study is designed to provide 
confirmation of the durability of this effect.  Additionally, both parts of the 
study will contribute to understanding the safety of lixivaptan, particularly any 
effects on liver chemistry tests.  If agreeable to the participant and at the 
discretion of the Investigator, designated visits may be done remotely by a 
home healthcare clinician (HHC) (where available and locally approved by 
the Competent Authority (CA) and/or IRB/EC). Some remote visits may also 
include telehealth (e.g., telemedicine virtual visit, telephone or video call 
(without recording)) with the study site, as applicable.  Remote visits may also 
be conducted by qualified site personnel who have been delegated the 
authority to carry out the procedures required at remote visits by the 
Investigator.  Those visits are indicated in the Schedule of Procedures – Part 1 
and Schedule of Procedures – Part 2. 
Part 1: Approximately 2250 participants with ADPKD will be screened in 
order to randomize 1350 participants to lixivaptan or placebo in a 2:1 ratio in 
Part 1 of this study.  After meeting entry criteria during a 3-to-5-week 
screening period (that may be extended up to 8 weeks to obtain baseline 
stability of medications), participants will enter a 1-week single-blind placebo 


Palladio Biosciences PA-ADPKD-301                                                                                   
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run-in period (participants will not know the identity of the study drug being 
administered) to obtain select baseline measurements followed by a 5 to 6 
week single-blind dose titration period during which lixivaptan administered 
twice daily will be titrated to the highest tolerated dose.  The minimum dose to 
enter the Double-blind, Randomized Treatment Period is 100 mg BID.  Those 
participants successfully titrated and tolerating the study drug will then be 
randomized (2:1) to either continue lixivaptan or switch immediately to 
matching placebo in a double-blind manner.  Randomization will be stratified 
for Chronic Kidney Disease (CKD) Stage and Mayo Clinic ADPKD Image 
Classification.  Double-blind treatment will continue for 52 weeks after which 
study drug will be held, and final eGFR assessments will be obtained off-
treatment during 3 follow-up visits starting on the 8th day after the last dose of 
double-blind study drug through the 28th day after the last dose of double-
blind study drug.   
Part 2: All participants (placebo and lixivaptan-treated) entering Part 1 will 
continue into Part 2 of the study and be treated with the active drug, 
lixivaptan, for an additional 52 weeks (following the Lixivaptan Re-titration 
Period) unless study drug was previously discontinued for a safety reason, or a 
participant withdraws consent.  Assuming 90% of participants complete the 
Double-Blind Treatment Period (Part 1), approximately 1215 participants are 
projected to continue into Part 2.  At the beginning of Part 2, all participants 
will start lixivaptan during the Lixivaptan Re-titration Period to re-establish 
the dose level that was tolerated during Part 1.  The dose will be increased at 
weekly intervals until the dose level taken at the end of the Double-blind, 
Randomized Treatment Period in Part 1 is achieved.  In order to maintain 
blinding of the treatment assignment from Part 1, re-titration during Part 2 will 
continue to be managed by the Interactive Response Technology (IRT) 
system. 
Following re-titration, participants will continue on lixivaptan therapy for 52 
weeks in the Maintenance Treatment Period of Part 2 and will be assessed at a 
study visit every 4 weeks. At the end of 52 weeks, study drug will be held, and 
final assessments will be obtained over 3 follow-up visits starting on the 8th 
day following the last dose of study drug through the 28th day after the last 
dose of study drug.   
Study Period 
Description and 
Estimated 
Duration: 
Part 1: The study schematic for Part 1 is depicted in Figure 1. 
Screening Period (Visits 1a, 1b, and 2): After obtaining informed consent 
screening assessments will be performed at Visit 1a to determine initial 
participant eligibility.  Participants will continue through Screening as 
follows: 
• 
Participants with appropriate blood pressure control for a minimum of 
3 weeks prior to enrollment (Visit 2) (as defined by the 2021 KDIGO 
guideline) including those on a stable regimen with an angiotensin-
converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker 
(ARB) treatment (unless not considered appropriate) and not 
receiving a diuretic will have a baseline MRI exam scheduled and will 
proceed to Visit 2, 3 to 5 weeks after Visit 1a, and after completion of 
the baseline MRI (allow approximately 1 week after completion of the 
MRI, however, a 3-week minimum between Visit 1a and Visit 2 is 


Palladio Biosciences PA-ADPKD-301                                                                                   
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required). (Screening may be extended to a maximum of 8 weeks, in 
the event of extenuating circumstances. Prior approval from the 
medical monitor is required.) 
• 
Participants who need to be discontinued from diuretic therapy and/or 
have their anti-hypertensive therapy optimized due to inadequate BP 
control (as defined by the 2021 KDIGO guideline) will return for 
Unscheduled visits for blood pressure monitoring following Visit 1a.  
Once their treatment and blood pressure have been stable for a 
minimum of 3 weeks, they will return for Visit 1b to have additional 
serum chemistry testing.  The baseline MRI exam should be 
scheduled after completion of Visit 1a but may be performed before, 
at, or after Visit 1b (but prior to Visit 2) depending on scheduling. 
Upon attaining stability of antihypertensive therapy and completion of 
the baseline MRI, the participant will be scheduled for Visit 2 
(approximately 1 week following the MRI and approximately 2 weeks 
following Visit 1b, whichever occurs later.)  The total duration of the 
Screening Period may be extended up to 8 weeks, including the time 
to completion of Visit 2.  
Participants who meet all of the inclusion criteria and none of the exclusion 
criteria and achieve stability of background anti-hypertensive medications (in 
the absence of diuretics) and appropriate blood pressure control (for a 
minimum of 3 weeks) will have Visit 2 end-of-screening assessments and 
eligibility determination (final eGFR eligibility will be delayed until Visit 2 
serum creatinine results are obtained); fasting morning spot (i.e., discard first 
void and sample will be obtained from next void within 30 to 45 minutes) 
urine osmolality will also be measured.  Participants who fail 
inclusion/exclusion criteria due to temporary or correctable reasons may be re-
screened (up to 2 additional times after obtaining new informed consents) and 
after consultation with the medical monitor.  At the successful completion of 
Visit 2, participants will be considered enrolled and will be provided with 
single-blind study drug (placebo) to start the Placebo Run-in Period.  
Participants will take 4 capsules of study drug twice daily (BID) 
approximately 10 hours apart. Throughout the study, participants will take 4 
capsules BID to mask transitions from one study period to the next. 
Placebo Run-in Period (Visit 3): During the 1-week Placebo Run-in Period, 
participants will receive single-blind placebo and take 4 capsules twice daily. 
At the end of the week, participants will attend Visit 3 at which time 
tolerability will be assessed to maintain participant blinding and final baseline 
measurements will be obtained.  Single-blind lixivaptan at a dose of 50 mg 
BID will be dispensed to start the Lixivaptan Titration Period.  At Visit 3, 
participants should take their first dose of study drug from the newly assigned 
(Visit 3) blister card in the clinic following completion of study visit 
procedures and in accordance with the sparse PK sampling schedule (0.5 hrs. 
to 1.5 hrs. post dose) detailed in the Schedule of Procedures – Part 1. 
Lixivaptan Titration Period (Visits 4 to 9):  During a period of 5 to 6 weeks 
for participants who complete the Placebo Run-in Period, the lixivaptan dose 
will be increased in a single-blind fashion according to the titration schedule 
in Table 1 to achieve the maximally tolerated dose up to the maximum dose 
allowed (Level 4 [200 mg BID]); as 4 capsules BID.  The minimum dose to 
enter the Double-blind, Randomized Treatment Period is Level 2 (100 mg 


Palladio Biosciences PA-ADPKD-301                                                                                   
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BID).  Once the maximally tolerated dose has been achieved, tolerability will 
be confirmed over an additional week of dosing before the participant 
advances to randomization.  At the 2 highest dose levels (Level 3 [150 mg 
BID] and Level 4 [200 mg BID]), there will be an opportunity to reduce the 
evening (PM) dose to Level 3a (150 mg AM/100 mg PM) or Level 4a (200 
mg AM/150 mg PM) if aquaretic effects are problematic in certain 
participants.  Further dose reductions are allowable as shown in the Lixivaptan 
Titration Period (Part 1) — Lixivaptan Titration Flowchart.  Fasting morning 
spot (i.e., discard first void and sample will be obtained from next void within 
30 to 45 minutes) urine osmolality will be measured at the last titration visit 
(Visit 9) and serum liver chemistry tests will be measured at Visits 5, 7, and 9. 
Double-blind, Randomized Treatment Period (Visits 10 to 22): Following 
successful completion of titration, participants will be randomized to continue 
to receive lixivaptan at the dose achieved at the end of the Lixivaptan Titration 
Period or matching placebo in a double-blind fashion for 52 weeks as 4 
capsules BID.  Visits will be performed every 4 weeks (± 5 days) during this 
period. Assessments at each visit are detailed in the Schedule of Procedures – 
Part 1. 
Follow-up Period I (Visits 23 to 25): Three visits will occur over a 28-day, 
study drug-free period following the last dose of study drug. Serum creatinine 
and serum cystatin C, to determine eGFR, for primary and exploratory 
analyses, respectively, will be drawn at 3 time points. The first visit (Visit 23) 
will occur on the 8th day (+ 3 days) after the last dose of study drug, and the 
last visit (Visit 25) will occur on the 28th day (± 3 days) after the last dose of 
study drug.  Visit 24 must be scheduled to occur at least 24 hours after Visit 
23 and at least 24 hours prior to Visit 25.  At Visit 25, additional efficacy and 
safety assessments will be performed; a post-baseline MRI for assessment of 
TKV and LV is to be obtained between 25 days and 31 days post last dose of 
study drug and must be completed prior to or on the same day as all other 
Visit 25 study procedures.  Following completion of these assessments, all 
participants (except those who discontinued due to an AE or who have 
withdrawn consent) will immediately continue into Part 2 at Visit 25. 
Note: In the event of tolerability issues at any time during the study, dosing 
may be decreased or temporarily stopped.  If dosing is resumed during the 
Double-Blind Treatment Period at a dose level less than that achieved at Visit 
9, attempts will be made every 4 to 8 weeks to re-establish the previously 
achieved dose level from Visit 9, if medically appropriate. If study drug is 
interrupted for longer than 8 weeks, then study drug treatment will be 
permanently discontinued. 
 
Part 2: The study schematic for Part 2 is depicted in Figure 2. 
Lixivaptan Re-titration Period (Visits 26 to 29): Titration of lixivaptan will 
occur over a 2 to 4-week re-titration period and will start at a dose of 50 mg 
BID beginning at the conclusion of Visit 25. The dose will be increased at 
weekly intervals until the dose level from the end of the Double-blind, 
Randomized Treatment Period in Part 1 is achieved. For participants 
randomized to placebo in Part 1, lixivaptan dosing will be titrated to the final 
blinded inferred dose level (the dose level equal to the active dose level had 
the participant been randomized to the active arm) achieved during the 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Double-Blind Treatment Period in accordance with Table 2.  In order to 
maintain blinding of the treatment assignment from Part 1, the dose level 
assignment for Part 2 will continue to be managed by the IRT. The dose-
titration schedule for this part of the study is described in Table 2.   
Maintenance Treatment Period (Visits 30 to 42): Following completion of the 
Lixivaptan Re-titration Period, participants will continue to receive lixivaptan 
in the Maintenance Treatment Period for 52 weeks at the same dose achieved 
at the end of the Re-titration Period.  Visits will be performed every 4 weeks 
(± 5 days) during this period.  Assessments at each visit are detailed in the 
Schedule of Procedures – Part 2. 
Note: In the event of tolerability issues at any time during the study including 
the Part 2 Lixivaptan Re-titration Period or during the Maintenance Treatment 
Period, dosing may be decreased or temporarily stopped.  Attempts will be 
made every 4 to 8 weeks to re-establish the previously achieved dose level at 
the end of the Double-blind, Randomized Treatment Period of Part 1, if 
medically appropriate. If study drug is interrupted for longer than 8 weeks, 
then study drug treatment will be permanently discontinued. 
Follow-up Period II (Visits 43 to 45):  Three visits will occur over a 28-day, 
study drug-free period following the last dose of lixivaptan in the Maintenance 
Treatment Period.  Serum creatinine and serum cystatin C, to determine eGFR 
for primary and exploratory analyses, respectively, will be drawn at 3 time 
points.  The first visit (Visit 43) will occur on the 8th day (+ 3 days) after the 
last dose of lixivaptan, and the last visit (Visit 45) will occur on the 28th day (± 
3 days) after the last dose of lixivaptan.  Visit 44 must be scheduled to occur 
at least 24 hours after Visit 43 and at least 24 hours prior to Visit 45. At the 
final study visit, Visit 45, additional efficacy and safety assessments will be 
obtained; a post-baseline MRI for assessment of TKV and LV is to be 
obtained between 25 days and 31 days post last dose of study drug and must 
be completed prior to or on the same day as all other Visit 45 study 
procedures. 
The total duration of participation in the study will be approximately 123 to 
131 weeks (up to 71 weeks in Part 1 and up to 60 weeks in Part 2) depending 
on the length of Screening (3 to 8 weeks), Titration (5 to 6 weeks), and Re-
titration (2 to 4 weeks).  Note that the study may be interrupted at any time if 
safety issues identified by an Independent Data Monitoring Committee 
(IDMC) and sponsor potentially compromise the safety of the participants.  
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Study Drug, 
Dosage, and Route 
of Administration: 
The sponsor (Palladio Biosciences, Inc.) will supply lixivaptan 50 mg 
capsules and matching placebo for use during the study. Throughout the study, 
participants will take 4 capsules BID to mask transitions from one study 
period to the next. All doses will be self-administered by participants orally at 
home with the exception of Visit 3 and any other study visit with scheduled 
sparse PK sampling, where in-clinic dosing may be warranted.   
Part 1: During the Placebo Run-in Period, each participant will take 4 placebo 
capsules BID (twice daily, approximately 10 hours apart) for 1 week.  During 
the Lixivaptan Titration Period, dosing will start at Level 1 (50 mg BID) and 
will be increased weekly minimally through Level 2 (100 mg BID) and 
maximally through Level 4 (200 mg BID) according to the dosing schedule 
shown in Table 1.  At the 2 highest dose levels (Level 3 [150 mg BID] and 
Level 4 [200 mg BID]) where aquaretic effects may be problematic in certain 
participants, there will be an opportunity to reduce the evening (PM) dose to 
Level 3a (150 mg AM/100 mg PM) for those at Level 3 or Level 4a (200 mg 
AM/150 mg PM) for those at Level 4.  Further dose reductions are allowable 
as shown in the Lixivaptan Titration Period (Part 1) — Lixivaptan Titration 
Flowchart. Throughout the study, participants will continue to take 4 capsules 
BID to mask transitions from one study period to the next. 
 
Table 1. Dosing Levels during the Titration Period 
Dose Level 
AM Dose 
PM Dose 
1* 
50 mg 
50 mg 
2 
100 mg 
100 mg 
3 
150 mg 
150 mg 
3a** 
150 mg 
100 mg 
4 
200 mg 
200 mg 
4a*** 
200 mg 
150 mg 
*Dose Level 1 is for initiation of treatment. 
**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). 
Once tolerability is achieved, participants will remain on that dose for 1 
additional week to confirm tolerability (Lixivaptan Titration Period (Part 1) — 
Lixivaptan Titration Flowchart). As the maximum duration of the Lixivaptan 
Titration Period is 6 weeks, participants who require a dose reduction at Week 
6 as a result of emerging tolerability issues, will proceed to the double-blind 
period on the newly assigned (reduced) dose level without extension of the 
titration period.  Participants who are unable to tolerate the minimum dose for 
entry into the Double-blind, Randomized Treatment Period (100 mg BID/ 
Level 2) will be discontinued from the study. 
Participants who tolerate their optimized dose will then enter the Double-
blind, Randomized Treatment Period during which time they will be 
randomized 2:1 (lixivaptan: placebo) to continue at the lixivaptan dose level 
achieved at the end of the Lixivaptan Titration Period or receive matching 
placebo capsules.  During the Double-blind, Randomized Treatment Period, 
the dose may be adjusted downward at the Investigator’s discretion if needed 


Palladio Biosciences PA-ADPKD-301                                                                                   
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to manage non-hepatic side effects.  For these participants, the dose level 
should be increased back to the dose at the start of the Double-Blind, 
Randomized Treatment Period, once symptoms resolve.  The Investigator may 
temporarily interrupt the study drug, if necessary, to manage acute intercurrent 
illness, tolerability issues, planned or unplanned surgical procedures or life 
situations, e.g., airplane travel, etc. In an effort to minimize missing data, 
wherever practicable, participants who experience a study drug interruption of 
7 or more days will be scheduled to have 3 separate serum creatinine samples 
obtained (minimally 24 hrs. apart between 8 and 28 days after their last dose) 
for determination of eGFR. Participants who require a prolonged interruption 
due to illness, including COVID-19, or other reasons may be able to restart the 
study drug when medically stable and following discussion with the medical 
monitor and sponsor. Re-titration is required in the event of a prolonged 
interruption. If study drug is interrupted for longer than 8 weeks, then study 
drug treatment will be permanently discontinued. 
Note: In the event of tolerability issues at any time during the study, dosing 
may be decreased or temporarily stopped.  If dosing is resumed during the 
Double-Blind Treatment Period at a dose level less than that achieved at Visit 
9, attempts will be made every 4 to 8 weeks to re-establish the previously 
achieved dose level from Visit 9, if medically appropriate.  
Part 2: During the Lixivaptan Re-titration Period, dosing will start at Level 1 
(50 mg BID) for all participants in Part 2 and will be increased weekly until 
the dose level taken at the end of the Double-blind, Randomized Treatment 
Period is achieved.  This is shown in Table 2.  That dose will be continued for 
the remainder of Part 2.  In the event of tolerability issues at any time during 
the study including either during the Lixivaptan Re-titration Period or during 
the Maintenance Treatment Period, dosing may be decreased or temporarily 
stopped.  Attempts will be made every 4 to 8 weeks to re-establish the 
previously achieved dose level at the end of the Double-blind, Randomized 
Treatment Period of Part 1, if medically appropriate. If tolerability continues 
to be problematic, the participant may continue at the lower dose.  If study 
drug is interrupted for longer than 8 weeks, then study drug treatment will be 
permanently discontinued. 
 
 
 
 
 
 
 
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Table 2. Dose Titration (Part 2) Based on Dose Level Achieved at End of 
Double-blind Randomized Treatment Period in Part 1 for 
Participants Assigned to Lixivaptan or Placebo in Part 1 
Dose Level in Part 1* 
Week 1 
Week 2 
Week 3 
Week 4 
Level 1 
100mg BID or Placebo 
50mg BID 
100mg BID 
 
 
Level 2 
150mg BID or Placebo 
50mg BID 
100mg BID 
150mg BID 
 
Level 3a 
150/100mg (AM/PM) 
or Placebo 
50mg BID 
100mg BID 
150/100mg  
(AM/PM) 
 
Level 4 
200mg BID or Placebo 
50mg BID 
100mg BID 
150mg BID 
200mg BID 
Level 4a 
200/150mg (AM/PM) 
or Placebo 
50mg BID 
100mg BID 
150mg BID 
200/150mg 
(AM/PM) 
*Participants whose dose was reduced to Level 1 (50 mg BID lixivaptan or placebo) during the 
double-blind phase as a result of tolerability issues or treatment-emergent AEs can continue on 
that dose during the open-label phase. These participants will initiate dosing with lixivaptan at 
50mg BID and remain on that dose for 2 weeks during the Re-titration Period and initiate the 
open-label phase at that dose.  Attempts will be made every 4 to 8 weeks to re-establish dosing 
at Level 2 (100 mg BID) during the open-label phase. 
Study 
Assessments: 
Efficacy: eGFR based on serum creatinine, TKV by MRI 
Safety: Liver chemistry tests (ALT, AST, total bilirubin, direct bilirubin, 
alkaline phosphatase), clinical laboratory parameters (hematology, non-
hepatic clinical chemistry including serum sodium and urinalysis), 12-lead 
ECGs, vital signs, physical examinations, adverse events (AEs), and serious 
adverse events (SAEs) 
Pharmacokinetic: Sparse plasma levels of lixivaptan for PopPK  
Health Outcomes: Medical resource utilization (e.g., medication 
use/changes; unplanned office visits; urgent care and emergency department 
usage; and hospitalizations) resulting from clinical events during the study; 
ADPKD-IS; ADPKD-PDS; ADPKD-UIS  
Exploratory: LV by MRI, urine osmolality, eGFR based on combined use of 
serum creatinine and cystatin C  
Criteria for 
Evaluation: 
Part 1: 
Primary Efficacy Endpoint: Annualized change in eGFR, calculated from 
the 2021 CKD-EPI equation (CKD-EPIcr_R) for serum creatinine, from 
baseline (mean of 3 eGFR determinations obtained during Screening and 
Placebo Run-in Periods (Visits 1a or 1b (if required), Visit 2, and Visit 3) to 
final assessment (mean of 3 eGFR determinations obtained during Follow-up 
Period I or, for participants who discontinue treatment prior to Visit 22, during 
the Follow-up Period 8 to 28 days following study drug treatment 
discontinuation).  
Key Safety Endpoint: Incidence of serum ALT levels >3 x ULN in 
participants randomized to lixivaptan compared to those randomized to 
placebo. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Part 2: 
Key Comparison Endpoint: Annualized change in eGFR from baseline (the 
mean of the 3 eGFR measurements obtained during Follow-up Period I) to the 
final post-treatment assessment in Part 2 (the mean of the 3 eGFR 
measurements obtained during Follow-up Period II). 
Key Safety Endpoint: Incidence of serum ALT levels > 3 x ULN in 
participants exposed to lixivaptan in Part 2. 
Independent Data 
Monitoring 
Committee 
An independent data monitoring committee (IDMC) has been appointed for 
this study.  
Statistical 
Methods: 
Sample Size: 
Part 1: Based on the results of the REPRISE trial with tolvaptan, it is 
assumed that the standard deviation for the primary efficacy endpoint, change 
from baseline to post-treatment follow-up in mean eGFR, is 6.20 mL per 
minute per 1.73 m2.  Assuming a between-treatment group difference of -1.40 
mL per minute per 1.73 m2 and a randomization ratio of 2:1 for lixivaptan to 
placebo, a sample size estimate of 1314 participants (438 placebo participants 
and 876 lixivaptan participants) is required to achieve 90% power at a 
significance level of 0.01.  In order to compensate for possible dropouts, this 
estimate has been adjusted up to 1350 participants (450 placebo participants 
and 900 lixivaptan participants).  It is estimated that approximately 2250 
participants will need to be screened in order to randomize 1350 participants. 
Part 2: This is a convenience sample based on the number of participants who 
continue into Part 2.  It is estimated that approximately 1350 participants will 
be randomized in Part 1.  All participants except those who discontinue due to 
an adverse event or withdraw consent will continue in Part 2.  Approximately 
90% (1215) of Part 1 participants are anticipated to continue in Part 2. 
Populations for Analysis: 
Part 1: The following populations will be used for analyzing the data from 
Part 1. 
Treated Safety Set:  The Treated Safety Set consists of all participants who 
received at least 1 dose of study drug in Part 1. 
Randomized Safety Set:  The Randomized Safety Set consists of all 
participants in the Treated Safety Set who are randomized and receive at least 
1 dose of randomized study drug. 
Primary Efficacy Analysis Set:  The Primary Efficacy Analysis Set consists of 
all participants in the Randomized Safety Set who have both baseline and at 
least 1 valid assessment of eGFR in the Follow-up Period. 
Secondary Efficacy Analysis Set:  The Secondary Efficacy Analysis Set 
consists of all participants in the Randomized Safety Set who have both 
baseline and at least 1 on-treatment assessment of eGFR. 
Part 2: The following populations will be used for analyzing the data from 
Part 2. 
Long-term Safety Set:  The Long-term Safety Set consists of all participants in 
the Randomized Safety Set of Part 1 who receive at least 1 dose of lixivaptan 


Palladio Biosciences PA-ADPKD-301                                                                                   
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during Part 2. 
Long-term Full Analysis Set: All participants in the Long-term Safety Set who 
have at least 1 on-treatment measurement of eGFR in Part 2. 
Long-term Efficacy Analysis Set: All participants in the Long-term Full 
Analysis Set who were randomized to lixivaptan in Part 1. 
Primary Efficacy Analysis: 
Part 1: Baseline eGFR is defined as the mean of the 3 eGFR assessments 
obtained during the Screening and single-blind, Placebo Run-in Periods.  The 
primary efficacy analysis will utilize the change from this baseline eGFR to 
the post-treatment follow-up eGFR, annualized by each participant’s treatment 
duration.  The post-treatment follow-up eGFR is defined as the mean of 3 
eGFR assessments obtained during the Follow-up Period I or the equivalent 
off-therapy eGFR determinations if a participant discontinues study drug 
earlier. The eGFR for the primary analysis will be based on serum creatinine 
using the CKD-EPIcr_R equation.  
The estimand corresponding to the primary objective is the between-treatment 
group difference in the change from baseline in eGFR if all the participants in 
the Primary Efficacy Analysis Set (PEAS) had tolerated and adhered to their 
treatment for 12 months.  Missing data due to randomized participants 
prematurely discontinuing from double-blind treatment will be handled by 
annualizing the changes from baseline as follows: each participant’s change 
from baseline will be divided by the duration in days from the median of the 
baseline eGFR assessments to the median of the 3 eGFR assessments obtained 
during Follow-up Period I and then multiplied by 365.25 days.    
The primary efficacy endpoint, the annualized change from baseline to post-
treatment follow-up in mean eGFR, will be analyzed by means of an analysis 
of covariance model with fixed effects for treatment group and the 
randomization stratification factors and the baseline eGFR as a covariate. 
The primary efficacy analysis will be performed at the 1% level of 
significance (P<0.01). 
Sensitivity analyses of the primary efficacy analysis will include the use of the 
mean of eGFR values obtained pretreatment and the mean of eGFR values 
obtained off treatment after the end of the 52-week treatment period, 
regardless of adherence to randomized treatment and/or withdrawal for all 
randomized participants, i.e., Intent-To-Treat participants. Week 52 missing 
values will be imputed using multiple imputations (assuming missing at 
random). Bi-directional tipping point analyses will be included using a 
pattern-mixture model to impute missing data at Week 52 (assuming missing 
not at random); allowing varying assumptions about the missing outcomes on 
the two treatment arms.  
Key Comparison  
Key Comparison Analysis 
Part 2: Baseline eGFR is defined as the mean of the 3 eGFR assessments 
obtained during Follow-up Period I.  
Descriptive statistics will be presented for the mean of the annualized changes 
from this baseline to the mean of the 3 eGFR measurements during Follow-up 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Period II for participants in the Long-term Efficacy Analysis Set.  This will be 
compared to descriptive statistics for the corresponding annualized change in 
eGFR for Part 1 for the same analysis set. 
Safety 
Key Safety – Liver Safety Analysis: 
Part 1 and 2: Incidence of serum ALT levels >3 x ULN will be summarized 
by treatment group in Part 1 and for all participants in Part 2. 
Additional Safety Analyses: 
Part 1: All safety analyses will be summarized for the following: 
• 
Single-Blind Placebo Run-in Period for the Treated Safety Set 
• 
Lixivaptan Titration Period for the Treated Safety Set 
• 
The Randomized, Double-blind Treatment and Follow-up Periods for 
the Randomized Safety Set 
Treatment-emergent adverse events, clinical laboratory data, 12-lead ECGs, 
and vital signs findings will be analyzed using appropriate descriptive 
statistics by treatment group.  Potentially clinically significant results in 
clinical laboratory tests, 12-lead ECGs, and vital signs identified using 
prospectively defined criteria, including criteria on liver enzyme elevations, 
will also be summarized by treatment group. 
Part 2: Safety analyses will be performed for the Long-term Safety Analysis 
Set based on TEAEs, clinical laboratory data, 12-lead ECGs, and vital signs 
findings using appropriate descriptive statistics overall and by treatment 
groups from Part 1.  Potentially clinically significant results in clinical 
laboratory tests, 12-lead ECGs, and vital signs identified using prospectively 
defined criteria, including criteria on liver enzyme elevations, will also be 
summarized overall and by treatment group from Part 1. 
 
 


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Figure 1. Part 1 Study Schematic 
 
    SB = Single-Blind, PBO = Placebo 
 
Figure 2. Part 2 Study Schematic 
 
 


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Figure 3. Lixivaptan Titration Period (Part 1) — Lixivaptan Titration Flowchart 
 


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Table 3. Schedule of Procedures – Part 1 
Screening Period 
Single-Blind 
Double-blind Randomized 
Treatment Period 
Follow-up Period Ib 
Placebo 
Run-in 
Period 
Lixivaptan Titration Perioda 
Period Duration 
3 to 8 weeksc 
1 week 
5 to 6 weeks 
52 weeks 
4 weeks 
Visit Number 
V1a (V1b) 
V2 
V3 
V4 
V5 V6 V7 (V8)d V9/ 
Last 
V10-V21e 
V22/ETf 
V23 
V24 
V25 
Visit Timing 
V1b is 
utilized as 
described 
belowc 
2-5
weeks 
after 
V1a; 1-5 
weeks 
after 
V1bc 
1 week ± 2 
days after 
V2 
Every week ± 2 days 
Every 4 
weeks ± 5 
days 
Week 52 ± 5 
days 
8 + 3 
days 
after last 
dose 
≥ 24 
hrs. 
after 
V23 and 
≥ 24 
hrs. 
before 
V25 
28 ± 3 
days 
after 
last dose 
Informed consent 
X 
Inclusion/exclusion 
X 
X 
X 
Demographic information 
X 
Medical history 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationh 
X 
V15 
X 
X 
Body weight/heighti 
X 
X 
X 
X 
X 
Urine pregnancy test 
(WOCBP)j 
X 
X 
X V12, V15, V18 
X 
X 
ECG 
X 
X 
V15 
X 
X 
MRIk 
X 
X 
Chemistry blood samplesl 
Chemistry  
X 
X 
X 
X V12, V15, V18 
X 
X 
Serum sodium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Serum cystatin C 
X 
X 
X 
X 
X 
X 
X 
Hematology  
X 
X 
X 
V15 
X 
X 


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Screening Period 
Single-Blind 
Double-blind Randomized 
Treatment Period 
Follow-up Period Ib 
Placebo 
Run-in 
Period 
Lixivaptan Titration Perioda 
Period Duration 
3 to 8 weeksc 
1 week 
5 to 6 weeks 
52 weeks 
4 weeks 
Visit Number 
V1a (V1b) 
V2 
V3 
V4 
V5 V6 V7 (V8)d V9/ 
Last 
V10-V21e 
V22/ETf 
V23 
V24 
V25 
Visit Timing 
V1b is 
utilized as 
described 
belowc 
2-5
weeks 
after 
V1a; 1-5 
weeks 
after 
V1bc 
1 week ± 2 
days after 
V2 
Every week ± 2 days 
Every 4 
weeks ± 5 
days 
Week 52 ± 5 
days 
8 + 3 
days 
after last 
dose 
≥ 24 
hrs. 
after 
V23 and 
≥ 24 
hrs. 
before 
V25 
28 ± 3 
days 
after 
last dose 
Serology (HbsAg, Anti-
HCV)m 
X 
PK plasma samplen 
X 
X 
X V12, V15, V18 
Urinalysis 
X 
X 
X 
X 
Urine osmolalityo 
X 
X 
V15 
X 
X 
Study drug tolerabilityp 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
Telephone contacte 
---------------------------------------X-------------------------------→ 
Study drug dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Study drug reconciliation and 
compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IRT entry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical resource utilization 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADPKD-IS 
X 
X V12, V15, V18 
X 
X 
ADPKD-PDS 
X 
X V12, V15, V18 
X 
X 
ADPKD-UIS 
X 
X 
X 
X 
X 
X 
X V12, V15, V18 
X 
X 
Adverse events/SAEs 
------------------------------------------------------------------------------------X----------------------------------------------------------------------------→ 
Prior/concomitant 
medications 
------------------------------------------------------------------------------------X----------------------------------------------------------------------------→ 


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ADPKD = Autosomal Dominant Polycystic Kidney Disease; ADPKD-IS =ADPKD-Impact Scale; ADPKD-PDS = ADPKD-Pain and Discomfort Scale; ADPKD-UIS 
= ADPKD-Urinary Impact Scale; Anti-HCV = hepatitis C antibody; ET = Early termination visit; HbsAg = hepatitis B surface antigen; hrs. = hours; IRT = interactive 
response technology; Last = Last titration visit; PK = pharmacokinetic; V = Visit; WOCBP = women of childbearing potential; ( ) = Not all participants will need 
these visits 
Visits 4 to 7, 10, 11, 13, 14, 16, 17, 19 to 21, 23 and 24 may be conducted in the clinic or remotely by a home healthcare clinician or qualified site personnel with the 
agreement of the participant and the discretion of the investigator, and where it is available and locally approved by the Competent Authority and/or Ethics 
Committee/Institutional Review Board.  If conducted remotely, Visits 4 to 7 will require a telehealth visit (e.g., telemedicine virtual visit, telephone or video call 
(without recording)) with the Investigator 2 days prior to the scheduled in-home visit to assess tolerability.  This will allow sufficient time for IRT study drug 
assignment and subsequent direct-to-participant drug dispensing prior to the scheduled in-home visit.  All other remote visits may include a telehealth visit with the 
Investigator as needed. 
 
a. Lixivaptan Titration Period will last 5 to 6 weeks. At Visits 4 to 8 the lixivaptan dose will be titrated to achieve the highest tolerated dose.  All participants will 
start at Level 1 (50 mg BID) at the end of V3 and will be titrated weekly through Level 2 (100 mg BID), Level 3 (150 mg BID), and Level 4 (200 mg BID), based 
on tolerability. The minimum dose to enter the Double-blind, Randomized Treatment Period is Level 2. If tolerability is limited at the 2 highest dose levels (Level 
3 [150 mg BID] and Level 4 [200 mg BID]) by aquaretic effects, reduction of the evening dose is allowed: to Level 3a (150/100 mg [AM/PM]) or Level 4a 
(200/150 mg [AM/PM]), respectively.  Further dose reductions are allowable as shown in the Lixivaptan Titration Period (Part 1) — Lixivaptan Titration 
Flowchart.  Note: In the event of tolerability issues at any time during the study, dosing may be decreased or temporarily stopped.  If dosing is resumed during 
the Double-Blind Treatment Period at a dose level less than that achieved at Visit 9 , attempts will be made every 4 to 8 weeks to re-establish the previously 
achieved dose level from Visit 9, if medically appropriate. If study drug is interrupted for longer than 8 weeks, then study drug treatment will be permanently 
discontinued. 
b.    During the study drug-free Follow-up Period I, 3 visits will occur to obtain the 3 serum creatinine values for calculation of eGFR to determine the primary 
endpoint.  The first visit (V23) will occur on the 8th day (+ 3 days) after the last dose of study drug and the last visit (V25) will occur on the 28th day (± 3 days) 
after the last dose of study drug.  V24 must be scheduled to occur at least 24 hours after V23 and at least 24 hours prior to V25.  At the final visit (V25), the listed 
additional safety and efficacy assessments will be completed.  Participants who have not discontinued due to an AE or withdrawn consent will then continue into 
the Re-titration Period of Part 2 by resuming study drug dosing at Level 1 (50 mg BID). 
c.    At Visit 1a all indicated information will be collected to determine preliminary eligibility and the baseline MRI to determine TKV and LV will be scheduled.   
i) Participants with appropriate blood pressure control for a minimum of 3 weeks prior to enrollment (Visit 2) (as defined by the 2021 KDIGO guideline) 
including those on stable ACEi or ARB treatment (unless not considered appropriate) and not receiving a diuretic will proceed to V2 3 to 5 weeks after Visit 1a, 
and after completion of the baseline MRI (allow approximately 1 week between the completion of the MRI and Visit 2). (Screening may be extended to a 
maximum of 8 weeks, in the event of extenuating circumstances. Prior approval from the medical monitor is required.)  
ii) Participants who need to be discontinued from diuretic therapy and/or have their anti-hypertensive therapy optimized due to inadequate BP control (as defined 
by the 2021 KDIGO guideline) will return for Unscheduled visits for blood pressure monitoring following Visit 1a.  Once their treatment and blood pressure have 
been stable for a minimum of 3 weeks, they will return for V1b to have additional serum chemistry testing.  The baseline MRI exam may be performed before, at, 
or after Visit 1b, depending on scheduling.  Upon attaining stability of antihypertensive therapy and completion of the baseline MRI, the participant will be 
scheduled for V2, approximately 1 week following the MRI and approximately 2 weeks following Visit 1b, whichever occurs later.  The total duration of 
Screening, including completion of V2 should not exceed 8 weeks. 
d. Participants who complete the Lixivaptan Titration Period in 5 weeks, including the additional week at the same dose to confirm tolerability, will skip V8 and 
instead complete the assessments scheduled for V9/Last Titration Visit.  Participants who may be eligible to skip V8 (Lixivaptan Titration Period (Part 1) — 
Lixivaptan Titration Flowchart) should be provided with a collection kit for urine osmolality at V7 in the event that they will have V9 assessments performed at 
the next visit. 
  
e. 
To encourage study compliance, during the Double-Blind Randomized Treatment Period, telephone contacts will be made 2 weeks (± 5 days) after every 
scheduled visit..  All telephone contacts with the participant will be recorded in the source document. 


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f.     Participants who discontinue study drug or withdraw from the study at any time after the start of the Placebo Run-In Period should undergo V22/ET procedures 
within 7 days of the last dose of study drug. Randomized participants should additionally continue into Follow-up Period I for final assessments of safety and 
efficacy.   
g.    Vital signs after the participant has been sitting for 5 minutes include heart rate, blood pressure, respiratory rate, and temperature at V1a.  At all subsequent visits, 
vital signs include sitting heart rate and sitting blood pressure.  The same position should be used at each visit (Section 7.3.3). 
h.  A full physical examination will be performed at V1a.  A brief physical examination will be performed at V15, V22 and V25.  Additional physical examinations 
will be performed only for assessment of signs or symptoms reported by the participant that might require further evaluation. 
i.  Height will be measured at V1a. Weight will be measured at V1a, V3, V9/Last Titration, V22/ET, and V25.  Weight may be measured at any other visit to assess 
hydration status, as necessary. 
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.  Baseline MRI will be scheduled at Visit 1a for all participants in order to determine eligibility according to Mayo Clinic ADPKD Image Classification in time for 
Visit 2.  The post-baseline MRI scheduled for Visit 25 must be completed between 25 days and 31 days post last dose of study drug and must be completed prior 
to or on the same day as all other Visit 25 study procedures.  Volumetric calculations and other derived data from any post-baseline MRI will NOT be shared with 
the participant, the investigator, the clinical sites, the sponsor, or the contract research organization (CRO) because of the potential for unblinding. 
l.     Sampling for analysis of blood chemistry will follow the visit schedule specified in Table 3. Chemistry includes the following parameters: albumin; blood urea 
nitrogen (urea); calcium; chloride; carbon dioxide (CO2); glucose; phosphorous; potassium; protein; sodium; uric acid. Serum sodium will be assessed at the time-
points specified in Table 3 either as part of chemistry or liver chemistry testing.  Liver chemistry includes alkaline phosphatase; ALT; AST; bilirubin (total and 
direct). Blood samples for serum creatinine and serum cystatin C will be collected for calculation of eGFR in accordance with Table 3.  At Visits 1a, 1b (if 
required), 2, and 3 and again at Visits 23, 24, and 25, every effort should be made to draw blood samples for serum creatinine and serum cystatin C at 
approximately the same clock time for a given participant. Laboratory test results from samples collected as specified in Table 3 are to be reviewed and assessed.  
   m.    Participants with positive test results for hepatitis C (HCV) antibody (Anti-HCV), will require a negative HCV RNA titer reflex test prior to enrollment.  
           HCV sero-positive participants will undergo reflex testing at an Unscheduled Visit prior to Visit 2. 
n.    A single plasma specimen for sparse PK sampling will be obtained at the following visits and time-points: V2 (any time), V3 (0.5 to 1.5 hours post-dose),     
           V9/Last Titration (any time post-dose), V12 (pre-dose), V15 (1 to 6 hours post-dose), and V18 (6 to 10 hours post-dose).  Results from PK samples will NOT be   
           shared with the participant, the investigator, the clinical sites, the sponsor, or the CRO because of the potential for unblinding. 
o.  Urine osmolality (analyzed centrally) will be collected as a fasting (≥8 hrs. except for water) AM trough (i.e., before the morning dose of study drug) urine 
specimen at V2, V9, V15, V22/ET, and V25. Participants will be provided with a collection kit for urine osmolality at the visit preceding urine osmolality 
assessments.  Results from those visits occurring after randomization will NOT be shared with the participant, the investigator, the clinical sites, the sponsor, or 
the CRO because of the potential for unblinding. 
p.    At Visits 3 to 9, the following single tolerability question will be asked, “Would you take the study drug for the next 24 months?” 
q.    Participants continuing into Part 2 will be dispensed open-label lixivaptan (50mg BID) for initiation of the Lixivaptan Re-titration Period. 
 
 


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Table 4. Schedule of Procedures – Part 2 
Lixivaptan Re-titration Perioda 
Maintenance Treatment Period 
Follow-up Period IIb 
Period Duration 
2 to 4 weeks 
52 weeks 
4 weeks 
Visit Number 
V26 
(V27) 
(V28) 
V29/ 
Last 
V30 – V41 
V42/ETc 
V43 
V44 
V45 
Visit Timing 
Every week ±2 days 
Every 4 weeks ± 5 
days 
Week 104 
± 5 days 
8 + 3 days 
after last dose 
≥ 24 hrs. 
after V23 and 
≥ 24 hrs. before 
V25 
28 ± 3 days 
after last dose 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
Physical examinatione 
V35 
X 
X 
Weightf 
X 
X 
X 
Urine pregnancy test (WOCBP)g 
V32, V35, V38 
X 
X 
MRIh 
X 
Chemistry blood samplesi 
Chemistry 
X 
V32, V35, V38 
X 
X 
Serum sodium 
X 
X 
X 
X 
Liver chemistry 
X 
X 
X 
X 
X 
Serum creatinine 
X 
X 
X 
X 
X 
X 
Serum cystatin C 
X 
X 
X 
Hematology 
X 
V35 
X 
X 
ECG 
X 
V35 
X 
X 
PK plasma samplej 
X 
V32, V35, V38 
Urinalysis 
X 
X 
X 
Urine osmolalityk 
X 
V35 
X 
X 
Telephone contactl 
---------------------------------------------------------X-------------------------------------------------→ 
Study drug dispensing 
X 
X 
X 
X 
X 
Study drug reconciliation and 
compliance 
X 
X 
X 
X 
X 
X 
Medical resource utilization 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADPKD-IS 
X 
V32, V35, V38 
X 
X 
ADPKD-PDS 
X 
V32, V35, V38 
X 
X 


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Lixivaptan Re-titration Perioda 
Maintenance Treatment Period 
Follow-up Period IIb 
Period Duration 
2 to 4 weeks 
52 weeks 
4 weeks 
Visit Number 
V26 
(V27) 
(V28) 
V29/ 
Last 
V30 – V41 
V42/ETc 
V43 
V44 
V45 
Visit Timing 
Every week ±2 days 
Every 4 weeks ± 5 
days 
Week 104 
± 5 days 
8 + 3 days 
after last dose 
≥ 24 hrs. 
after V23 and 
≥ 24 hrs. before 
V25 
28 ± 3 days 
after last dose 
ADPKD-UIS 
X 
X 
X 
X 
V32, V35, V38 
X 
X 
IRT Entry 
-------------------------------------------------------------------------------X------------------------------------------------------------------------------→ 
Adverse events/SAEs 
-------------------------------------------------------------------------------X------------------------------------------------------------------------------→ 
Concomitant medications 
-------------------------------------------------------------------------------X------------------------------------------------------------------------------→ 
ADPKD = Autosomal Dominant Polycystic Kidney Disease; ADPKD-IS =ADPKD-Impact Scale; ADPKD-PDS = ADPKD-Pain and Discomfort Scale; ADPKD-UIS 
= ADPKD-Urinary Impact Scale; ET= Early termination visit; hrs. = hours; IRT = interactive response technology; Last = Last re-titration visit; PKD = Polycystic 
Kidney Disease; V = Visit; WOCBP = women of childbearing potential; ( ) = Not all participants will need these visits. 
Visits 26 to 28, 30, 31, 33, 34, 36, 37, 39 to 41, 43, and 44 may be conducted in the clinic or remotely by a home healthcare clinician or qualified site personnel with 
the agreement of the participant and the discretion of the investigator, and where it is available and locally approved by the Competent Authority and/or Ethics 
Committee/Institutional Review Board.  Remote visits may include a telehealth visit with the investigator as needed. 
a.
Lixivaptan will be resumed at V25 at a dose of 50 mg BID for 1 week, after which the dose will be increased weekly until the dose taken at the end of the
Double-blind, Randomized Treatment Period of Part 1 (as determined by the IRT) is achieved (Table 2).  Dosing will continue for the remainder of the study at
this level.  However, if there is difficulty with tolerability either during the Lixivaptan Re-titration Period or during the Maintenance Treatment Period, the dose
may be decreased or temporarily stopped.  Attempts will be made every 4 to 8 weeks to re-establish the previously achieved dose level from Part 1, if medically
appropriate.  If tolerability continues to be problematic, the participant may continue at the lower dose.  If study drug is interrupted for longer than 8 weeks, then
study drug treatment will be permanently discontinued.  Participants who complete the Lixivaptan Re-Titration Period in 2 weeks will skip V27 and V28 and
those completing the re-titration period in 3 weeks will skip V28; instead, the assessments scheduled for V29/Last Titration Visit will be completed.
b.
Follow-Up Period II will start at the completion of V42. During this study drug-free period, 3 visits will occur to obtain 3 serum creatinine values for calculation
of eGFR to determine the key comparison endpoint. At the final follow-up visit (V45), the listed additional safety and efficacy assessments will be completed.
The first visit will occur on the 8th day (+ 3 days) after the last dose of lixivaptan and the last visit will occur on the 28th day (± 3 days) after the last dose of
lixivaptan.  V44 must be scheduled to occur at least 24 hours after V43 and at least 24 hours prior to V45.
c.
Participants who discontinue from the study should undergo V42/ET procedures within 7 days of the last dose of lixivaptan and subsequently continue into
Follow-up Period II for final assessments of safety and efficacy.
d.
Vital signs will include sitting heart rate and sitting blood pressure. The same position should be used at each visit (Section 7.3.3).
e.
A brief physical examination will be performed at V35, V42/ET and V45.  Additional physical examinations will be performed only for assessment of signs or
symptoms reported by the participant that might require further evaluation.
f.
Weight may be measured to assess hydration status as necessary at visits other than those indicated in Table 4.
g.
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.


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  h.     The post-baseline MRI scheduled for Visit 45 must be completed between 25 days and 31 days post last dose of study drug and must be completed prior to or on  
           the same day as all other Visit 45 study procedures.  Volumetric calculations and other derived data from any post-baseline MRI will NOT be shared with the  
           participant, the investigator, the clinical sites, the sponsor, or the CRO because of the potential for unblinding. 
i. 
Sampling for analysis of blood chemistry will follow the visit schedule specified in Table 4. Chemistry includes the following parameters:  
albumin; blood urea nitrogen (urea); calcium; chloride; carbon dioxide (CO2); glucose; phosphorous; potassium; protein; sodium; uric acid. Serum sodium will be 
assessed at the time-points specified in Table 4 either as part of chemistry or liver chemistry testing.  Liver chemistry includes alkaline phosphatase; ALT; AST; 
bilirubin (total and direct).  Blood samples for serum creatinine and serum cystatin C will be collected for calculation of eGFR in accordance with Table 4.  At 
Visits 43, 44, and 45 every effort should be made to draw blood samples for serum creatinine and serum cystatin C at approximately the same clock time as for 
Visits 23, 24, and 25 for a given participant. Laboratory test results from samples collected as specified in Table 4 are to be reviewed and assessed. 
   j.      A single plasma specimen for sparse PK sampling will be obtained at the following visits and time-points: V29/Last Re-titration (1 to 6 hours post-dose),  
           V32 (pre-dose), V35 (6 to 10 hours post-dose), and V38 (any time post-dose).  Results from PK samples will NOT be shared with the participant, the  
           investigator, the clinical sites, the sponsor, or the CRO because of the potential for unblinding. 
  k.      Urine osmolality (analyzed centrally) will be collected as a fasting (≥8 hrs. except for water) AM trough (i.e., before the morning dose of study drug) urine  
        specimen at V29, V35, V42, and V45. Participants should be provided with a collection kit for urine osmolality at the visit preceding urine osmolality  
assessments.  Results from those visits occurring after randomization will NOT be shared with the participant, the investigator, the clinical sites, the sponsor, or 
the CRO because of the potential for unblinding. 
  l.       During the Maintenance Treatment Period, participant follow-up via a telephone contact will be made 2 weeks (± 5 days) after every scheduled visit.   All  
           telephone contacts with the participant will be recorded in the source document.


Palladio Biosciences PA-ADPKD-301                                                                                   
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACEi 
angiotensin-converting enzyme inhibitor 
ADPKD 
autosomal dominant polycystic kidney disease 
ADPKD-IS 
ADPKD-Impact Scale 
ADPKD-PDS 
ADPKD-Pain and Discomfort Scale 
ADPKD-UIS 
ADPKD-Urinary Impact Scale 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
ART 
anti-retroviral therapy 
AST 
aspartate aminotransferase 
BID 
twice per day 
BMI 
body mass index 
BP 
blood pressure 
cAMP 
cyclic adenosine 3’,5’-monophosphate 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CKD-EPIcr_R 
Chronic Kidney Disease Epidemiology Collaboration eGFR 
creatinine equation refit without the race variable  
CKD-EPIcr-cys_R Chronic Kidney Disease Epidemiology Collaboration eGFR 
creatinine and cystatin C equation refit without the race variable  
CRA 
clinical research associate 
CRO 
contract research organization 
CS 
clinically significant 
CT 
computerized tomography 
DILI 
drug induced liver injury 
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 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Abbreviation 
Definition 
GCP 
Good Clinical Practices 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HERC 
Hepatic Events Review Committee 
HHC 
home healthcare clinician 
HIF-PH 
hypoxia-inducible factor prolyl hydroxylase 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
KDIGO 
The Kidney Disease: Improving Global Outcomes  
LV 
liver volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model for repeated measures 
MRI 
magnetic resonance imaging 
NCS 
not clinically significant 
OTC 
over-the-counter 
PEAS 
primary efficacy analysis set 
PK 
Pharmacokinetics 
PKD 
polycystic kidney disease 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEAS 
secondary efficacy analysis set 
SGLT2 
sodium-glucose cotransporter 2 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TKV 
total kidney volume 
ULN 
upper limit of normal 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Abbreviation 
Definition 
Uosm 
urine osmolality  
US 
United States 


Palladio Biosciences PA-ADPKD-301                                                                                   
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1 INTRODUCTION 
1.1 Background 
Lixivaptan (also known as VPA985, 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 (Uosm), increasing urine flow, 
and increasing serum osmolality as well as restoring normal levels of intracellular cyclic 
adenosine 3’,5’-monophosphate (cAMP) (Chebib, 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 can be found in the Lixivaptan 
Investigator’s Brochure (IB). 
1.2 Overview of ADPKD 
Definition 
ADPKD is a hereditary kidney disorder characterized by cyst formation and progressive 
enlargement in the kidney, liver, and other organs.  It results from loss-of-function mutations 
in either of 2 genes (pkd1 and pkd2), encoding transmembrane proteins polycystin 1 (PC1) 
and polycystin 2 (PC2), respectively.  
In the kidney, loss-of-function mutations in pkd1 or pkd2 disrupt the normal differentiated 
phenotype of the renal tubular epithelium.  These mutations lead to elevated intracellular 
levels of cAMP, which in turn results in increased cellular division and apoptosis, a loss of 
mitotic polarity, a disruption of the normal differentiated cellular phenotype, cyst formation, 
and fluid secretion into kidney cysts (Antignac et al, 2015).  The progressive development 
and growth of numerous bilateral kidney cysts results in fibrosis, kidney architectural 
derangement, and destruction of normal kidney tissue.  Disease progression is characterized 
by urine concentration defects, hypertension, acute and chronic pain, kidney stones, 
haematuria, cyst and urinary tract infections, and, most importantly, kidney function loss and 
kidney failure (Antignac et al, 2015, Chapman et al, 2015).  
The most frequent extrarenal manifestation of ADPKD is polycystic liver disease, which is 
typically associated with increased kidney volume, older age, and female sex.  Liver cysts are 
usually asymptomatic, and the liver chemistry is normal.  However, in some cases the 
increased liver volume may lead to hepatomegaly as a result of the continuous cyst 
enlargement (Hogan et al, 2015).  This may cause symptoms of extrinsic compression, such 
as abdominal pain, early satiety, and obstruction of the hepatic veins or bile duct.  Moreover, 
liver cyst infections may cause fever, right upper abdominal pain, and/or possible elevated 
CA19.9 and alkaline phosphatase levels.  


Palladio Biosciences PA-ADPKD-301                                                                                   
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Epithelial cells derived from human ADPKD cysts generate elevated intracellular levels of 
cAMP in response to vasopressin, which in turn promotes cell proliferation and electrolyte 
secretion (Belibi et al, 2004). Increased fluid secretion into cysts is due to vasopressin-
induced transepithelial secretion of chloride.  Patients with ADPKD also have elevated 
plasma concentrations of vasopressin or an exaggerated vasopressin response to sodium 
challenge as compared to normal individuals (Torres, 2005).  Pharmacological interventions 
aimed at inhibiting vasopressin signalling are, therefore, expected to restore normal cellular 
function and provide a disease-modifying effect on disease progression in ADPKD. 
1.3 Overview of Available Therapies for ADPKD 
Demonstration of the utility of vasopressin V2 receptor antagonists for the treatment of 
ADPKD is provided by the experience with tolvaptan.  Results from the TEMPO 3:4 Phase 3 
trial showed that tolvaptan slowed the progression of kidney enlargement and delayed the 
worsening of kidney function (Torres et al, 2012).  The study also established suppression of 
urine osmolality to <250 mOsm/kg as a predictive pharmacodynamic marker of clinical 
efficacy for a vasopressin V2 antagonist for the treatment of ADPKD (Devuyst et al, 2017).  
Subsequently, the REPRISE Phase 3 study with tolvaptan demonstrated that the efficacy of 
vasopressin V2 receptor antagonism is maintained in patients with later stage ADPKD (Torres 
et al, 2017).   
The European Medicines Agency granted a positive opinion for tolvaptan (JINARC®) in 
2015 to slow the progression of cyst development and failing kidney function in adult 
patients with ADPKD with normal to moderately-reduced kidney function who have rapidly 
progressing ADPKD.  The Committee for Medicinal Products for Human Use recommended 
additional monitoring of the risk of liver damage with tolvaptan.  Similar approvals were 
granted in Japan, Canada, and Australia/New Zealand.  
In April 2018, tolvaptan (JYNARQUE®) was approved in the United States (US) to slow 
kidney function decline in adults at risk of rapidly progressing ADPKD.  However, because 
of the risk of serious liver injury, Jynarque is only available through a restricted distribution 
program under a Risk Evaluation and Mitigation Strategy. 
1.4 Rationale for Lixivaptan Therapy for ADPKD 
Given that elevated kidney cAMP plays a pivotal role in the complex phenotypical 
manifestation of ADPKD (Belibi et al, 2004), and that vasopressin is the principal agonist 
pathway leading to the formation of cAMP in kidney tubule cells, it has been suggested that 
therapeutic interventions aimed at counterbalancing the effect of vasopressin and/or 
normalizing intracellular levels of cAMP may be effective in delaying disease progression in 
ADPKD (Torres, 2005).  This hypothesis was confirmed by genetic experiments in mutated 
rats with no circulating serum vasopressin (Brattleboro rats).  When these rats were crossed 
with rats harboring a PKD mutation, their offspring did not develop cysts (Wang et al, 2008), 
thus demonstrating that an intact vasopressin signaling pathway is a necessary requirement 
for the development of cystic disease.  In addition, vasopressin receptor antagonists, 
including mozavaptan and tolvaptan, (Gattone et al, 2003 and Wang et al, 2005) have proved 
efficacious in normalizing kidney cAMP levels and correcting disease manifestations in 
preclinical rodent models of ADPKD.  In ADPKD patients, elevated levels of circulating 


Palladio Biosciences PA-ADPKD-301                                                                                   
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copeptin, a marker for serum vasopressin concentration, are associated with faster disease 
progression (Boertien et al, 2012).  
Further, definitive evidence in favor of the utility of vasopressin antagonism as a therapeutic 
approach for ADPKD is derived from tolvaptan, like lixivaptan a non-peptide vasopressin V2 
receptor antagonist in the drug class of vaptans.  In Europe, tolvaptan (JINARC®) is 
approved to slow the progression of cyst development and kidney insufficiency of ADPKD 
in adults with CKD stage 1 to 3 at initiation of treatment with evidence of rapidly progressing 
disease.  Approval was granted based on the findings from the pivotal Phase 3 trial TEMPO 
3:4. The trial randomized 1445 patients with ADPKD with a total kidney volume of ≥750 mL 
and an estimated creatinine clearance of ≥60 mL/min to tolvaptan or placebo.  Over a 3-year 
period, tolvaptan delayed the worsening of kidney function, a therapeutic effect that was 
subsequently found to have disease-modifying properties and slowed the progression of 
kidney enlargement (Torres et al, 2012 and 2017a).  Importantly, the TEMPO 3:4 trial also 
demonstrated that, in patients receiving tolvaptan, there was a strong, inverse relationship 
between the magnitude of the aquaretic response, measured by decrease in urinary 
osmolality, and the loss of kidney function during the study (Devuyst et al, 2017).   Because 
complete vasopressin suppression is ensured if urinary osmolality is lowered to <250 
mOsm/kg, these findings strongly suggest that achieving urinary osmolality reduction below 
this target threshold can be considered a predictive biomarker of clinical efficacy of 
vasopressin antagonists for the treatment of ADPKD (Devuyst et al, 2017).  
More recently, the results of REPRISE, a second pivotal Phase 3 trial with tolvaptan for the 
treatment of ADPKD, were published (Torres et al, 2017).  This trial randomized 1370 
patients with later stage ADPKD, which was defined as having a baseline estimated 
glomerular filtration rate (eGFR) of <65 mL/min for patients in the 18-55 age group or <45 
mL/min for patients in the 56-65 age group, to tolvaptan or placebo.  Over a 12-month 
period, tolvaptan delayed the eGFR decline, a surrogate for worsening kidney function, with 
a magnitude of effect that was comparable to the one seen in the TEMPO 3:4 study (35%; 
p<0.0001).  Taken together, the results of these two studies demonstrate that the efficacy of 
vasopressin antagonism is maintained across multiple time periods and stages of disease. 
The evidence supporting the potential utility of lixivaptan for the treatment of ADPKD is 
provided by experiments in animal models of polycystic kidney disease (PKD) and by the 
clinical effect of lixivaptan on urine osmolality, a pharmacodynamic biomarker of effective 
vasopressin antagonism that is correlated with efficacy in ADPKD, as discussed below.  
Lixivaptan ameliorates disease manifestations in animal models of PKD 
Lixivaptan was tested in rat and mouse animal models of PKD.   
The PCK rat, an orthologous model of human PKD caused by a splicing mutation in the 
pkhd1 gene, is one of the best-studied models in the field of PKD research because it is 
characterized by a phenotype that is highly reminiscent of the human disease.  Compared to 
control animals, PCK rats treated with lixivaptan showed a marked protective effect on the 
development of kidney disease manifestations, including reduced cystic burden, reduced 
kidney volume increase, and delayed kidney function decline.  These beneficial effects were 
accompanied by a reduction in kidney cAMP levels, as expected (Wang et al, 2019).  


Palladio Biosciences PA-ADPKD-301                                                                                   
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The Pkd1RC/RC mouse is a hypomorphic genetic model which closely mimics human ADPKD 
with slowly progressive PKD.  Compared to control animals, Pkd1RC/RC mice treated with 
lixivaptan showed a significant reduction in kidney weight, cyst volume, and fibrosis volume 
(Di Mise et al, 2021). The magnitude of efficacy observed with lixivaptan in the RC/RC 
mouse model is comparable to historical experiments conducted with tolvaptan (Hopp et al, 
2015).   
Additional background information on the effect of lixivaptan in the PCK rat and Pkd1RC/RC 
mouse can be found in the IB. 
Lixivaptan causes sustained suppression of urine osmolality to levels that are associated 
with therapeutic efficacy in ADPKD 
The expectation about the efficacy of lixivaptan in ADKPD is supported by the observed 
clinical effects of lixivaptan on the pharmacodynamic biomarker of urinary osmolality.  
Clinical studies conducted with lixivaptan in healthy participants, ADPKD patients, and 
various other patient populations (patients with hypervolemic and euvolemic hyponatremia 
and patients with ESRD) demonstrated that treatment with lixivaptan readily suppresses 
urinary osmolality to levels below the target threshold of 250 mOsm/kg, irrespective of the 
specific patient population tested.  Importantly, the magnitude of the effect observed with 
lixivaptan was comparable to the effect observed with tolvaptan in the same patient 
populations.  In addition, like tolvaptan, treatment with lixivaptan was associated with a 
rapid-onset and fully reversible increase in serum creatinine. Taken together, these results 
suggest that treatment with lixivaptan can inhibit vasopressin receptor signaling to the extent 
necessary to observe clinical efficacy of a vasopressin antagonist for the treatment of 
ADPKD (Devuyst et al, 2017).  
Additional background information on the effect of lixivaptan on urine osmolality can be 
found in the IB. 
Lixivaptan as an alternative to tolvaptan with potentially less risk of liver toxicity  
While tolvaptan has been approved in many territories to slow the progression of kidney 
function deterioration in patients with ADPKD, drug-induced liver injury (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 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 using DILIsymTM, a Quantitative Systems Pharmacology model of drug-
induced liver injury, has allowed for the assessment of potential abnormal liver chemistry 
tests prior to conducting large clinical trials (Woodhead et al, 2017a).  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, all 
of which have been identified as putative cellular mechanisms for DILI. 
DILIsym was employed to model tolvaptan-mediated liver injury and was able to 
successfully recapitulate the observed toxicity (Woodhead et al, 2017b).  The frequency of 


Palladio Biosciences PA-ADPKD-301                                                                                   
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predicted 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 main 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 5).   
Additional information regarding the DILIsym evaluation of lixivaptan can be found in the 
IB. 
Table 5. DILIsym Simulations of Lixivaptan and Tolvaptan 
Drug 
Dose, Duration 
Clinical ALT >3 x 
ULN 
Simulated ALT >3 x 
ULN, n/N 
Lixivaptan 
200/100 mg  
q AM/PM, 12 weeks 
UNK* 
0/285 
Tolvaptan** 
90/30 mg 
q AM/PM, 24 weeks 
4.4% 
18/229 
7.86% 
*UNK = Unknown; data to be acquired in Phase 3 
**Source: Woodhead et al, 2017b 
1.5 Summary of Nonclinical Studies 
Experiments in rats and dogs, with or without pretreatment with vasopressin, and with or 
without free access to water, confirmed that lixivaptan is a potent vasopressin V2 receptor 
antagonist. Selectivity for the V2 receptor was demonstrated using cloned receptors and cell 
membranes isolated from kidney, platelet, and liver. Furthermore, using cell proliferation 
assays, lixivaptan had no agonist activity at human V1a or rat V1b (V3) receptors.  
Compared with conventional diuretics, lixivaptan increases urinary volume output about 3 to 
4 times more than furosemide or hydrochlorothiazide at comparable doses and decreases 
urinary osmolality.  Three identified human metabolites of lixivaptan (WAY-138451, WAY-
138758, and WAY-141624) were found to be weakly active or inactive as vasopressin V2 
receptor antagonists as assessed by in vitro receptor binding and in vivo aquaretic studies in 
rats.  


Palladio Biosciences PA-ADPKD-301                                                                                   
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In addition to the pharmacology studies, lixivaptan was evaluated in a comprehensive 
toxicology program. Results showed the PK and metabolism are well characterized and there 
were no significant safety signals identified.  
Additional information regarding nonclinical studies conducted with lixivaptan can be found 
in the IB. 
1.6 Summary of Clinical Studies  
Lixivaptan is a novel, highly selective, non-peptide, vasopressin V2 receptor antagonist.  It 
was previously developed for treating disease states associated with water retention, e.g., 
euvolemic and hypervolemic hyponatremia.  Pharmacokinetic (PK), safety, tolerability, and 
efficacy data for lixivaptan are available from 36 clinical studies, including 22 Phase 1 
studies in healthy and/or CKD participants, 10 Phase 2a studies, and 4 Phase 3 studies in 
participants with hyponatremia.  More than 1600 participants received at least one dose of 
lixivaptan as part of the hyponatremia development program, including 867 who participated 
in Phase 2 and 3 studies.  Lixivaptan was generally safe and well-tolerated in this patient 
population.  The most common adverse events (AEs) were headaches, dizziness, thirst, 
orthostatic hypotension, and tachycardia events.  Additional information regarding the 
clinical evaluation of lixivaptan in hyponatremia can be found in the IB. 
Subsequent to the conclusion of the hyponatremia program, lixivaptan was tested in ADPKD 
patients in the open-label Phase 2 study, PA-102.  This study was conducted to characterize 
the PK, safety, and pharmacodynamic profiles of lixivaptan following administration of twice 
per day (BID) oral doses of 50 and 200 mg for 7 days in participants with both ADPKD and 
CKD stage 1 (CKD1), stage 2 (CKD2), or stage 3 (CKD3).  The dose of 200 mg BID 
successfully suppressed mean spot urine osmolality below 300 mOsm/kg (denoting dilute 
urine) throughout the 24-hour period on Day 7 in 100% of study participants with CKD2 and 
CKD3, indicating continuous vasopressin V2 receptor inhibition.  Lixivaptan was well 
tolerated by participants.  Although a dose of 50 mg BID reduced Uosm over part of the 
dosing interval, the duration was not long enough to ensure effective blockade of the 
vasopressin V2 receptor throughout 24 hours.  However, 50 mg BID is an appropriate starting 
dose to allow accommodation to the aquaretic effects of the drug.  Lixivaptan was well 
tolerated by ADPKD participants; the most common AEs reported in 3 or more participants 
were dry mouth, headache, and nausea. No participant was discontinued because of an AE.  
Additional information regarding the results of this study can be found in the IB. 
Study PA-103 was a Phase 2, open-label, repeat dose expanded access study designed to 
reduce the abdominal pain related to ADPKD in a single participant who had been 
incapacitated by ADPKD-related pain.  The participant had been successfully treated for the 
pain with tolvaptan but was unable to continue with the drug because of DILI, which manifested 
as elevated ALT levels that occurred during 3 separate trials of repeated tolvaptan dosing 
following initial treatment and following 2 re-challenges after treatment discontinuations due to 
the elevations. The participant’s nephrologist contacted Palladio and requested the use of 
lixivaptan in this participant. Lixivaptan doses up to 150 mg in the morning and 100 mg in the 
evening were allowed during the titration period and subsequently were allowed to increase 
to 200 mg BID in the Maintenance Treatment Period.  Lixivaptan was well-tolerated by the 
participant in the study.  Importantly, the participant completed 413 days of treatment with 


Palladio Biosciences PA-ADPKD-301                                                                                   
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lixivaptan without any evidence of liver injury.  All liver chemistry tests were normal while 
the participant had been receiving lixivaptan.  The participant’s pain and quality of life 
modestly improved while on lixivaptan therapy, but because of continued discomfort the 
participant elected to discontinue lixivaptan in order to pursue more aggressive pain 
management treatments. 
Study PA-ADPKD-303, which is currently ongoing, is a Phase 3, open-label, repeat dose 
study designed to assess hepatic safety, non-hepatic safety, and efficacy in participants who 
previously experienced abnormal liver chemistry test results while treated with tolvaptan. 
Participants who had to stop tolvaptan therapy due to abnormal liver chemistry test results do 
not currently have available therapeutic options.  In this study, such participants are treated 
with lixivaptan to determine if it is a safer alternative.  Up to 50 participants are being 
enrolled and treated.  Evaluations include frequent testing of liver chemistry (every 1 week 
during the Titration Period and every 4 weeks during the Treatment Period), physical 
examinations, vital signs, safety labs (chemistry, hematology, urinalysis), urine osmolality 
determinations, and trough serum concentration of lixivaptan.    
1.7 Study Rationale 
This is a Phase 3, double-blind, placebo-controlled, randomized trial to demonstrate the 
efficacy and safety of lixivaptan compared with placebo in participants with ADPKD during 
a 52-week, double-blind treatment phase (Part 1).  Participants who are not discontinued due 
to an adverse event or who have not withdrawn consent, will immediately continue into a 52-
week open-label treatment phase (Part 2) with lixivaptan. This study is designed to 
demonstrate the efficacy of lixivaptan in slowing the decline in kidney function as measured 
by eGFR with confirmation of the durability of this effect in the open-label phase of the 
study.  Additionally, the study will contribute to understanding the safety of lixivaptan in 
ADPKD patients, particularly any effects on liver chemistry tests.   
1.8 Dose Rationale 
The human equivalent exposure range of lixivaptan proposed for this study has been shown 
to be safe and tolerated in nonclinical animal studies and in previous clinical investigations 
conducted in a robust sample of healthy volunteers and participants with hyponatremia of 
various etiologies, as well as in Phase 2 investigations in participants with ADPKD.   
The dose range selected for this study, 100 mg BID to 200 mg BID (with 50 mg BID as a 
starting dose), provides a minimal and maximal dose that has been shown to effectively 
reduce Uosm throughout a 24-hour daily dosing cycle in patients with ADPKD and CKD 
stages 2-3.  In a previous dose-ranging study, while 50 mg BID of lixivaptan was effective in 
reducing Uosm over part of the dosing interval, the duration was not long enough to ensure 
effective blockade of the vasopressin V2 receptor throughout 24 hours in a meaningful 
proportion of participants. In this study, the 50 mg BID dose will, therefore, be used as a 
starting dose to acclimate participants to vasopressin V2 receptor blockade and assess 
tolerability.  Throughout the study, doses will be titrated in individual patients based on 
tolerability or up to the maximum dose. 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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1.9 Benefit/Risk Assessment 
Safety data gathered to date in participants with ADPKD are consistent with the robust safety 
experience from lixivaptan treatment in studies in earlier indications investigated for 
lixivaptan—congestive heart failure, liver cirrhosis with ascites, or syndrome of 
inappropriate antidiuretic hormone secretion. The most common (≥ 2%) adverse effects of 
lixivaptan are related to the exaggerated pharmacology of blockade of the renal concentrating 
mechanism. This results in urinary dilution with the production of increased amounts and 
frequency of urine output and, secondarily, the stimulation of thirst. No adverse effects on 
other body systems have been noted. Lixivaptan as a vasopressin V2 receptor antagonist is in 
the same pharmacological class as tolvaptan.  DILI has been observed during the use of 
tolvaptan for ADPKD and JINARC/Jynarque® (brand names for tolvaptan) have boxed 
warnings for DILI in their Summary of Product Characteristics/US Prescribing Information.  
Although there have been no reports of DILI related to lixivaptan to-date, the potential risk of 
DILI during lixivaptan treatment exists; this protocol has been designed to frequently 
monitor the participants for liver test abnormalities, has established an IDMC for safety 
oversight and has established an independent Hepatic Event Review Committee to monitor 
and review any participant’s signs, symptoms, and/or laboratory tests that meet hepatic event 
criteria, and described procedures to prevent liver toxicity.  One of the two primary 
objectives of this study is to determine the risk of DILI as a result of lixivaptan treatment for 
ADPKD. 
 
Additionally, pharmacodynamic data generated for vasopressin V2 receptor antagonists that 
assess the mechanism of action, primarily through the development program for tolvaptan, 
have been confirmed in Phase 2 studies with lixivaptan and support continued development 
of lixivaptan for this indication. As there additionally remains a large unmet medical need to 
address chronic treatment in patients with ADPKD, particularly those who have experienced 
liver chemistry abnormalities leading to discontinuation of treatment with tolvaptan, 
continued investigation of this drug for ADPKD is warranted. Based on the totality of 
evidence generated to date on lixivaptan, the benefit/risk assessment of lixivaptan remains 
favorable. 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Objectives of the Double-blind Phase (Part 1/Year 1) 
The primary efficacy objective of Part 1 is: 
• To demonstrate the efficacy of lixivaptan compared to placebo in the slowing of 
deterioration in kidney function in participants with ADPKD as demonstrated by the 
annualized change from baseline in estimated glomerular filtration rate (eGFR). 
The key safety objective of Part 1 is: 
• To compare the incidences of liver chemistry test elevations in participants 
randomized to lixivaptan with participants randomized to placebo.  
The secondary efficacy objectives of Part 1 are: 
• To compare the rate of change (slope) in on-treatment eGFR in participants treated 
with lixivaptan to participants treated with placebo. 
• To assess the effect of lixivaptan on total kidney volume (TKV) as measured by 
magnetic resonance imaging (MRI) compared to placebo. 
The secondary safety objective of Part 1 is: 
• To assess the non-hepatic safety and tolerability of lixivaptan. 
The health outcomes-related objectives of Part 1 are: 
• To evaluate medical resource utilization (e.g., medication use/changes; unplanned 
office visit; urgent care and emergency department usage; and hospitalizations) 
resulting from clinical events in participants randomized to lixivaptan compared with 
those on placebo and assess which events are driving any observed differences in 
medical resource utilization between lixivaptan and placebo. 
• To evaluate the change from baseline in domain scores of the ADPKD Impact Scale 
(ADPKD-IS), ADPKD Pain and Discomfort Scale (ADPKD-PDS), and ADPKD 
Urinary Impact Scale (ADPKD-UIS) in participants treated with lixivaptan compared 
with participants treated with placebo. 
The population pharmacokinetics (PopPK) objective of Part 1 is: 
• To characterize the PK profile of lixivaptan utilizing PopPK based on sparse plasma 
sampling.  
The exploratory objectives of Part 1 are: 
• To assess the effect of lixivaptan on liver volume (LV) as measured by MRI 
compared to placebo. 
• To evaluate the change from baseline in urine osmolality in participants treated with 
lixivaptan compared with participants treated with placebo. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• To evaluate the effect of lixivaptan on kidney function as assessed by eGFR using a 
novel serum creatinine and serum cystatin C-based Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation refit without the race variable 
(CKD-EPIcr-cys_R) compared with placebo. 
2.1.2 Objectives of the Open-label Phase (Part 2/Year 2) 
The key objective of Part 2 is: 
• To demonstrate the continued efficacy of lixivaptan in the slowing of deterioration in 
kidney function in participants randomized to lixivaptan in the double-blind phase 
(Part 1) as measured by the annualized change from baseline (Part 2) in eGFR at the 
end of the open-label phase (Part 2). 
The key safety objective of Part 2 is: 
•  To assess the incidence of liver chemistry test abnormalities during the open-label 
phase. 
The secondary objectives of Part 2 are: 
 
•  To assess the rate of change (slope) in on-treatment eGFR in Part 2 in participants 
treated with lixivaptan in Part 1 and Part 2; 
• To assess the effect of lixivaptan on TKV as measured by MRI in Part 2 in 
participants treated with lixivaptan in Part 1 and Part 2. 
The secondary safety objective of Part 2 is: 
• To assess the non-hepatic safety and tolerability of lixivaptan. 
The health outcomes-related objectives of Part 2 are: 
•  To evaluate medical resource utilization (e.g., medication use/changes; unplanned 
office visits; urgent care and emergency department usage; and hospitalizations) 
resulting from clinical events in participants on lixivaptan.  
•  To evaluate the change in domain scores of the ADPKD-IS, ADPKD-PDS, and 
ADPKD-UIS. 
The PopPK objective of Part 2 is: 
• To further characterize the PK profile of lixivaptan utilizing PopPK based on sparse 
plasma sampling. 
The exploratory objectives of Part 2 are: 
• To assess the effect of lixivaptan on LV as measured by MRI following 52 weeks of 
open-label treatment. 
• To evaluate the change in urine osmolality. 
• To evaluate the effect of lixivaptan on kidney function as assessed by eGFR using the 
CKD-EPIcr-cys_R equation following 52 weeks of open-label treatment. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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2.2 Study Endpoints 
2.2.1 Part 1/Year 1 
2.2.1.1 Primary Efficacy Endpoint 
• The primary endpoint is the annualized change in eGFR calculated from the CKD-
EPIcr_R equation for serum creatinine from baseline (mean of 3 eGFR 
determinations obtained during Screening and Placebo Run-in Periods (Visits 1a/1b 
(if required), Visit 2, and Visit 3) to final assessment (mean of 3 eGFR determinations 
obtained during Follow-up Period I or, for participants who discontinue treatment 
prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug 
treatment discontinuation).  
2.2.1.2 Key Safety Endpoint 
The key liver safety endpoint is: 
• Incidence of serum ALT levels >3 x ULN in participants randomized to lixivaptan 
compared to those randomized to placebo. 
2.2.1.3 Secondary Efficacy Endpoints 
The additional secondary endpoints are: 
• The annualized rate of change (slope) from baseline in on-treatment eGFR, based on 
all on-treatment eGFR determinations during the Double-Blind, Randomized 
Treatment Period in Part 1, calculated from the CKD-EPI equation (CKD-EPIcr_R) 
for serum creatinine;  
• The annualized change from baseline in TKV, determined by MRI, during Follow-up 
Period I. 
2.2.1.4 Secondary Safety Endpoints 
The safety and tolerability of lixivaptan assessed through evaluation of: 
• Treatment-emergent adverse events (TEAEs); 
• Clinical laboratory findings (clinical chemistry including additional analyses of liver 
chemistry and serum sodium, hematology and urinalysis); 
• Vital signs;  
• 12-lead electrocardiograms (ECG). 
2.2.1.5 Health Outcome Endpoints 
• Medical resource utilization (e.g., medication use/changes; unplanned office visits; 
urgent care and emergency department usage; and hospitalizations) resulting from 
clinical events. 
• Patient Reported Outcomes: ADPKD-IS; ADPKD-PDS; ADPKD-UIS. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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2.2.1.6 Population Pharmacokinetics Endpoints 
• Area under the plasma concentration-time curve during the dosing interval. 
• Maximum plasma concentration. 
2.2.1.7 Exploratory Endpoints 
• The annualized change from baseline in LV determined by MRI during Follow-up 
Period I. 
• Mean change from baseline in morning spot urine osmolality. 
• The annualized change in eGFR calculated from the CKD-EPIcr-cys_R equation 
from baseline to final assessment. 
2.2.2 Part 2/Year 2 
2.2.2.1 Key Comparison Endpoint 
• The primary endpoint of Part 2 is the annualized change in eGFR calculated from the 
CKD-EPI equation (CKD-EPIcr_R) for serum creatinine from baseline (mean of 3 
eGFR determinations obtained during Follow-up Period I) to final assessment (mean 
of 3 eGFR determinations obtained during Follow-up Period II).  
2.2.2.2 Key Safety Endpoint 
The key liver safety endpoint is: 
• Incidence of serum ALT levels > 3 x ULN in participants exposed to lixivaptan in 
Part 2. 
2.2.2.3 Other Comparison Endpoints 
The additional secondary endpoints are: 
• The annualized rate of change (slope) from baseline (mean of 3 eGFR determinations 
obtained during Follow-up Period I) in on-treatment eGFR, based on all on-treatment 
eGFR determinations during the Maintenance Treatment Period in Part 2, calculated 
from the CKD-EPI equation (CKD-EPIcr_R) for serum creatinine;  
• The annualized change in TKV determined by MRI. 
2.2.2.4 Secondary Safety Endpoints 
The safety and tolerability of lixivaptan assessed through evaluation of: 
• Treatment-emergent adverse events (TEAEs); 
• Clinical laboratory findings (clinical chemistry including additional analyses of liver 
chemistry tests, and serum sodium, hematology and urinalysis); 
• Vital signs;  
• 12-lead electrocardiograms (ECG). 


Palladio Biosciences PA-ADPKD-301                                                                                   
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2.2.2.5 Health Outcome Endpoints 
• Clinical events resulting in medical resource utilization; 
• Patient Reported Outcomes: ADPKD-IS; ADPKD-PDS; ADPKD-UIS. 
2.2.2.6 Population Pharmacokinetics 
• Area under the plasma concentration-time curve during the dosing interval. 
• Maximum plasma concentration. 
2.2.2.7 Exploratory Endpoints 
• The annualized change in LV determined by MRI; 
• Mean change from baseline in morning spot urine osmolality; 
• The annualized change in eGFR calculated from the CKD-EPIcr-cys_R equation from 
baseline to final assessment. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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3 INVESTIGATIONAL PLAN 
3.1 Study Design 
3.1.1 Overview of Study Design 
This is a global, Phase 3 trial consisting of a 2-arm, double-blind, placebo-controlled, 
randomized phase followed by a single-arm open-label phase to demonstrate the efficacy and 
safety of lixivaptan in participants with ADPKD.  The randomized phase of the study (Part 1) 
is designed to demonstrate the efficacy and safety of lixivaptan in slowing the decline in 
kidney function as measured by eGFR and to demonstrate a difference between the 
lixivaptan-treated and placebo-treated participants.  The open-label phase of the study (Part 
2) is designed to provide confirmation of the durability of this effect.  Importantly, this study 
will contribute to understanding the safety of lixivaptan, particularly any effects on liver 
chemistry tests.   
Approximately 2250 participants with ADPKD will be screened in order to randomize 1350 
participants to lixivaptan or placebo in a 2:1 ratio in Part 1 of the study.  After meeting entry 
criteria during a 3- to 5-week Screening Period (that may be extended up to 8 weeks as 
described in Section 3.1.2), participants will enter a 1-week single-blind, Placebo Run-in 
period to obtain select baseline measurements. This will be followed by a 4 to 6 week single-
blind dose titration period during which lixivaptan administered twice daily will be titrated to 
the highest tolerated dose (Lixivaptan Titration Period (Part 1) — Lixivaptan Titration 
Flowchart).  The minimum dose to enter the Double-blind, Randomized Treatment Period is 
Level 2 (100 mg BID).  Those participants successfully titrated and tolerating the drug will 
then be randomized (2:1) to either continue lixivaptan or switch immediately to matching 
placebo in a double-blind manner.  Randomization will be stratified for CKD Stage and 
Mayo Clinic ADPKD Image Classification. Double-blind treatment will continue for 52 
weeks after which study drug will be held, and final assessments obtained off-treatment over 
3 visits starting on the 8th day after the last dose of double-blind study drug through the 28th 
day after the last dose of study drug. 
Participants who have not discontinued due to an adverse event or withdrawn consent will 
continue into the 2- to 4-week Lixivaptan Re-titration Period to initiate Part 2 of the study. 
Dosing with lixivaptan will start at Level 1 (50 mg BID) for all participants in Part 2 and will 
be increased weekly until the dose level taken at the end of the Double-blind, Randomized 
Treatment Period is achieved. Lixivaptan treatment will continue for 52 weeks during the 
Maintenance Treatment Period after which study drug will be held, and final assessments 
obtained off-treatment over 3 visits starting on the 8th day after the last dose of double-blind 
study drug through the 28th day after the last dose of study drug. 
The study schematic is depicted in Figure 1 and Figure 2. 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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3.1.2 Detailed Study Design 
Part 1: 
Screening Period (Visits 1a, 1b, 2): Participants who provide written informed consent will 
have medical history collected and undergo baseline testing over a 3 to up to 8-week 
Screening Period. The variable length of the Screening Period is intended to allow for 
discontinuation of diuretics or other disallowed medications (e.g., CYP3A4 inhibitors), 
antihypertensive medication optimization, stabilization of blood pressure and completion of 
the baseline MRI for Mayo Clinic ADPKD Image classification (Irazabal et al, 2015) by the 
central imaging vendor prior to Visit 2.  For participants who do not require changes to 
background therapy, the Screening Period should be completed in 3 to 5 weeks.   
Participants will continue through Screening as follows: 
• Participants with appropriate blood pressure control for a minimum of 3 weeks prior 
to enrollment (Visit 2) (as defined by the 2021 KDIGO guideline) including those on 
stable ACEi or ARB treatment (unless not considered appropriate) and not receiving a 
diuretic will have a baseline MRI exam scheduled and will proceed to Visit 2, 3 to 5 
weeks after Visit 1a, and after completion of the baseline MRI (allow approximately 1 
week after completion of the MRI, however a 3-week minimum between Visit 1a and 
Visit 2 is required.)  Screening may be extended to a maximum of 8 weeks, in the 
event of extenuating circumstances; prior approval from the medical monitor is 
required. 
• Participants who need to be discontinued from diuretic therapy and/or have their anti-
hypertensive therapy optimized due to inadequate BP control (as defined by the 2021 
KDIGO guideline) will return for Unscheduled visits for blood pressure monitoring 
following Visit 1a.  Once their treatment and blood pressure have been stable for a 
minimum of 3 weeks, they will return for Visit 1b to have additional serum chemistry 
testing.  The baseline MRI examination should be scheduled after completion of Visit 
1a but may be performed before, at, or after Visit 1b, dependent on scheduling 
availability. Upon attaining stability of antihypertensive therapy, completion of the 
baseline MRI, and following receipt of the Mayo Clinic ADPKD Classification from 
the central imaging vendor, the participant will complete Visit 2 (a minimum of 2 
weeks after Visit 1b or approximately 1 week after completion of the MRI, whichever 
occurs later.)  The total duration of the Screening Period may be extended up to 8 
weeks, including the time to completion of Visit 2.  
Participants are eligible for enrollment if they are between the ages of 18 to 60 years 
(inclusive), have a diagnosis of ADPKD, have an eGFR of 25 to 90 mL/min/1.73 m2 as 
calculated using the 2021 CKD-EPIcr_R equation Appendix 1 (Section 13.1); (note that the 
final determination of eligibility will be made during the Placebo Run-in Period based on the 
mean of the eGFR values obtained at Visits 1a and 2 or 1b and 2, if Visit 1b is required), have 
a Mayo Clinic ADPKD classification of 1C, 1D, or 1E as determined by the central imaging 
vendor’s assessment of the baseline MRI, have appropriately controlled blood pressure 
without the use of a diuretic, and meet all other study entry criteria (Section 4.1).  
Participants who were enrolled based on the 2009 CKD-EPI equation (referenced in 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Appendix 1 (Section 13.1) will not be discontinued from the study should their baseline 
eGFR calculated subsequently with the CKD-EPIcr_R equation, yield a mean eGFR value 
outside of the range of 25 to 90 mL/min/1.73 m2.  The stratification by CKD stage (Section 
8.4.1) will be based on the baseline eGFR creatinine equation in effect at the time of 
randomization.  However, all efficacy analyses of change in eGFR will be based on the 
CKD-EPIcr_R equation. Participants who fail inclusion/exclusion criteria due to temporary 
or correctable reasons may be re-screened (up to 2 additional times after obtaining new 
informed consents) and after consultation with the medical monitor.  Note: Discontinuation 
of effective treatment for the sole purpose of making a participant eligible for participation in 
the study is prohibited. 
At the successful completion of Visit 2, participants will be considered enrolled and will be 
assigned single-blind study drug (placebo) via the IRT to start the Placebo Run-in Period.  
Participants will take 4 capsules of study drug twice daily (BID) approximately 10 hours 
apart. All dosing throughout the study will be 4 capsules BID. 
Placebo Run-in Period (Visit 3): During the 1-week Placebo Run-in Period, participants will 
receive single-blind placebo and take 4 capsules twice daily. At the end of the 1-week 
Placebo Run-in Period, participants will attend Visit 3 at which time tolerability will be 
assessed to maintain participant blinding and final baseline measurements will be obtained.  
At this visit and those during the Lixivaptan Titration Period (Visits 4 to 9), tolerability will 
be assessed by asking the participant a single question “Would you take the study drug for 
the next 24 months?”  Participants reporting tolerability issues will be discontinued from the 
study and complete Visit 22/Early Termination (ET) procedures. All other participants will be 
assigned single-blind lixivaptan via IRT at a dose of 50 mg BID to start the Lixivaptan 
Titration Period.  At Visit 3, participants should take their first dose of study drug from the 
newly assigned (Visit 3) blister card in the clinic following completion of study visit 
procedures and in accordance with the sparse PK sampling schedule for this visit (0.5 hrs. to 
1.5 hrs. post dose).  
Lixivaptan Titration Period (Visits 4 to 9):  During a period of 5 to 6 weeks for participants 
who complete the Placebo Run-in Period, the lixivaptan dose initiated at Visit 3 will be 
increased in a single-blind fashion according to the titration schedule in Lixivaptan Titration 
Period (Part 1) — Lixivaptan Titration Flowchart to achieve the maximally tolerated dose up 
to the maximum dose allowed (Level 4 [200 mg BID]).  At the 2 highest dose levels (Level 3 
[150 mg BID] and Level 4 [200 mg BID])), there will be an opportunity to reduce the evening 
(PM) dose to Level 3a (150 mg AM/100 mg PM) or Level 4a (200 mg AM/150 mg PM) if 
aquaretic effects are problematic in certain participants.  Further dose reductions are 
allowable as shown in the Lixivaptan Titration Period (Part 1) — Lixivaptan Titration 
Flowchart. However, the minimum dose to enter the Double-blind, Randomized Treatment 
Period is Level 2 (100 mg BID).     
Tolerability will be assessed at each titration visit (Visit 4 to Visit 9, as applicable).  If the 
participant confirms the dose can be tolerated, the participant will be titrated to the next dose 
level (i.e., the dose will be increased).  This assessment of tolerability will continue at weekly 
intervals until either the maximum dose level is reached (Level 4 [200 mg BID]) or until the 
participant confirms the dose cannot be tolerated for a 24-month period.  If the dose cannot 


Palladio Biosciences PA-ADPKD-301                                                                                   
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be tolerated, it will be reduced by one dose level per titration visit as described in the 
Lixivaptan Titration Period (Part 1) — Lixivaptan Titration Flowchart. 
 
Once the maximally tolerated dose has been achieved, tolerability will be confirmed over an 
additional week of dosing before the participant advances to randomization.  As the 
maximum duration of the Lixivaptan Titration Period is 6 weeks, participants who require a 
dose reduction at Week 6 as a result of emerging tolerability issues will proceed to the 
Double-blind, Randomized Treatment Period on the newly assigned (reduced) dose level 
without extension of the titration period.  Serum liver chemistry tests will be performed at 
Visits 5, 7, and 9 and fasting morning urine osmolality, collected prior to the morning dose of 
study drug, will be measured at the last titration visit (Visit 9). 
Double-blind, Randomized Treatment Period (Visits 10 to 22): Following successful 
completion of titration, participants will be randomized 2:1 (lixivaptan: placebo) to continue 
to receive lixivaptan at the dose achieved at the end of the Lixivaptan Titration Period or to 
matching placebo in a double-blind fashion for 52 weeks.  Study visits will be scheduled 
every 4 weeks during this period. Assessments at each visit are detailed in the Schedule of 
Procedures – Part 1. 
Follow-up Period I (Visits 23 to 25): Three visits will occur over a 28-day, study drug-free 
period following the last dose of study drug. Blood samples will be drawn at 3 time points for 
serum creatinine and serum cystatin C, to determine eGFR for primary and exploratory 
analyses, respectively. The first visit (Visit 23) will occur on the 8th day (+ 3 days) after the 
last dose of study drug, and the last visit (Visit 25) will occur on the 28th day (± 3 days) after 
the last dose of study drug.  Visit 24 must be scheduled to occur at least 24 hours after Visit 
23 and at least 24 hours prior to Visit 25.  At Visit 25, additional efficacy and safety 
assessments will be performed; a post-baseline MRI for assessment of TKV and LV is to be 
obtained between 25 days and 31 days post last dose of study drug and must be completed 
prior to or on the same day as all other Visit 25 study procedures.  Following completion of 
these assessments, all participants (except those who discontinued due to an AE or who have 
withdrawn consent) will immediately continue into Part 2 at Visit 25. 
Note: In the event of tolerability issues at any time during the study, dosing may be 
decreased or temporarily stopped.  If dosing is resumed during the Double-Blind Treatment 
Period at a dose level less than that achieved at Visit 9 , attempts will be made every 4 to 8 
weeks to re-establish the previously achieved dose level from Visit 9, if medically 
appropriate. If study drug is interrupted for longer than 8 weeks, then study drug treatment 
will be permanently discontinued. 
 
Part 2: 
Lixivaptan Re-Titration Period (Visits 26 to 29): For all participants, titration of lixivaptan 
will occur over a 2 to 4-week re-titration period and will start at a dose of 50 mg BID 
beginning at the conclusion of Visit 25. The dose will be increased at weekly intervals until 
the dose level from the end of the Double-blind, Randomized Treatment Period in Part 1 is 
achieved.  In order to maintain blinding of the treatment assignment from Part 1, the dose 
level assignment for Part 2 will continue to be managed by the IRT. The dose-titration 
schedule for this part of the study is described in Table 2.  In the event of tolerability issues, 


Palladio Biosciences PA-ADPKD-301                                                                                   
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dosing may be decreased.  Note: during the Re-titration Period of Part 2, all participants are 
re-titrated with lixivaptan to the last actual dose level if they had received lixivaptan during 
the Double-blind, Randomized Treatment Period, or, if they had received placebo during the 
Double-blind, Randomized Treatment Period, to the last inferred dose level (the dose level 
equal to the active dose level had the participant been randomized to the active arm). Re-
titration will be performed by the IRT, and the site, participant, and sponsor maintain a 
blinded status to the prior treatment assignment in Part 1. If no adjustment is made to the 
inferred dose during the Double-Blind, Randomized Treatment Period, the last inferred dose 
for a participant randomized to placebo will be equal to the maximal tolerated lixivaptan dose 
established during the Titration Period in Part 1. 
 
Maintenance Treatment Period (Visits 30 to 42): Following completion of the Lixivaptan Re-
titration Period, participants will continue to receive lixivaptan in the Maintenance Treatment 
Period for 52 weeks at the same dose achieved at the end of the Re-titration Period in Part 2.  
If the participant’s dose was decreased during the Lixivaptan Re-Titration Period, attempts 
will be made every 4 to 8 weeks to re-establish the previously achieved dose level (actual or 
inferred) at the end of  the Double-blind, Randomized Treatment Period of Part 1. Visits will 
be performed every 4 weeks during this period.  Assessments at each visit are detailed in the 
Schedule of Procedures – Part 2.   
Note: In the event of tolerability issues at any time during the study including the Part 2 
Lixivaptan Re-titration Period or during the Maintenance Treatment Period, dosing may be 
decreased or temporarily stopped.  Attempts will be made every 4 to 8 weeks to re-establish 
the previously achieved dose level at the end of the Double-blind, Randomized Treatment 
Period of Part 1, if medically appropriate. If study drug is interrupted for longer than 8 weeks, 
then study drug treatment will be permanently discontinued. 
Follow-up Period II (Visits 43 to 45): Three visits will occur over a 28-day, study drug-free 
period following the last dose of lixivaptan in the Maintenance Treatment Period.  Blood 
samples will be drawn at 3 time points for serum creatinine and serum cystatin C, to 
determine eGFR for primary and exploratory analyses, respectively.  The first visit (Visit 43) 
will occur on the 8th day (+ 3 days) after the last dose of lixivaptan, and the last visit (Visit 
45) will occur on the 28th day (± 3 days) after the last dose of lixivaptan.  Visit 44 must be 
scheduled to occur at least 24 hours after Visit 43 and at least 24 hours prior to Visit 45. At 
the final study visit, Visit 45, additional efficacy and safety assessments will be obtained; a 
post-baseline MRI for assessment of TKV and LV is to be obtained between 25 days and 31 
days post last dose of study drug and must be completed prior to or on the same day as all 
other Visit 45 study procedures. 
The maximum duration of participation in this study is 131 weeks (up to 71 weeks in Part 1 
and up to 60 weeks in Part 2) depending on the length of Screening (3 to 8 weeks), Titration 
(5 to 6 weeks) and Re-titration (2 to 4 weeks). Note that the study may be interrupted at any 
time if safety issues identified by an IDMC and sponsor potentially compromise the safety of 
the participants. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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3.2 Rationale for Study Design 
A placebo-controlled, double-blind assessment of lixivaptan is the preferred study design for 
demonstrating the efficacy and safety of the drug in the treatment of patients with ADPKD.  
This type of design was used both in the TEMPO 3:4 and REPRISE studies to assess the 
efficacy and safety of tolvaptan.  Furthermore, following the double-blind phase of the study 
with a 52-week open label treatment phase allows for the demonstration of the durability of 
effect of lixivaptan as well as assessment of long-term safety.  The inclusion/exclusion 
criteria in Section 4.1 were chosen to recruit an appropriate number of participants 
representative of the ADPKD population with declining kidney function who are most likely 
to benefit from vasopressin V2 receptor blockade in order to achieve the study’s primary 
objective as presented in Section 2.1.1.   
Treatment with lixivaptan is associated with transient and reversible increases in serum 
creatinine related to acute kidney hemodynamic effects.  In addition, based on clinical 
evidence with the related vasopressin antagonist tolvaptan (Torres et al, 2012), lixivaptan 
may be associated with transient and reversible decreases in TKV.  In order to eliminate these 
confounding influences on these endpoints, assessment of serum creatinine for the primary 
endpoint (change in eGFR) and the secondary endpoint of annualized change in TKV will 
occur at baseline before the start of study drug and shortly after completion of study drug (8 
to 28 days following the last dose).   
The sample size of 1350 participants in total, randomized 2:1, lixivaptan to placebo, will 
provide adequate power to detect a clinically meaningful change in the primary endpoint of 
eGFR over 1 year of treatment. A blinded sample size re-estimation (BSSR) to estimate the 
variance corresponding to the primary efficacy estimand is planned after 20% of the total 
randomized participants have completed Part 1 of the study or before screening for the study 
has ended (Section 8.1).   


Palladio Biosciences PA-ADPKD-301                                                                                   
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4 PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
4.1 Selection of Study Population 
Approximately 2250 participants will be screened in order to randomize 1350 participants at 
approximately 250 sites globally.  Participants will be enrolled only if they meet all of the 
inclusion criteria and none of the exclusion criteria. Eligibility criteria are to be assessed at 
Visits 1a, 1b (if required) and 2.  Note: On or prior to Visit 3, eligibility based on mean eGFR 
(Inclusion criterion #4) from Visit 1a and 2 or Visit 1b and 2 (if Visit 1b is required) and liver 
chemistry tests (Exclusion criterion #9) from Visit 2 must be re-confirmed.)  
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.  Prospective approval of protocol deviations to eligibility criteria, also known as 
protocol waivers or exemptions, is not permitted. 
4.1.1 Inclusion Criteria 
The following are requirements for entry into the study: 
 
1. Male or female, between 18 and 60 years of age (inclusive) at the time of Screening 
(Visit 1a).  
2. Diagnosis of ADPKD by modified Pei criteria: 
• For participants with family history of ADPKD, by ultrasound: 
o 18-39 years: ≥3 cysts, unilateral or bilateral;   
o 40-59 years: ≥2 cysts in each kidney; 
o 60 years: ≥4 cysts in each kidney; or 
• For participants with family history of ADPKD, by computerized tomography 
(CT) or MRI: 
o 18-40 years: ≥10 cysts in both kidneys; or 
• For participants without family history of ADPKD 
o a minimum of 10 cysts per kidney by any radiologic method and 
exclusion of other cystic kidney diseases (multiple simple kidney 
cysts, renal tubular acidosis, cystic dysplasia of the kidney, multicystic 
kidney, multilocular cysts of the kidney, medullary cystic kidney and 
acquired cystic disease of the kidney); or 
o genetic diagnosis of ADPKD. 
3. At risk for rapid progression of ADPKD as based on the Mayo Clinic ADPKD Image 
Classification of 1C, 1D, or 1E based on age and height-adjusted total kidney volume 
(TKV) as determined by kidney MRI obtained during Screening, where class (class 1 
[typical] versus class 2 [atypical]) and TKV are determined by a central imaging 
vendor. 
4. eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m2 based on the mean of 2 eGFR 


Palladio Biosciences PA-ADPKD-301                                                                                   
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determinations (Visits 1a and 2 or Visits 1b and 2, if Visit 1b is required) calculated 
by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR 
creatinine equation refit without the race variable (CKD-EPIcr_R) from serum 
creatinine values obtained during Screening (Appendix 1 (Section 13.1)) Note: This 
criterion will preliminarily be reviewed at Visit 2 based on Visit 1a or Visit 1b results 
(if Visit 1b is required).  The criterion must be re-evaluated no later than Visit 3 when 
results for Visits 1a and 2 or Visits 1b and 2 are available to confirm that the 
participant remains eligible for participation.  
5. Appropriate control of hypertension for a minimum of 3 weeks including the use of 
an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless 
not considered appropriate for the participant) as suggested by the 2021 Kidney 
Disease Improving Global Outcomes (KDIGO) “Clinical Practice Guideline for the 
Management of Blood Pressure in Chronic Kidney Disease,” without the use of a 
diuretic. 
6. Body mass index (BMI) between 18 and 40 kg/m2 (inclusive) at the time of 
Screening. 
7. 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), agree to practice 
acceptable 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 
trial and for 30 days after the last dose of study drug.  Birth control methods 
that can be used during the study include the following: 
• hormonal contraceptives: combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of 
ovulation (i.e., oral, intravaginal, transdermal); progestogen-only 
hormonal contraception (i.e., oral, injectable, implantable). Note: in 
women with severe polycystic liver disease, contraceptives containing 
estrogen (and hormone replacement therapy) may be involved in the 
development and growth of liver cysts and polycystic liver disease 
progression; the supplemental risk of initiating or continuing estrogen 
treatment, as well as potential alternative contraceptives for WOCBP 
will  be discussed with the potential participant 
• 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 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• 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 male condom). 
8. Male participants must agree 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 
study drug. 
9. Have read, understood, and provided written informed consent after the nature of the 
study has been fully explained and must be willing to comply with protocol 
requirements and study-related procedures. 
4.1.2 Exclusion Criteria 
1. Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or 
glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), 
other significant kidney disease, kidney cancer, transplanted kidney, single kidney, 
kidney surgery within the past 6 months (including cyst drainage or fenestration) or 
acute kidney injury within 6 months prior to Screening. 
2. Clinically significant 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. History of infection with human immunodeficiency virus (HIV) unless the participant 
is clinically stable and doing well on a non-CYP interacting ART regimen and the 
participant has not required more than 2 changes in their ART regimen since 
treatment inception. 
5. History of clinically significant drug or alcohol abuse in the 2 years prior to Screening 
Visit 1a. 
6. Contraindications to or interference with MRI assessments (e.g., ferromagnetic metal 
prostheses, aneurysm clips, severe claustrophobia, or large abdominal/back tattoos).  
Investigator should seek MRI safety guidance from the local MRI facility. 
7. Any malignancy within 5 years prior to Screening except for basal cell carcinoma 
successfully treated with local therapy or malignancies that are considered by the 
Investigator not to affect participant survival (after discussion with the medical 
monitor). 
8. Medical history or findings that preclude safe participation in the trial or participants 
who are likely to be non-compliant with trial procedures in the opinion of the 
Investigator or medical monitor. 
9. Clinically significant liver disease or impairment or alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or total bilirubin values >1.2 x ULN during 
Screening. Note: This criterion will preliminarily be reviewed at Visit 2 based on 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Visit 1a and Visit 1b results (if Visit 1b is required).  The criterion must be re-
evaluated no later than Visit 3 when results for Visit 2 are available. 
10. Requirement for ongoing diuretic use. 
11. Participants who are currently taking, or are expected to be taking, strong or moderate 
CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, 
Seville oranges, or St. John’s wort.  If applicable, there should be a 14-day washout of 
these treatments prior to Visit 2. 
12. Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, 
dapagliflozin, empagliflozin, etc.) within the 2 months prior to Screening Visit 1a or 
expected need for initiation of treatment with a SGLT2 inhibitor during the study. 
13. Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within 
the 2 months prior to Screening Visit 1a or expected need for initiation of treatment 
with a HIF-PH inhibitor during the study. 
14. Simvastatin at a total daily dose >10 mg or amlodipine at a total daily dose >5 mg. 
15. Prior use of tolvaptan or lixivaptan within the 2 months prior to Screening Visit 1a. 
16. Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, 
etc.), metformin (except for diabetes), nicotinamide, bardoxolone, demeclocycline, 
mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.) or KetoCitra™ or any beta-
hydroxybutyrate (BHB) containing supplements within the 2 months prior to 
Screening Visit 1a. 
17. Participants who have taken any investigational drug or used an investigational 
device within 30 days, or 5 half-lives, whichever is longer, prior to Screening Visit 1a 
or plan to participate in an interventional trial during the study. 
18. Hypovolemia on physical examination at Screening.  
19. Abnormal serum sodium concentration at Screening. 
20. Positive test results for hepatitis B surface antigen (HBsAg). 
21. Positive test results for hepatitis C (HCV) antibody (Anti-HCV), with the exception 
of participants for whom the reflex HCV RNA titer test is negative. 
22. Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.  
 
4.2 Completion and Withdrawal of Participants from the Study 
4.2.1 Definition of Completed Participants 
For the purposes of this study, participants who are randomized, take double-blind study drug 
in accordance with the protocol through Visit 22 (Week 52), and complete some or all of their 
required trial visits/assessments through Visit 22 and have at least one follow-up serum 
creatinine assessment during Follow-up Period I will be defined as “Part 1 On-Treatment 
Completers.” 
Participants who are randomized, but permanently discontinue double-blind study drug (or 
never begin double-blind treatment) and complete some or all of their required study 
visits/assessments through Visit 22 and have at least one follow-up serum creatinine 
assessment during Follow-up Period I will be defined as “Part 1 Off-Treatment Completers.” 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Participants who enter Part 2 of the study, take open-label study drug in accordance with the 
protocol through Visit 42 (Week 104), and complete some or all of their required study 
visits/assessments through Visit 42 and have at least one follow-up serum creatinine 
assessment during Follow-up Period II will be defined as “Part 2 On-Treatment Completers.” 
Participants who enter Part 2 of the study, but permanently discontinue open-label study drug 
(or never begin open-label treatment) and complete some or all of their required study 
visits/assessments through Visit 42 and have at least one follow-up serum creatinine 
assessment during Follow-up Period II will be defined as “Part 2 Off-Treatment Completers.” 
The end of the study is defined as the last participant’s last visit. 
4.2.2 Screening and Placebo Run-in/Lixivaptan Titration 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 of 
the entry criteria to participate in the study will be designated as “Screen failures.”  These 
participants will not complete an ET visit (Visit 22).  Screen failures will be recorded as such 
on the electronic Case Report Form (eCRF). Screen failures who do not meet study entry 
requirements may be rescreened at a later date (up to two times) after consultation with the 
medical monitor. 
Participants who discontinue or are discontinued after screening but before randomization 
(i.e., during the Placebo Run-in Period or Lixivaptan Titration Period) will be considered 
“Placebo Run-in/Lixivaptan Titration failures.”   
Placebo Run-in/Lixivaptan Titration failures will complete an ET visit (Visit 22) upon 
withdrawal from the trial and within 7 days of the last dose of study drug. The ET visit 
assessments for Part 1 are delineated in the Schedule of Procedures – Part 1.  Placebo Run-
in/Lixivaptan Titration Failures will not participate in Follow-up Period I, however, Placebo 
Run-in/Lixivaptan Titration failures with ongoing AEs will continue to be followed 
according to the instructions in Section 7.3.8.7. 
4.2.3 Treatment Interruption 
In a study of this duration, it is expected that some participants may have one or more 
treatment interruptions during the Double-blind, Randomized Treatment Period of Part 1 or 
the Lixivaptan Re-Titration or Maintenance Treatment Periods of Part 2.  If a participant’s 
study drug must be interrupted for medical or surgical reasons, liver chemistry test 
abnormalities, tolerability issues, temporary use of a prohibited concomitant medication, life 
situations, e.g., airplane travel, etc... or other reasons, the interruption should be recorded as a 
“Treatment Interruption” on the eCRF. The participant’s study drug should be resumed as 
early as the situation allows, e.g., airplane travel ends or recovery from surgery allows re-
initiation/re-establishment of study drug treatment.  The maximum duration of an 
interruption is 8 weeks; if interruption is greater than 8 weeks, study drug will be 
permanently discontinued.  
The participant should be instructed to immediately inform the Investigator of any missed 
doses reaching or expected to reach 2 days or more so that the Investigator can continue to 
monitor the participant’s treatment and prepare for a possible extended study drug 


Palladio Biosciences PA-ADPKD-301                                                                                   
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interruption.  The Investigator and/or site staff will notify the CRA and/or medical monitor of 
a potential interruption within 24 hours. 
If a study drug interruption is expected to last 7 or more consecutive days, the participant will 
be scheduled to have 3 separate serum creatinine and serum cystatin C samples obtained 
(minimally 24 hrs. apart) beginning on Day 8 after the last dose of study drug for 
determination of eGFR in the event the study drug interruption leads to permanent 
discontinuation of treatment.  In such cases, the 3rd sample will be collected up to Day 28 (± 
3 days) after the last dose of study drug.  If, in the Investigator’s opinion, the treatment 
interruption is expected to be prolonged (i.e., >4 weeks in duration) or permanent, then a 
postbaseline MRI will also be obtained. 
Treatment may still be restarted during or after these assessments are completed; any 
remaining serum creatinine assessments and the post-baseline MRI will not need to be 
completed if treatment is restarted during this period.  If treatment is restarted, and the 
participant resumes study visits to Week 52 (completion of Visit 22 if in Part 1) or Week 104 
(completion of Visit 42 if in Part 2), and has at least 1 scheduled Follow-up Period 
assessment for Part 1 or Part 2, respectively, then the eGFR assessments and MRI obtained 
during the period of study drug interruption will be considered as unscheduled and will not 
be included in the primary efficacy analysis for eGFR or the secondary efficacy analysis 
related to TKV.  This procedure is designed to ensure that data for the primary and secondary 
endpoints are collected from all participants. 
Participants with a study drug interruption 4 weeks or less in duration should resume study 
treatment at their last dispensed dose (or at a lower dose, if medically appropriate) without 
the need for stepwise dose re-establishment.   
Participants with a prolonged study drug interruption (i.e., greater than 4 weeks in duration) 
equal to or less than 8 weeks), who are re-initiating treatment are required to re-establish 
their last tolerated dose over a 2-week interval.  Re-initiation of treatment will begin with 
study drug at Level 2 for one week and will then be increased to the highest level the 
participant was receiving prior to the study drug interruption during the second week as 
described in Table 6 (see pharmacy manual for further details related to study drug 
dispensing following a prolonged drug interruption.) The dose level assigned during Week 2 
may be lowered based on Investigator discretion and clinical need. The IRT system will be 
used to manage re-establishment of dose. 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Table 6. Dose Re-establishment Following a Prolonged (> 4-week) Study Drug 
Interruption 
Last tolerated study drug 
dose level/ dose* 
Week 1 
Week 2** 
Level 2/  
100mg BID 
100mg BID 
100mg BID 
Level 3/  
150mg BID 
100mg BID 
150mg BID 
Level 3a/  
150/100mg (AM/PM) 
100mg BID 
150/100mg  
(AM/PM) 
Level 4/  
200mg BID 
100mg BID 
200mg BID 
Level 4a/  
200/150mg (AM/PM) 
100mg BID 
200/150mg (AM/PM) 
*Participants whose last tolerated dose level was 50mg BID prior to the prolonged treatment interruption, will 
re-initiate study drug dosing at Level 1/ 50mg BID. 
**A lower dose level may be assigned at Week 2 if clinically indicated. 
 
Participants with a prolonged study drug interruption of greater than 8 weeks will not be 
allowed to re-initiate and/or re-establish study drug treatment i.e., study drug treatment will 
be permanently discontinued.  These participants should be encouraged to continue their 
participation in the study following the procedures described in Section 4.2.7 and Appendix 5 
(Section 13.5). 
4.2.4 Treatment Discontinuation 
Participants may elect to stop treatment, (i.e., stop taking their study drug) permanently 
before the end of the study for various reasons.  This is separate and distinct from study 
discontinuation and/or withdrawal (Section 4.2.5) although the reason(s) for study drug 
discontinuation may be identical and/or similar to reason(s) for study discontinuation.  Every 
effort should be made to keep randomized participants in the study and offer them options for 
continued treatment and, at a minimum, continued study participation to the degree possible 
as described in Section 4.2.7 and Appendix 5 (Section 13.5) in order to minimize missing 
data.  Participants who permanently discontinue study drug will have the reason for study 
drug discontinuation (e.g., adverse event) recorded on the eCRF.  They will have an ET visit 
(Visit 22 if in Part 1 or Visit 42 if in Part 2), which should be scheduled within 7 days of the 
participant’s last dose of study drug, to collect data listed in the Schedule of Procedures – 
Part 1 and Schedule of Procedures – Part 2.  Randomized participants who permanently 
discontinue treatment will immediately proceed into the 4-week Follow-up Period and will 
complete the 3 visits in the Follow-up Period between Day 8 and Day 28 following the last 
dose of study drug.  The first two visits, Visits 23 and 24 in Part 1 or Visits 43 and 44 in Part 
2 (performed no less than 24 hours apart), will be for the collection of serum creatinine and 
serum cystatin C to determine eGFR, and the third visit, Visit 25 (Part 1) or Visit 45 (Part 2) 
(performed on Day 28 ± 3 days, and no less than 24 hours from Visit 24 (Part 1) or Visit 44 
(Part 2)) will have additional safety and efficacy measurements (including the post-baseline 


Palladio Biosciences PA-ADPKD-301                                                                                   
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MRI) in addition to serum creatinine and serum cystatin C eGFR measurements (unless the 
participant withdraws consent for further data collection).     
Following completion of the ET visit and Follow-up Period procedures in Part 1 or Part 2, 
participants who have permanently discontinued study treatment should be encouraged to 
remain in the study, in an effort to minimize missing data, and to continue to complete all 
protocol visits and assessments up to and including their originally scheduled Visit 45 (end of 
Follow-up Period II). Changes to or initiation of new medications during this time-period 
should continue to be recorded on the eCRF. 
4.2.5 Reasons for Treatment/Study Discontinuation 
Participants who permanently discontinue study treatment before the end of the study, should 
be encouraged to continue in the study through the last study visit.  They may discontinue or 
may be discontinued from study drug or from the study for any of the following reasons.  
Note: Participants who discontinue from the study following randomization are not eligible 
to re-enroll.  
1. Noncompliance with the protocol (protocol deviation); 
2. Noncompliance with study drug; 
3. Lack of efficacy (including need for transplantation or dialysis); 
4. A serious or intolerable AE that, in the Investigator’s opinion, requires discontinuation 
of study drug or permanent withdrawal from the study, including but not limited to 
laboratory safety assessments that reveal clinically significant (CS) hematological or 
biochemical changes from the baseline values, other than changes that are expected for 
vasopressin antagonists, and symptoms or an intercurrent illness that justifies 
withdrawal.  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 due to mildly 
elevated serum creatinine or serum sodium and should be discussed with the medical 
monitor, if necessary; 
5. Death; 
6. Lost to follow-up (detailed procedures to prevent such loss are discussed further); 
7. Withdrawal of consent (partial or complete); 
8. Investigator or sponsor decides to discontinue the participant’s participation in the 
study; 
9. Pregnancy; 
10. Site terminated by sponsor; 
11. Study terminated by sponsor; 
12. Other (e.g., trial burden, development of contraindication to use of study drug). 
Upon occurrence of an SAE or intolerable AE, the Investigator will confer with the medical 
monitor and sponsor.  If a participant is discontinued from study drug because of an AE, the 
event will be followed until it is resolved or stable as determined by the Investigator.  


Palladio Biosciences PA-ADPKD-301                                                                                   
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Additionally, the procedures described in Section 4.2.4 (Treatment Discontinuation) should 
be followed.  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).   
4.2.6 Study Termination 
The study may be stopped at a study site at any time by the site investigator or the sponsor.  
The sponsor may stop the study for any reason with appropriate notification, including 
inability to enroll a sufficient number of participants to meet study goals, an untoward safety 
signal as recommended by the IDMC and sponsor, or discontinuation of development of 
lixivaptan for ADPKD.  The study may also be stopped by a regulatory authority. 
 
4.2.7 Methods to Prevent Loss to Follow Up 
The Investigator must make every attempt to contact participants who fail to return for 
scheduled visits to prevent participants from being “lost to follow-up” and follow-up with 
participants who have withdrawn from the study at any time and for any reason. Appendix 6 
(Section 13.6) specifies the steps expected to be taken to prevent loss to follow-up.  All 
attempts to follow-up with participants in accordance with Section (13.6), must be 
documented in the source document. Only after all measures to mitigate loss to follow-up 
have been exhausted should participants be identified as “lost to follow-up” in the eCRF. 
4.2.8 Withdrawal of Consent 
Participants are free to withdraw from the study or study drug at any time.  Participation in 
the study may be stopped at any time at the discretion of the Investigator or at the request of 
the sponsor.  Participants should be followed for all protocol-specified evaluations and 
assessments, even after premature discontinuation of study drug, unless there is written 
withdrawal of consent or other written documentation by the Investigator confirming the 
participants’ verbal intent to completely withdraw from the trial.  Declining follow up by all 
of the methods listed below will constitute a withdrawal of consent (these methods of follow 
up will also be noted in the trial ICF). 
• Participation in all study visits and/or procedures specified in the protocol (whether in-
clinic, by telephone, or by an in-home visit). 
• Participation in a subset of protocol-specified visits and/or procedures (by a frequency 
schedule and method as agreed by participant and Investigator). 
• Contact of the participant by trial personnel, even if only by telephone, to assess current 
medical condition and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
• Access to medical information from alternative sources (e.g., hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Withdrawal of consent is a critical trial event and should be handled with a high degree of 
importance and care.  Reasons for participants’ intended withdrawal must be understood, 
documented and managed to protect the rights of participants and the integrity of the trial.  
Participants may initially want to interrupt or discontinue study drug, but that is not the same 
as complete withdrawal of consent for further participation.  A participant may, for example, 
consider that further trial participation is a burden. The Investigator should then follow the 
procedures outlined in Appendix 5 (Section 13.5) to determine if the participant can continue 
participation in the trial if modifications to his/her treatment and/or schedule of procedures 
can be accommodated, including the potential to continue in the study at a lower dose level.  
The scientific value of collecting data and information even after study drug is discontinued 
should be discussed with a participant who is at risk of withdrawing consent.  Participants 
who withdraw their permission for all of the follow-up procedures listed above are 
considered to have completely withdrawn their consent to participate in the study. 
4.2.9 Replacements 
Participants who are randomized and subsequently withdraw from the study (either Part 1 or 
Part 2) will not be replaced. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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5 STUDY DRUG AND CONCOMITANT MEDICATION 
5.1 Study drug 
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 7. 
Table 7. Investigational Product 
 
Lixivaptan 
Strength 
50 mg 
Formulation 
Capsules 
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 – USA 
Packager 
PCI Pharma Services 
4545 Assembly Drive 
Rockford, IL 61109 – USA 
5.1.2 Identity of Placebo 
The placebo capsule is identical in size and appearance to the lixivaptan capsule.  The 
placebo capsule does NOT contain the active ingredient (lixivaptan) but contains the same 
inactive ingredients as in the investigational product.   
5.1.3 Route of Administration 
The study drug (lixivaptan or placebo capsule) is intended to be taken orally, i.e., to be 
swallowed whole with water. The study drug can be taken with or without food. The capsule 
should NOT be opened.   
5.1.4 Study Drug Packaging, Labeling, and Storage 
Study drug will be packaged by the sponsor according to all local legal requirements and 
labeled in accordance with applicable regulatory requirements. It will be packaged in blister 
cards designed to dispense four capsules BID throughout the study.  
All investigational drug supplies should be stored in a secure, locked area, under the 
responsibility of the Investigator or other authorized individual. Study drug should be stored 
in accordance with the specifications detailed in the study pharmacy manual. Participants 
should be instructed to store study drug in its original packaging and in accordance with 
study drug labelling at all times until ready to take.  


Palladio Biosciences PA-ADPKD-301                                                                                   
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For study visits that are conducted remotely, study drug may be dispensed via a secure and 
traceable delivery method (where permissible by local, statutory, federal/country law) and 
after approval by the sponsor or sponsor designee.  In such cases, 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 home healthcare 
clinician (HHC)/qualified site personnel arrives.  Alternatively, where permissible and 
approved by the sponsor or sponsor designee, qualified study staff conducting remote visits 
may dispense study drug directly to participants at the time of the remote visit. 
5.1.5 Accountability 
The Investigator will maintain accurate records of study drug receipt and disposition.  In 
addition, accurate records will be kept regarding when and how much study drug is 
dispensed, used, and returned 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 drug accountability, all unused study drugs 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, study drug will be administered BID, with the PM dose 
administered approximately 10 hours after the AM dose. Study drug will be packaged in 
blister cards designed to dispense four capsules BID throughout the study to reduce the 
awareness of transitions during the study.  Depending on the study period, treatment arm to 
which the participant is randomized, and current dose level, the set of 4 capsules may be all 
placebo, all active or a combination of active and placebo. Study drug will be assigned via 
the IRT system throughout the study.  During the Placebo Run-in Period, participants will 
receive four capsules of single-blind placebo BID over one week of dosing.  During the 
Lixivaptan Titration Period, single-blind lixivaptan will be started at Level 1 (50 mg BID) 
and will be increased weekly through Levels 2 (100 mg BID), 3 (150mg BID), and 4 (200 
mg BID) according to the dosing schedule in Table 1. Two additional dose levels (Levels 3a 
and 4a) are provided that reduce the evening (PM) dose by 50 mg (from 150 mg to 100 mg 
and from 200 mg to 150 mg) if aquaretic effects are limiting participants’ tolerability at either 
the 150 mg BID or 200 mg BID dose levels, respectively (Note: further dose reductions are 
allowable as shown in the Lixivaptan Titration Period (Part 1) — Lixivaptan Titration 
Flowchart.)   
Tolerability will be assessed by asking the participant a single question “Would you take the 
study drug for the next 24 months?”  If the participant confirms the dose can be tolerated, the 
participant will be titrated to the next dose level (i.e., the dose will be increased).  This 
assessment of tolerability will continue at weekly intervals until either the maximum dose 
level is reached (Level 4 [200 mg BID]) or until the participant confirms that the dose cannot 
be tolerated for a 24-month period.  In that case, the dose will be reduced by one dose level 
(assigned by the IRT system) as depicted in the Lixivaptan Titration Period (Part 1) — 
Lixivaptan Titration Flowchart.  Note: Assessment of tolerability will begin at Visit 3, the 
end of the Placebo Run-in Period. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Once the maximum tolerated dose is achieved during the Lixivaptan Titration Period, 
participants will generally stay on that dose for 1 additional week to confirm tolerability.  As 
the maximum duration of the Lixivaptan Titration Period is 6 weeks, participants who require 
a dose reduction at Week 6, as a result of emerging tolerability issues, will proceed to the 
double-blind period on the newly assigned (reduced) dose level without extension of the 
titration period.  Participants who are unable to tolerate the minimum dose for entry into the 
Double-Blind, Randomized Treatment Period, (100 mg BID/ Level 2) will be discontinued 
from the study.   
At the start of the Double-blind Randomized Treatment Period participants will be 
randomized to either continue at the lixivaptan dose level achieved at the end of the 
Lixivaptan Titration Period or receive matching placebo capsules.  During the Double-blind, 
Randomized Treatment Period, the dose may be adjusted downward at the Investigator’s 
discretion if needed to manage non-hepatic side effects.  For these participants, the dose level 
should be increased back to the dose at the start of the Double-Blind, Randomized Treatment 
Period, once symptoms resolve and if medically advisable. Attempts will be made every 4 to 
8 weeks to reinstate the dose achieved at Visit 9.  The Investigator may temporarily interrupt 
the study drug, if necessary, to manage acute intercurrent illness, tolerability issues, planned 
or unplanned surgical procedures or life situations, e.g., airplane travel, etc. The participant’s 
study drug should be resumed as early as the situation allows, e.g., airplane travel ends or 
recovery from surgery allows re-initiation/re-establishment of study drug treatment.  The 
maximum duration of an interruption is 8 weeks; if interruption is greater than 8 weeks, study 
drug treatment will be permanently discontinued (Section 4.2.3).  
At the completion of Follow-up Period I (Visit 25), participants will be dispensed lixivaptan 
at a dose of 50 mg BID to initiate the Lixivaptan Re-titration Period of study Part 2. Dosing 
will be increased weekly until the dose level taken at the end of the Double-blind, 
Randomized Treatment Period is achieved (2 to 4 weeks).  This is shown in Table 2.  That 
dose will be continued into the Maintenance Treatment Period for the remainder of Part 2 
unless tolerability issues arise either during the Lixivaptan Re-titration Period or during the 
Maintenance Treatment Period, in which case the dose may be lowered or temporarily 
stopped. Attempts will be made every 4 to 8 weeks to re-establish the previously achieved 
dose level from Part 1, if medically appropriate. If tolerability continues to be problematic, 
the participant may continue at the lower dose.  If study drug is interrupted for longer than 8 
weeks, then study drug treatment will be permanently discontinued. 
5.3 Method of Assigning Participants to Treatment Groups 
Each investigator will be assigned a unique 5-digit site number (XXXXX) where the first 2 
digits represent the country, and the last 3 digits are unique for a site. This site number will 
be concatenated with a leading protocol number (301) and a following 3-digit participant 
number (YYY) to assure that each participant will be uniquely identified in the clinical 
database. Thus, a prototypical participant number in this study will look like 301-XXXXX-
YYY.  As participants are screened, the next participant qualified chronologically at a site 
will be assigned the next number in ascending numerical order.  The participant identification 
number assigned at Screening will be used for that participant throughout the study.  
Participants who screen fail and are subsequently eligible to re-screen, will retain their 
original identification number. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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All treatment periods will use active or placebo study drug that is identical in appearance.  
During the single-blind, Placebo Run-in and Lixivaptan Titration Periods, participants should 
not be told whether they are receiving active or placebo medication although site personnel 
will be aware.   
At the randomization visit (Visit 9), participants will be randomized to receive either 
lixivaptan capsules or placebo capsules during the Double-blind Randomized Treatment 
Period. Throughout the study, and at all subsequent visits or contacts with the participant, the 
participant will be reminded of the importance of their commitment to continue participation 
in the study, however, the participant will not be told that this day is the point at which 
randomization to long-term therapy occurs.  Randomization will occur through an IRT 
system that will be programmed for the stratification factors and the randomization ratio (2:1 
lixivaptan to placebo).  After randomization, treatment allocation will be blinded to all 
participants, investigators, site personnel, and sponsor employees and representatives.   
5.4 Treatment Compliance 
Dispensing of study drug and reconciliation will be performed at each visit during the 
Placebo Run-in and Lixivaptan Titration Periods in Part 1 and during the Lixivaptan Re-
titration Period in Part 2. Dispensing and reconciliation will be performed monthly during the 
Double-blind Randomized Treatment Period.  Participant compliance will be monitored by 
capsule counts as study drug is returned.  For visits that are conducted remotely, direct-to-
participant drug dispensing will be utilized (where applicable) prior to the scheduled in-home 
visit with the HHC/qualified site personnel.  Participants should be instructed not to open the 
study drug shipment until the contents can be verified by the HHC/qualified site personnel.  
Compliance will be assessed by the HHC/qualified site personnel during these visits. 
The dates of all study drug dosing, including interruptions, missed doses or overdose, must 
be recorded in the source document and study drug accountability forms. Compliance is 
defined as a minimum of 80% dosing compliance during any study interval.  If the 
participant is not ≥ 80% compliant with the prescribed study drug doses during the study 
overall, it will be noted as a protocol deviation. The participant should be re-educated 
regarding the correct study drug doses to be administered whenever compliance is < 80%. 
However, if the Investigator, medical monitor, and sponsor have agreed to a study drug 
interruption (Section 4.2.3), then this period of non-compliance will not be considered a 
protocol deviation.   
5.5 Prior and Concomitant Therapy 
Participants will be allowed to take their chronic medications unless excluded by the protocol 
(Section 5.5.1.2) and provided that their chronic medication therapy meets the conditions 
outlined in Section 5.5.1.1, including remaining constant throughout the duration of the 
study.  
Use of all prior medications within 2 months prior to study drug administration will be 
recorded in the participant’s eCRF.  The minimum requirement is that drug name and the 
dates of administration are recorded.  This will include all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter (OTC) medications.  Any changes in prior 
or concomitant medications will also be recorded in the participant’s eCRF. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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 (Section 5.5).  Note: in female participants with severe polycystic liver disease, 
contraceptives (and hormone replacement therapy) containing estrogen may be involved in 
the development and growth of liver cysts and polycystic liver disease progression; the 
supplemental risk of initiating or continuing estrogen treatment, as well as potential 
alternative contraceptives for WOCBP will be discussed with the potential participant.  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, date and time of administration, and reason for medication use. 
Upon entering the study, each participant will be instructed on the importance of not taking 
any medication (including OTC medications) without consulting the Investigator. 
5.5.1.1 Permitted Therapy 
Treatment considered necessary for the participant’s welfare may be given at the discretion of 
the Investigator.  Allowed medications include those typically prescribed to treat CKD and its 
complications such as hypertension; these include ARBs (e.g., valsartan, candesartan, 
telmisartan, irbesartan) and ACE inhibitors (e.g., enalapril, lisinopril). While optimization of 
these medications is allowed during the Screening Period, it is expected that the dose will 
remain stable for the duration of the study. Any dose adjustments in antihypertensive 
medications must be discussed with the medical monitor. 
Acetaminophen (paracetamol), 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 kidney function, use of non-steroidal anti-inflammatory drugs (NSAIDs) 
should be minimized. 
Non-sedating antihistamines (other than loratadine) and decongestants may be permitted on 
an as-needed basis.  Low-dose aspirin (up to 150 mg per day) is permitted. 
Vaccines, including the COVID-19 vaccine and/or vaccine booster are permitted during study 
participation.    
Chronic use of other concomitant medications that are required to treat a medical condition 
may be permitted unless otherwise prohibited (Sections 4.1.2 and 5.5.1.2).  All medication 
treatment dosing regimens should be stable for 1 month prior to screening, allowing for 
minor adjustments per the standard of care to treat medical conditions and avoiding, 
whenever possible, adjustments that will significantly impact serum creatinine levels.  The 
stability of treatment regimens of certain drugs, such as insulin and warfarin, should be based 
on the standard of care rather than on a stable dose.   
5.5.1.2 Prohibited Therapy 
The following medications are prohibited throughout the study: 
• bardoxolone; 
• conivaptan; 
• demeclocycline;  


Palladio Biosciences PA-ADPKD-301                                                                                   
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• diuretics (must be discontinued during Screening when anti-hypertensive medications 
are being adjusted) except for a short course (up to 4 weeks at a time) of loop diuretic 
therapy to manage a temporary fluid retention condition; 
• 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, PaxlovidTM 
(nirmatrelvir co-packaged with ritonavir), posaconazole, voriconazole, 
quinupristin/dalfopristin, remdesivir, ritonavir and ritonavir-containing products, 
telaprevir, teriflunomide, tofisopam, troleandomycin, verapamil, and voriconazole; 
• any investigational drug or device; 
• KetoCitra™ or any beta-hydroxybutyrate (BHB) containing supplements; 
• medications, supplements, and herbal preparations that may interfere with the 
accurate measurement of serum creatinine including cimetidine, trimethoprim, 
pyrimethamine, phenacemide, and aspirin (aspirin dose above 150 mg per day); 
• vasopressin or drugs with vasopressin activity. 
5.6 Diet, Fluid, and Activity Control 
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 study drug 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 Placebo Run-In Period, all participants should receive the 
recommendation to ingest at least 3-4 quarts (or liters as an approximation of quarts) of fluid 
(including in solid, semi-solid, and liquid foods) per day, unless otherwise directed by the 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Investigator.  This recommendation should start at the beginning of the Placebo Run-In 
Period and continue through the end of the study (Part 1 and Part 2).  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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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6 TIMING OF STUDY PROCEDURES  
The timing of study procedures is presented in the Schedule of Procedures – Part 1 and 
Schedule of Procedures – Part 2.  As detailed in the Schedule of Procedures for each part of 
the study, certain visits must occur in the clinic, while other visits may occur in the clinic or 
may be conducted remotely by an HHC/qualified site personnel (with the agreement of the 
participant and the discretion of the investigator and where available and locally approved by 
the CA and/or IRB/EC).  Note: During the Lixivaptan Titration Period (Part 1), designated 
visits that are conducted remotely also require a telehealth visit (e.g., telemedicine virtual 
visit, telephone or video call (without recording)) with the Investigator as described in 
Section 6.3.1.  
For a given participant, every attempt will be made to draw blood samples for eGFR 
determinations at approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 
23, 24, and 25, and again at Visits 43, 44, and 45.  
In response to local, regional, or national restrictions resulting from the ongoing SARS-CoV-
2 (COVID-19) pandemic or in the event of other public health crises that may limit or 
interfere with the conduct of this study protocol, modifications to the study plan may be 
permitted.  In such cases, impacted in-person study visits may be conducted remotely by an 
HHC/qualified site personnel and/or via a telehealth visit with the Investigator and/or study 
assessments may be deferred following approval from the medical monitor and sponsor.  In 
such cases, the source documents and eCRFs must clearly denote the study visits/assessments 
impacted by the public health crisis.     
6.1 Screening Period 
The Screening Period will last from 3 to 8 weeks. Screening for participants who do not 
require adjustments to medications should be completed in 3 to 5 weeks. Longer screening is 
available for participants who require modification of medical care for this trial or where 
scheduling baseline tests is difficult, as examples. Visit 1a will be used to collect historical 
information to determine (i) whether the participant is preliminarily eligible; and (ii) whether 
additional time is needed to modify background medical treatment, e.g., discontinuation of 
diuretics or intensification of anti-hypertensive therapy.   
If longer screening is required for modification of medical care, then Visit 1b should be 
delayed until those modifications are completed, and blood pressure and treatment have been 
stable for a minimum of 3 weeks. At that point Visit 1b may occur. Note: All laboratory 
results from Visit 1b should be available prior to the completion of Visit 2. The baseline MRI, 
which may be completed before, at, or after Visit 1b, is to be completed approximately 1 
week prior to Visit 2 to allow for receipt of the Mayo Clinic ADPKD Image Classification 
from the central imaging vendor (Note: Visit 2 should be scheduled approximately 1 week 
after the baseline MRI and approximately 2 weeks after completion of Visit 1b, whichever 
occurs later). All assessments needed for evaluation of eligibility and for establishing  
baseline values during the Screening Period must be completed within 8 weeks. 
Participants who do not require modification to medical treatment should be scheduled for 
the baseline MRI and should proceed to Visit 2 in 3 to 5 weeks following Visit 1a. Note: 
Visit 2 should be scheduled approximately 1 week following completion of the MRI to allow 


Palladio Biosciences PA-ADPKD-301                                                                                   
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for receipt of the Mayo Clinic ADPKD Image Classification from the central imaging vendor.  
Participants must have adequate BP control for a minimum of 3 weeks prior to enrollment 
(Visit 2). The Screening Period may be extended up to 8 weeks for these participants under 
extenuating circumstances and with prior approval from the medical monitor. 
6.1.1 Visit 1a 
Visit 1a will be conducted at the clinical site.  Participants will undergo informed consent and 
after signing the informed consent form, the following screening procedures will be 
performed at Visit 1a: 
• Collect and review demographic information. 
• Collect and review medical history information, including smoking and alcohol 
history.  
• Collect and review prior and concomitant medication information with particular 
emphasis on collection of use and dosing of any protocol-excluded medications 
(Section 4.1.2 and 5.5.1.2). 
• Perform a complete physical examination including assessment for hypovolemia. 
• Collect body weight and height measurements; BMI will be auto-calculated by the 
EDC system.  
• Check vital signs (includes sitting blood pressure, heart rate, respiratory rate, and 
temperature).  
• Perform a 12-lead ECG. 
• Collect blood samples for:  
o chemistry, including serum sodium;  
o liver chemistry; 
o serum creatinine and serum cystatin C for eGFR determinations. (Note: For a 
given participant, every attempt will be made to draw blood samples for eGFR 
determinations at approximately the same clock time during Visits 1a/1b, 2, 
and 3 and Visits 23, 24, and 25, and again at Visits 43, 44, and 45); 
o hematology; 
o serology: HbsAg and Anti-HCV (Note: A positive anti-HCV test requires a 
negative HCV RNA titer reflex test prior to enrollment.  HCV sero-positive 
participants should undergo reflex testing at an Unscheduled Visit prior to 
Visit 2). 
• Collect urine for: 
o urinalysis; 
o local urine pregnancy test (Note: all positive tests will be confirmed by a 
serum pregnancy test at the central laboratory). 
• Review and assess AEs and SAEs. 
• Review eligibility criteria (Section 4.1.1 and 4.1.2).   
• Contact the IRT to assign the participant an identification number as described in 
Section 5.3.  


Palladio Biosciences PA-ADPKD-301                                                                                   
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• If no medication changes are necessary: 
o schedule baseline MRI to determine eligibility according to Mayo Clinic 
ADPKD Image Classification criteria;   
o schedule Visit 2 approximately 1 week after the scheduled MRI (to allow for 
receipt of the Mayo Clinic ADPKD Image Classification from the central 
imaging vendor). Visit 2 should be 3 to 5 weeks after Visit 1a. 
o provide participant with a urine collection container and written instructions to 
produce a first morning, fasting (≥8 hours, except for water) urine specimen to 
be brought in at Visit 2 for assessment of urine osmolality.     
• If medication changes are necessary (i.e., discontinuation of diuretics or revision of 
anti-hypertensive medications), participants should return for Unscheduled visits for 
blood pressure monitoring per medical standard of care.  The participant should then 
be observed on stable medications for a minimum of 3 weeks and then: 
o schedule Visit 1b; 
o schedule baseline MRI to determine eligibility according to Mayo Clinic 
ADPKD Image Classification criteria (may be completed before, at, or after 
Visit 1b, but prior to Visit 2). 
6.1.2 Visit 1b 
This visit only applies to those participants who require modification of medical treatment. 
The following procedures will be performed at Visit 1b: 
• Collect and review new concomitant medication information.  
• Check vital signs. 
• Review and assess AEs and SAEs. 
• Review eligibility (Section 4.1.1 and 4.1.2). 
• Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 
o liver chemistry; 
o serum creatinine and serum cystatin C for eGFR determinations. Note: Every 
attempt will be made to draw blood samples for eGFR determinations at 
approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 
24, and 25, and again at Visits 43, 44, and 45, for a given participant. 
• Provide participant with a urine collection container and written instructions to 
produce a first morning, fasting (≥8 hours, except for water) urine specimen to be 
brought in at Visit 2 for assessment of urine osmolality. 
• Contact the IRT to register the participant visit. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Schedule Visit 2 approximately 1 week after completion of the baseline MRI to allow 
for receipt of the Mayo Clinic ADPKD Image Classification from the central imaging 
vendor and approximately 2 weeks following Visit 1b (whichever occurs later).    
6.1.3 Visit 2 
The following procedures will be performed at Visit 2: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 2 for determination of urine osmolality. 
• Collect and review new concomitant medication information.  
• Check vital signs.   
• Review and assess AEs and SAEs. 
• Review all eligibility (Section 4.1.1 and 4.1.2) including prior laboratory results, ECG 
results, and Mayo Clinic ADPKD Image Classification from central imaging vendor. 
Note: the eGFR criterion (Inclusion #4) will be preliminarily assessed on the basis of 
the single measurement from Visit 1a or 1b (if Visit 1b was required). Mean eGFR 
will be reviewed again no later than Visit 3 after the results of the Visit 2 eGFR 
measurement are available.  Additionally, eligibility based on liver chemistry tests 
(Exclusion #9) must also be re-confirmed by Visit 3, following receipt of laboratory 
results from Visit 2. 
o If the participant is not eligible to participate, record the participant as a 
Screen Failure and contact the IRT to discontinue the participant from the 
study and complete the appropriate eCRFs. 
o If the participant is eligible to participate: 
▪ Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 
o liver chemistry; 
o serum creatinine and serum cystatin C for eGFR 
determinations. Note: Every attempt will be made to draw 
blood samples for eGFR determinations at approximately the 
same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 24, 
and 25, and again at Visits 43, 44, and 45, for a given 
participant; 
o sparse PK sampling (blood draw can occur at any time during 
this visit). 
▪ Administer the following health-outcomes scales to participant (Note: 
responses should be reviewed prior to completion of the visit in order 
to clarify any ambiguous or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 


Palladio Biosciences PA-ADPKD-301                                                                                   
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o ADPKD-UIS 
▪ Contact the IRT to obtain a study drug kit number and dispense study 
drug to initiate the single-blind, Placebo Run-in Period – the 
participant is blinded. Instruct the participant to take 4 capsules twice a 
day daily approximately 10 hours apart. 
▪ Remind the participant to increase fluid intake to prevent dehydration 
▪ Schedule the participant to return for Visit 3 (to occur in 1 week ± 2 
days).  Provide the participant with an appointment reminder card and 
any written instructions. 
6.2 Placebo Run-in Period and Visit 3 
During the single-blind, Placebo Run-in Period, participants will self-administer 4 capsules 
containing placebo twice daily for 1 week.  The afternoon dose will be taken approximately 
10 hours after the morning dose.  Visit 3 will occur at the end of the Placebo Run-in Period 
(± 2 days). The following procedures will be performed at Visit 3: 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results. 
• Review the mean eGFR (based on serum creatinine) from Visits 1a and 2 or Visits 1b 
and 2, if Visit 1b was required.  If less than 25 ml/min/1.73 m2 or greater than 90 
ml/min/1.73 m2, complete procedures for ET visit (Visit 22) and contact the IRT to 
discontinue the participant from the study and complete early termination procedures 
(Section 6.4.2).  Participant will not participate in the Follow-up Period. 
• Review ALT, AST, and total bilirubin from Visit 2.  If ALT, AST, or total bilirubin 
>1.2 x ULN complete procedures for ET visit (Visit 22) and contact the IRT to 
discontinue the participant from the study and complete early termination procedures 
(Section 6.4.2).  Participant will not participate in the Follow-up Period. 
• Perform study drug reconciliation and review study drug compliance. 
• Review tolerability of dosing.   
o If the participant reports the study drug was not tolerated (in response to the 
question, “Would you take the study drug for the next 24 months?”), contact 
the IRT to discontinue the participant from the study and complete early 
termination procedures (Section 6.4.2).  Participant will not participate in the 
Follow-up Period. 
For participants who remain eligible to continue in the study: 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Collect body weight measurement.  
• Check vital signs. 
• Perform a urine pregnancy test for WOCBP. 
• Collect blood samples for the following laboratory testing:  
o serum sodium 
o liver chemistry; 
o serum creatinine and serum cystatin C for eGFR determinations. Note: Every 
attempt will be made to draw blood samples for eGFR determinations at 
approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 
24, and 25, and again at Visits 43, 44, and 45, for a given participant; 
o hematology. 
• Contact the IRT to obtain a study drug kit number and dispense study drug to initiate 
the single-blind, Lixivaptan Titration Period – the participant is blinded.  
o Administer the first dose from the newly assigned study drug kit in the clinic. 
o Collect a blood sample for sparse PK (blood draw to occur 0.5 hrs to 1.5 hrs 
post dose).   
o Instruct the participant to take 4 capsules twice a day daily approximately 10 
hours apart. 
o Remind the participant to increase fluid intake to prevent dehydration 
o Schedule the participant for Visit 4 (to occur in 1 week ± 2 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
6.3 Lixivaptan Titration Period 
The Lixivaptan Titration Period will last from 5 to 6 weeks.  Participants will self-administer 
lixivaptan at home (following the initial dose in the clinic).  All participants will start at 
Level 1 (50 mg BID) and will be increased weekly through Level 2 (100 mg BID), Level 3 
(150 mg BID), and Level 4 (200 mg BID), as necessary, according to the schedule described 
in Table 1 until either the maximum dose level (Level 4/200 mg BID) or maximum tolerated 
dose is achieved.  Two additional dose levels (Levels 3a and 4a) are provided that reduce the 
evening (PM) dose by 50 mg (from 150 mg to 100 mg and from 200 mg to 150 mg) if 
aquaretic effects are limiting participants’ tolerability at either the 150 mg BID or 200 mg 
BID dose levels, respectively.  Further dose reductions are allowable as shown in the 
Lixivaptan Titration Period (Part 1) — Lixivaptan Titration Flowchart.  However, the 
minimum dose to enter the Double-blind, Randomized Treatment Period is Level 2 (100 mg 
BID). Once the maximum dose or maximum tolerated dose is achieved, participants will 
generally stay on that dose for 1 additional week to confirm tolerability.  As the maximum 
duration of the Lixivaptan Titration Period is 6 weeks, participants who require a dose 
reduction at Week 6 as a result of emerging tolerability issues, will proceed to the double-
blind period on the newly assigned (reduced) dose level without extension of the titration 
period.  Participants will then proceed to Week 9/Last Titration Visit.   


Palladio Biosciences PA-ADPKD-301                                                                                   
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6.3.1 Visits 4 to 8 (Lixivaptan Titration Period) 
Visits 4, 5, 6, 7, and 8 (Visit 8 only if needed) will occur weekly ± 2 days for titration.  
Titration visits 4 to 7 may either be conducted in the clinic or remotely by an HHC/qualified 
site personnel (with the agreement of the participant and the discretion of the investigator and 
where available and locally approved by the CA and/or IRB/EC).  Note: If conducted 
remotely, Visits 4 to 7 will require a telehealth visit (e.g., telemedicine virtual visit, telephone 
or video call (without recording)) with the Investigator 2 days prior to the scheduled in-home 
visit to assess tolerability.  This will allow sufficient time for IRT study drug assignment and 
subsequent direct-to-participant drug dispensing prior to the scheduled in-home visit.  Some 
participants may complete the Lixivaptan Titration Period in 5 weeks, depending on their 
highest tolerated dose.  These participants will skip Visit 8 assessments and will instead 
complete the assessments for Visit 9/Last Titration Visit. For participants requiring Visit 8, 
Visit 8 will be conducted in the clinic. The following procedures will be performed at each 
visit unless otherwise noted: 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results (from Visit 4 and Visit 7 blood collection). 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Check vital signs. 
• Perform study drug reconciliation and review study drug compliance. 
• Review tolerability of dosing.   
o At Visit 4 (only): If the participant reports the study drug was not tolerated (in 
response to the question, “Would you take the study drug for the next 24 
months?”), contact the IRT to discontinue the participant from the study. 
o At Visits 5 to 8: If the participant reports the study drug was not tolerated (in 
response to the question, “Would you take the study drug for the next 24 
months?”), reduce the dose by 1 level (via IRT) in accordance with the 
Lixivaptan Titration Period (Part 1) — Lixivaptan Titration Flowchart.    
o If the participant reports the study drug was tolerated, proceed with titration to 
the next dose level (via IRT) based on the Lixivaptan Titration Period (Part 1) 
— Lixivaptan Titration Flowchart and these general principles (Note: all study 
drug assignments will continue to be managed by the IRT system): 
▪ Level 1 is an introductory dose to allow participants to become 
accustomed to the aquaretic effects of the study drug. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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▪ The goal of titration is to continue to escalate the dose to achieve 
either the maximum dose (Level 4 [200 mg BID]) or the highest 
tolerated dose. 
▪ In those participants who are titrated up to Levels 3 and 4 but have 
limited aquaretic tolerability at these dose levels, the reduced dose 
Levels 3a and 4a are available, respectively, which lower the evening 
dose by 50 mg.  Further dose reductions are allowable as shown in the 
Lixivaptan Titration Period (Part 1) — Lixivaptan Titration Flowchart.  
This is meant to assist with aquaretic tolerability, and, in particular, 
nocturia.   
▪ As shown in the flowchart, most dose levels incorporate a second 
week of dosing at the same level to assure tolerability.  However, as 
the Lixivaptan Titration Period is designed to be a maximum of 6 
weeks in duration, participants will stay on the final tolerable dose for 
only 1 week if a dose adjustment (i.e., dose decrease) is required at 
Week 6 (Visit 9/Last Titration).  Those participants will immediately 
proceed to the Double-Blind, Randomized Treatment Period on the 
newly decreased dose. 
• At Visit 4, document CKD Stage based on mean eGFR calculated from Visits 1a, 2, 
and 3 or Visits 1b, 2, and 3 (if Visit 1b was required). 
o CKD Stage 2: eGFR 60 to 90 ml/min/1.73 m2 
o CKD Stage 3: eGFR 30 to 59 ml/min/1.73 m2 
o CKD Stage 4: eGFR 15 to 29 ml/min/1.73 m2  
• Administer the following health-outcomes scale to participant (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
▪ ADPKD-UIS 
• Collect blood samples for the following laboratory testing:  
o Liver chemistry and serum sodium (Visits 5 and 7 only) (Note: For 
participants exhibiting an increase in liver chemistry tests during the 
Lixivaptan Titration Period (>1.2 x ULN), follow the instructions in Section 
7.3.7.1.2 (Liver Test Abnormalities during the Placebo Run-in and/or 
Lixivaptan Titration Period). 
• At Visit 7 (if participant is initiating his/her second week to confirm tolerability and 
may not require Visit 8 or at Visit 8 for all other participants), provide participant 
with a urine collection container and written instructions to produce a first morning, 
fasting (≥8 hour except for water) urine specimen to be brought in at Visit 9 for 
assessment of urine osmolality. 
• Contact the IRT to obtain a study drug kit number and dispense study drug. Instruct 
the participant to take 4 capsules twice a day daily approximately 10 hours apart. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Remind the participant to increase fluid intake to prevent dehydration 
• Schedule the participant for the next visit in the Lixivaptan Titration Period (to occur 
in 1 week ± 2 days).  Provide the participant with an appointment reminder card and 
any written instructions.     
 
Participants who do not tolerate the study drug during the titration period and have no further 
adjustment step available in accordance with the Lixivaptan Titration Period (Part 1) — 
Lixivaptan Titration Flowchart will terminate from the study.  Participants who terminate 
from the study during the titration period will undergo Visit 22/ET procedures within 7 days 
of the last dose of study drug. 
 
6.3.2 Visit 9/Last Titration Visit 
Visit 9/Last Titration Visit is intended to confirm that the participant tolerates lixivaptan at 
the dose determined during the Lixivaptan Titration Period, to collect additional data, and to 
randomize the participant to study drug for the Double-blind Randomized Treatment Period.  
The following procedures will be performed at Visit 9/Last Titration Visit: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 9 for determination of urine osmolality. 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results. 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Review tolerability of dosing. 
• Collect body weight measurement.  
• Check vital signs. 
• Collect urine for: 
o urinalysis; 
o local urine pregnancy test (Note: all positive tests will be confirmed by a 
serum pregnancy test at the central laboratory). 
• Perform a 12-lead ECG. 
• Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 


Palladio Biosciences PA-ADPKD-301                                                                                   
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o liver chemistry; 
o serum creatinine for eGFR determination; 
o hematology; 
o sparse PK sampling (blood draw can occur at any time post-dose). 
• Administer the following health-outcomes scales to participants (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to randomize the participant and to obtain 4 study drug kit numbers 
(4-week supply). Note: Mayo Clinic ADPKD Image Classification as assessed by the 
central imaging vendor (prior to Visit 2) and CKD Stage will be used by the IRT 
System for stratification purposes.  Dispense study drug to initiate the Double-blind, 
Randomized Treatment Period.  Instruct the participant to take 4 capsules twice a day 
daily approximately 10 hours apart. 
• Remind the participant to increase fluid intake to prevent dehydration 
• Schedule the participant for the next visit (to occur in 4 weeks ± 5 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
Note: During the Double-Blind Randomized Treatment Periodsites will contact participants 
by telephone 2 weeks (± 5 days) after every scheduled visit to ascertain continued 
tolerability and adherence to study drug treatment.  Telephone contacts will be recorded in 
the source document. 
 
6.4 Double-blind, Randomized Treatment Period 
The Double-blind Randomized Treatment Period will last 52 weeks, and visits will occur 
every 4 weeks ± 5 days (Visit 10 to Visit 22).  
6.4.1 Visits 10 to 21 
Visits 10 to 21 will occur every 4 weeks ± 5 days.  Visits 10, 11, 13, 14, 16, 17, 19, 20 and 21 
may be conducted remotely by an HHC/qualified site personnel (with the agreement of the 
participant and the discretion of the investigator and where available and locally approved by 
the CA and/or IRB/EC). Visits 12, 15, and 18 must be conducted in the clinic. The following 
procedures will be performed at each visit unless otherwise noted: 
• Provide participant with a urine collection container and written instructions to 
produce a first morning, fasting (≥8 hours, except for water) urine specimen to be 
brought in at Visit 15 for assessment of urine osmolality. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 15 only for determination of urine osmolality. 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results. 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Check vital signs. 
• Perform a urine pregnancy test for WOCBP (Visit 12, Visit 15, and Visit 18 only). 
• Perform a brief physical examination (Visit 15 only or if indicated by signs or 
symptoms). 
• Perform a 12-lead ECG (Visit 15 only). 
• Collect blood samples for the following laboratory testing:  
o chemistry (Visit 12, Visit 15, and Visit 18 only); 
o serum sodium (all visits); assessed as part of chemistry at Visits 12, 15 and 18 
and as part of liver chemistry at all other visits; 
o liver chemistry; 
o serum creatinine for eGFR determination; 
o hematology (Visit 15 only); 
o sparse PK sampling (Visit 12 (pre-dose), Visit 15 (1 to 6 hrs post-dose), and 
Visit 18 (6 to 10 hrs post-dose) only and in accordance with sparse PK 
sampling schedule (Schedule of Procedures – Part 1). 
• Administer the following health-outcomes scales to participants at Visits 12, 15, and 
Visit 18 only. (Note: responses should be reviewed prior to completion of the visit in 
order to clarify any ambiguous or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to obtain 4 study drug kit numbers (4-week supply). Dispense 
double-blind study drug.  Instruct the participant to take 4 capsules twice a day daily 
approximately 10 hours apart. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• At Visit 21, provide participant with a urine collection container and written 
instructions to produce a first morning, fasting (≥8 hours, except for water) urine 
specimen to be brought in the morning of Visit 22 for assessment of urine osmolality. 
• Remind the participant to increase fluid intake to prevent dehydration 
• Schedule the participant for the next visit (to occur in 4 weeks ± 5 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
6.4.2 Visit 22/Early Termination 
Visit 22 is the end of the double-blind period and will also serve as the Early Termination 
visit. For participants completing the Double-blind, Randomized Treatment Period, the visit 
will occur at Week 52 ± 3 days.  For participants prematurely terminating from study 
treatment (any time after the start of the Placebo Run-in Period), the ET visit must be 
conducted within 7 days of the last dose of study drug; randomized participants will 
subsequently be required to complete Follow-up Period I.  Visit 22/ET must be conducted in 
the clinic.  The following procedures will be performed at Visit 22/ET: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 22 for determination of urine osmolality. 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results. 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Check vital signs. 
• Collect body weight measurement.  
• Collect urine for: 
o urinalysis; 
o local urine pregnancy test (Note: all positive tests will be confirmed by a 
serum pregnancy test at the central laboratory). 
• Perform a brief physical examination. 
• Perform a 12-lead ECG. 
• Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 
o liver chemistry; 


Palladio Biosciences PA-ADPKD-301                                                                                   
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o serum creatinine for eGFR determination; 
o hematology. 
• Administer the following health-outcomes scales to participants (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to register completion of or early termination from the double-blind 
period.  
• Randomized Participants: Schedule the post-baseline MRI for assessment of TKV 
and LV to occur between 25 days and 31 days post last dose of study drug and must 
be completed prior to or on the same day as all other Visit 25 study procedures.  
• Randomized Participants: Schedule the next visit (to occur 8 + 3 days after the last 
dose).  During Follow-up Period I, every attempt will be made to draw blood samples 
for serum creatinine and serum cystatin C at approximately the same clock time as for 
Visits 1a, 2, and 3 or Visits 1b, 2 and 3, for a given participant. Provide the participant 
with an appointment reminder card for the next visit as well as for the post-baseline 
MRI and provide any written instructions that might be required. 
6.5 Follow-up Period I 
The Follow-up Period will consist of 3 visits and will last up to 28 (± 3 days).  
6.5.1 Visit 23 and Visit 24 
Visit 23 will occur no earlier than 8 (+ 3) days after the last dose of double-blind study drug 
and Visit 24 will occur at least 24 hours after Visit 23 and at least 24 hours prior to Visit 25.  
Visits 23 and 24 may be conducted remotely by an HHC/qualified site personnel (with the 
agreement of the participant and the discretion of the investigator and where available and 
locally approved by the CA and/or IRB/EC).  The following procedures will be performed at 
each visit: 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results (at Visit 23). 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Collect a blood sample for:  


Palladio Biosciences PA-ADPKD-301                                                                                   
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o serum creatinine and serum cystatin C for eGFR determination. Note: Every 
attempt will be made to draw blood samples for eGFR determination at 
approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 
24, and 25, and again at Visits 43, 44, and 45, for a given participant. 
• Contact the IRT to register completion of the visit. 
• At Visit 23, schedule the participant for the second follow-up visit (Visit 24) to occur 
at least 24 hours from Visit 23. 
• At Visit 24, provide participant with a urine collection container and written 
instructions to produce a first morning, fasting (≥8 hours, except for water) urine 
specimen to be brought in at the next visit for assessment of urine osmolality. 
• At Visit 24, schedule the participant to return for the final follow-up visit (Visit 25) 
(to occur 28 ± 3 days after the last dose of double-blind study drug, and minimally 24 
hours after Visit 24). (Note: The post-baseline MRI must be completed between 25 
days and 31 days post last dose of study drug and must be completed prior to or on 
the same day as all other Visit 25 study procedures.) 
6.5.2 Visit 25 
Visit 25 is the last visit of Part 1 and initiates Part 2 of the study. It will occur 28 ± 3 days 
after the last dose of double- blind study drug. The following procedures will be performed at 
Visit 25: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 25 for determination of urine osmolality. 
• Confirm the post-baseline MRI for assessment of TKV and LV has been completed. 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Check vital signs. 
• Collect body weight measurement.  
• Collect urine for: 
o urinalysis; 
o local urine pregnancy test (Note: all positive tests will be confirmed by a 
serum pregnancy test at the central laboratory). 
• Perform a brief physical examination. 
• Perform a 12-lead ECG. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 
o liver chemistry; 
o serum creatinine and serum cystatin C for eGFR determinations. Note: Every 
attempt will be made to draw blood samples for eGFR determinations at 
approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 
24, and 25, and again at Visits 43, 44, and 45, for a given participant; 
o hematology. 
• Administer the following health-outcomes scales to participants (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to register completion of the visit and to obtain 1 study drug kit 
number to initiate the Lixivaptan Re-Titration Period (Part 2). Dispense open-label 
study drug.  Instruct the participant to take 4 capsules twice a day daily approximately 
10 hours apart. 
• Remind the participant to increase fluid intake to prevent dehydration 
• Schedule the participant for the next visit (to occur in 1 week ± 2 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
6.6 Lixivaptan Re-titration Period – Part 2 
During the 2-to-4-week Lixivaptan Re-titration Period, all participants in Part 2 will be re-
titrated to the dose level last taken during the Double-blind, Randomized Treatment Period in 
Part 1 (i.e., the last actual dose level if they had received lixivaptan during the Double-blind, 
Randomized Treatment Period or, if they received placebo during the Double-blind, 
Randomized Treatment Period, the last inferred dose level (the dose level equal to the active 
dose level had the participant been randomized to the active arm)) in accordance with Table 
2.  This will be performed by the IRT and the site, participant, and sponsor maintain a 
blinded status.  For example, if no adjustment is made to the inferred dose during the Double-
Blind, Randomized Treatment Period, the last inferred dose for a participant randomized to 
placebo will be equal to the maximal tolerated lixivaptan dose established during the 
Titration Period in Part 1.   
All participants will initiate re-titration at a lixivaptan dose of 50 mg BID (at Visit 25).  Visits 
26 to 29 will occur weekly ± 2 days as needed to achieve the last dose level. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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6.6.1 Visits 26 to 28 
Re-titration visits (26 to 28) may be performed remotely by an HHC/qualified site personnel 
(with the agreement of the participant and the discretion of the investigator and where 
available and locally approved by the CA and/or IRB/EC) or in the clinic. Remote visits may 
include a telehealth visit (e.g., telemedicine virtual visit, telephone or video call (without 
recording)) with the investigator as needed. Participants who complete re-titration in 2 weeks 
will skip Visit 27 and Visit 28 and those completing the re-titration period in 3 weeks will 
skip Visit 28; instead, the assessments scheduled for Visit 29/Last Titration Visit will be 
completed.  The following procedures will be performed at each visit unless otherwise noted: 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results (from Visit 27 if Visit 28 is conducted) 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Check vital signs. 
• Administer the following health-outcomes scale to participant (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
▪ ADPKD-UIS 
• At Visit 27, collect a blood specimen for liver chemistry. 
• Contact the IRT to obtain 1 study drug kit number. Dispense study drug.  Instruct the 
participant to take 4 capsules twice a day daily approximately 10 hours apart. 
• At Visit 28 (or earlier if the participant will be completing titration in 2 or 3 weeks), 
provide participant with a urine collection container and written instructions to 
produce a first morning, fasting (≥8 hours, except for water) urine specimen to be 
brought in at Visit 29 for assessment of urine osmolality. 
• Remind the participant to increase fluid intake to prevent dehydration 
• Schedule the participant for the next visit (to occur in 1 week ± 2 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
6.6.2 Visit 29/Last Re-titration Visit 
The following procedures will be performed at Visit 29: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 29 for determination of urine osmolality. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results (from Visit 27 if Visit 28 is not conducted) 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Check vital signs. 
• Collect body weight measurement.  
• Collect urine for urinalysis. 
• Perform a 12-lead ECG. 
• Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 
o liver chemistry; 
o serum creatinine for eGFR determination; 
o hematology; 
o sparse PK sampling (1 to 6 hrs post-dose). 
• Administer the following health-outcomes scales to participants (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to obtain 4 study drug kit numbers (4-week supply). Dispense open-
label study drug.  Instruct the participant to take 4 capsules twice a day daily 
approximately 10 hours apart. 
• Remind the participant to increase fluid intake to prevent dehydration 
• Schedule the participant for the next visit (to occur in 4 weeks ± 5 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
6.7 Maintenance Treatment Period 
The Maintenance Treatment Period will last 52 weeks, and visits will occur every 4 weeks ± 
5 days (Visit 30 to Visit 42).  


Palladio Biosciences PA-ADPKD-301                                                                                   
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Sites will contact participants by telephone 2 weeks (± 5 days) after every scheduled visit 
during the Maintenance Treatment Period to ascertain continued tolerability and adherence to 
study drug treatment.  Telephone contacts will be recorded in the source document. 
 
6.7.1 Visits 30 to 41 
Visits 30 to 41 will occur every 4 weeks ± 5 days.  Visits 30, 31, 33, 34, 36, 37, 39, 40 and 41 
may be conducted remotely by an HHC/qualified site personnel (with the agreement of the 
participant and the discretion of the investigator and where available and locally approved by 
the CA and/or IRB/EC). Remote visits may include a telehealth visit (e.g., telemedicine 
virtual visit, telephone or video call (without recording)) with the investigator as needed. 
Visits 32, 35, and 38 must be conducted in the clinic. The following procedures will be 
performed at each visit unless otherwise noted: 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results. 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Check vital signs. 
• Perform a urine pregnancy test for WOCBP (Visit 32, Visit 35, and Visit 38 only). 
• Perform a brief physical examination (Visit 35 only). 
• Perform a 12-lead ECG (Visit 35 only). 
• Collect blood samples for the following laboratory testing:  
o Chemistry (Visit 32, Visit 35, and Visit 38 only); 
o serum sodium (all visits); assessed as part of chemistry at Visits 32, 35 and 38 
and as part of liver chemistry at other visits; 
o liver chemistry; 
o serum creatinine for eGFR determination; 
o hematology (Visit 35 only); 
o sparse PK sampling (Visit 32 (pre-dose), Visit 35 (6 to 10 hrs post-dose), and 
Visit 38 (any time post-dose) only and in accordance with sparse PK sampling 
schedule in the Schedule of Procedures – Part 2). 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Administer the following health-outcomes scales to participants at Visit 32, Visit 35 
and Visit 38 only. (Note: responses should be reviewed prior to completion of the 
visit in order to clarify any ambiguous or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to obtain 4 study drug kit numbers (4-week supply). Dispense open-
label study drug.  Instruct the participant to take 4 capsules twice a day daily 
approximately 10 hours apart. 
• At Visit 34 and Visit 41, provide participant with a urine collection container and 
written instructions to produce a first morning, fasting (≥8 hours, except for water) 
urine specimen to be brought in at the next scheduled visit, Visit 35 and Visit 42, 
respectively, for assessment of urine osmolality. 
• At Visit 35, process urine specimen collected by participant as a fasting AM urine 
specimen the morning of Visit 35 for determination of urine osmolality. 
• Remind the participant to increase fluid intake to prevent dehydration. 
• Schedule the participant for the next visit (to occur in 4 weeks ± 5 days).  Provide the 
participant with an appointment reminder card and any written instructions. 
6.7.2 Visit 42/Early Termination (Part 2) 
Visit 42 is the end of the Maintenance Treatment Period and will also serve as the Early 
Termination visit for Part 2 of the study. For participants completing the Maintenance 
Treatment Period, the visit will occur at Week 104 ± 3 days.  For participants prematurely 
terminating from open-label study treatment, the ET visit must be conducted within 7 days of 
the last dose of study drug and will be followed by completion of Follow-up Period II. Visit 
42/ET must be conducted in the clinic.  The following procedures will be performed at Visit 
42/ET: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 42 for determination of urine osmolality. 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results. 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Perform study drug reconciliation and review study drug compliance. 
• Check vital signs. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Collect body weight measurement.  
• Collect urine for: 
o urinalysis; 
o local urine pregnancy test (Note: all positive tests will be confirmed by a 
serum pregnancy test at the central laboratory). 
• Perform a brief physical examination. 
• Perform a 12-lead ECG. 
• Collect blood samples for the following laboratory testing:  
o Chemistry, including serum sodium; 
o liver chemistry; 
o serum creatinine for eGFR determination; 
o hematology. 
• Administer the following health-outcomes scales to participants (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to register completion of the Maintenance Treatment Period.  
• Schedule participant for the post-baseline MRI for assessment of TKV and LV to 
occur between 25 days and 31 days after the last dose of study drug; the MRI must be 
completed prior to or on the same day as all other Visit 45 study procedures.  
• Schedule the participant for the next visit (to occur 8 + 3 days after the last dose).  
During Follow-up Period II, every attempt will be made to draw blood samples for 
serum creatinine at approximately the same clock time as for Visits 23, 24, and 25, for 
a given participant.  Provide the participant with an appointment reminder card for the 
next visit as well as for the post-baseline MRI and provide any written instructions 
that might be required. 
6.8 Follow-up Period II 
The Follow-up Period will consist of 3 visits and will last up to 28 (± 3 days).  
6.8.1 Visit 43 and Visit 44 
Visit 43 will occur no earlier than 8 (+ 3) days after the last dose of double-blind study drug 
and Visit 44 will occur at least 24 hours after Visit 43 and at least 24 hours prior to Visit 45.  
Visits 43 and 44 may be conducted remotely by an HHC/qualified site personnel (with the 
agreement of the participant and the discretion of the investigator and where available and 
locally approved by the CA and/or IRB/EC).  Remote visits may include a telehealth visit 


Palladio Biosciences PA-ADPKD-301                                                                                   
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(e.g., telemedicine virtual visit, telephone or video call (without recording)) with the 
investigator as needed. The following procedures will be performed at each visit: 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 
• Review and assess laboratory test results (Visit 43). 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Collect a blood sample for:  
o serum creatinine and serum cystatin C for eGFR determination. Note: Every 
attempt will be made to draw blood samples for eGFR determination at 
approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 
24, and 25, and again at Visits 43, 44, and 45, for a given participant. 
• Contact the IRT to register completion of the visit. 
• At Visit 43, schedule the participant to return for the second follow-up visit (Visit 44) 
(to occur at least 24 hours from Visit 43). 
• At Visit 44, provide participant with a urine collection container and written 
instructions to produce a first morning, fasting (≥8 hours, except for water) urine 
specimen to be brought in at Visit 45 for assessment of urine osmolality. 
• At Visit 44, schedule the participant to return for the final follow-up visit (Visit 45) 
(to occur 25 to 31 days after the last dose of study drug and minimally 24 hours after 
Visit 44). Provide the participant with an appointment reminder card for the next visit 
and provide any written instructions that might be required.  Note: the post-baseline 
MRI must be completed between 25 days and 31 days post last dose of study drug 
and must be completed prior to or on the same day as all other Visit 45 study 
procedures. 
6.8.2 Visit 45 
Visit 45 is the last visit in this study and will occur 28 ± 3 days after the last dose of open-
label study drug. The following procedures will be performed at Visit 45: 
• Process urine specimen collected by participant as a fasting AM urine specimen the 
morning of Visit 45 for determination of urine osmolality. 
• Confirm the post-baseline MRI for assessment of TKV and LV has been completed. 
• Review and assess AEs and SAEs. 
• Collect and review new concomitant medication information. 
• Collect and review any acetaminophen use information. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• Review and assess laboratory test results (after the visit). 
• Collect medical resource utilization data since the last visit (i.e., medication use or 
changes; unplanned office visits; urgent care or emergency department usage and 
hospitalizations) based on any AEs/SAEs reported. 
• Check vital signs. 
• Collect body weight measurement.  
• Collect urine for: 
o urinalysis; 
o local urine pregnancy test (Note: all positive tests will be confirmed by a 
serum pregnancy test at the central laboratory). 
• Perform a brief physical examination. 
• Perform a 12-lead ECG. 
• Collect blood samples for the following laboratory testing:  
o chemistry, including serum sodium; 
o liver chemistry; 
o serum creatinine and serum cystatin C for eGFR determinations. Note: Every 
attempt will be made to draw blood samples for eGFR determinations at 
approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 23, 
24, and 25, and again at Visits 43, 44, and 45, for a given participant; 
o hematology. 
• Administer the following health-outcomes scales to participants (Note: responses 
should be reviewed prior to completion of the visit in order to clarify any ambiguous 
or missing responses): 
o ADPKD-IS 
o ADPKD-PDS 
o ADPKD-UIS 
• Contact the IRT to register completion of the study. 
6.9 Early Termination Procedures 
Participants who terminate from the study during Screening will not have follow up 
assessments. 
Participants who terminate from the study during Part 1 at any time after the start of the 
Placebo Run-in Period will undergo Visit 22/ET procedures within 7 days of the last dose of 
study drug.  Randomized participants will additionally complete Follow-up Period I for final 
assessments of safety and efficacy.  Participants who terminate from the study at any time 
during Part 2 will undergo Visit 42/ET procedures within 7 days of the last dose of study 


Palladio Biosciences PA-ADPKD-301                                                                                   
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drug and additionally complete Follow-up Period II for final assessments of safety and 
efficacy.  
Note: the intent of this study is that all randomized participants complete all visits and 
procedures regardless of whether study drug is continued or not.  Detailed information about 
accommodating participants who may not be able or want to continue in the study is 
available as follows: 
• Treatment Discontinuation – Section 4.2.4 
• Methods to Prevent Loss to Follow Up – Section 4.2.7 
• Withdrawal of Consent – Section 4.2.8 
• Minimization of Missing Data: Study and Study Treatment Modification – Appendix 
5 (Section 13.5) 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7 DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study procedures, all potential participants will sign an ICF.  
Participants will have the opportunity to have any questions answered before signing the ICF.  
The Investigator must address all questions raised by the participant. 
The study assessments to be performed at each visit and timepoint are specified in the study 
Schedule of Procedures – Part 1 and Schedule of Procedures – Part 2. 
7.1 Efficacy Assessments 
7.1.1 eGFR Determination 
The eGFR values for the primary analysis will be calculated according to the 2021 CKD-EPI 
formula (CKD-EPIcr_R) (Appendix 1 (Section 13.1)) from the serum creatinine 
concentrations taken during the Screening Period and at the visits specified in the Schedule 
of Procedures – Part 1 and Schedule of Procedures – Part 2 of the study.    During the 
Screening Period, serum creatinine assessments obtained at Visits 1a, 2, and 3 or Visits 1b, 2, 
and 3 (if Visit 1b is required) will be used to determine the mean eGFR for analysis purposes. 
The averaged value will be used as the eGFR baseline.  For Part 2, the serum creatinine 
assessments obtained during Follow-up Period I (Visit 23, Visit 24, and Visit 25) will be used 
as the eGFR baseline.  Every attempt will be made to draw blood samples for eGFR 
determination at approximately the same clock time during Visits 1a/1b, 2, and 3 and Visits 
23, 24, and 25, and again at Visits 43, 44, and 45 for a given participant.  
As an exploratory endpoint, eGFR will also be assessed by the measurement of serum 
creatinine and serum cystatin C using a novel CKD-EPI equation (CKD-EPIcr-cys_R) 
(Appendix 1 (Section 13.1)).  Along with serum creatinine concentrations, serum cystatin C 
will be obtained at Visits 1a, 2 and 3 or Visits 1b, 2 and 3 and during Follow-up Period 1 
(Visits 23, 24, and 25) and during Follow-up Period II (Visits 43, 44 and 45). The mean of 
the 3 eGFR measurements calculated from the CKD-EPIcr-cys equation during each period 
will be used for the baseline and follow-up period for analyses of the exploratory eGFR 
endpoint.  To reduce potential decision errors, eGFR calculated from the CKD-EPIcr-cys_R 
equation will not be shared with sites as all eligibility and treatment decisions will be based 
on eGFR calculated from the CKD-EPIcr_R equation. 
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 5.6. 
7.1.2 MRI Assessment 
MRI scans will be obtained for 2 purposes:   
 
1) to qualify each participant’s participation during Screening based on the Mayo Clinic 
ADPKD Image Classification (prognostic criteria) (Irazabal et al, 2015);  
2) to investigate lixivaptan’s pharmacodynamic effect on TKV and LV. 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Participants will undergo a standardized abdominal MRI assessment without use of 
intravenous contrast agent for the determination of TKV (combined kidney volume of both 
kidneys) and LV at 3 timepoints: Screening; Follow-up Period I (Visit 25); and Follow-up 
Period II (Visit 45).  
 
The MRI acquisition protocol will be detailed in the study imaging manual.  MRI images will 
be sent to a blinded central imaging vendor for a) quality control; b) determination of Mayo 
Clinic ADPKD Image Classification (Class 1 [typical] or Class 2 [atypical] at Screening 
only); and c) measurement of TKV and LV. 
   
Participants with ferro-magnetic prostheses, aneurysm clips, severe claustrophobia, or other 
contraindications or exclusions interfering with MRI measurements will not be enrolled in 
the study.  Investigator should seek MRI safety guidance from the local MRI facility.  
To maintain study blinding, volumetric calculations and other derived data from MRI 
imaging obtained after randomization (Visit 9) will not be shared with the participant, the 
investigator, the clinical sites, the sponsor, or the CRO. 
7.1.3 Urine Osmolality 
Fasting (≥ 8 hrs, except for water) spot first AM urine collections will be obtained at the 
timepoints specified in the Schedule of Procedures – Part 1 and Schedule of Procedures – 
Part 2 of the study.  Participants will be provided a urine collection container in advance of 
each visit where Uosm is determined. They will be asked to completely empty their bladders 
upon arising in the morning and then provide a spot urine specimen within the next 30-45 
minutes, prior to taking the morning dose of study drug. They will bring that specimen to 
their clinic visit.  All Uosm assessments in the study will conducted using this method. 
All samples will be sent to the central laboratory for analysis. To maintain study blinding, 
results of Uosm assessments obtained after randomization (Visit 9) will not be shared with the 
participant, the investigator, the clinical sites, the sponsor, or the CRO. 
7.2 Health Outcomes Assessments 
7.2.1 Medical Resource Utilization 
Medical resource utilization will be evaluated throughout Part 1 and Part 2 of the study. 
Beginning at Visit 3, participants reporting clinical events as either AEs or SAEs should be 
questioned on whether any of the clinical events resulted in medication use or medication 
changes (e.g., change in dose; change in medication); an unplanned office visit, an urgent 
care visit and/or an emergency department visit or in-patient hospitalization in order to 
diagnose, treat or manage the clinical event).  Data collected will be entered in the 
appropriate eCRF. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.2.2 ADPKD- Impact Scale 
The ADPKD-IS (Oberdhan et al, 2017), a participant self-administered questionnaire 
consisting of 14 items, measures the impact of ADPKD on a patient’s health-related quality 
of life (HRQoL) using 3 conceptual domains: physical, emotional, and fatigue plus 4 
additional questions.  Each item is measured on a scale of 1 (not difficult/bothered at all) to 5 
(extremely difficult/bothered) with a recall period of 14 days.  Each domain is scored by 
summing the scores of all items in the domain and dividing the total number by the number 
of items in that domain.  Each domain score is measured on a scale of 1–5, from 1, not 
difficult/bothered at all, to 5, extremely difficult/bothered, with a recall period of 14 days. 
The ADPKD-IS will be administered throughout Part 1 and Part 2 of the study at the time-
points specified in the Schedule of Procedures – Part 1 and Schedule of Procedures – Part 2.  
In this study, participants will directly record their responses into an electronic data capture 
device (i.e., tablet).  During remote visits, participants will record their responses on a paper 
copy, which will later be transcribed into the database by site personnel. 
7.2.3 ADPKD- Pain and Discomfort Scale 
ADPKD-PDS (Oberdhan et al, 2015), a participant self-administered questionnaire 
consisting of 20 items, measures the impact of three distinct types of ADPKD-related pain: 
dull kidney pain, sharp kidney pain, and fullness/discomfort. Each item is measured on a 5-
point scale from 1 (no pain/discomfort) to 5 (extreme pain/discomfort). The questionnaire has 
a recall period of 7 days. The ADPKD-PDS will be administered throughout Part 1 and Part 2 
of the study at the time-points specified in the Schedule of Procedures – Part 1 and Schedule 
of Procedures – Part 2.  In this study, participants will directly record their responses into an 
electronic data capture device (i.e., tablet).  During remote visits, participants will record 
their responses on a paper copy, which will later be transcribed into the database by site 
personnel. 
7.2.4 ADPKD- Urinary Impact Scale 
The ADPKD-UIS (Oberdhan et al, 2013), a participant self-administered questionnaire, 
measures the burden of urinary concerns in ADPKD using 11 items that assess 3 domains: 
daytime urinary frequency, daytime urinary urgency, and nocturia. Each item is measured on 
a scale from 1 (not difficult/bothered) to 5 (very difficult/bothered). ADPKD-UIS measures 
each domain by summing the scores for all items in the domain and dividing it by the number 
of items in that domain.  The questionnaire has a recall period of 7 days. The ADPKD-UIS 
will be administered throughout Part 1 and Part 2 of the study at the time-points specified in 
the Schedule of Procedures – Part 1 and Schedule of Procedures – Part 2.  In this study, 
participants will directly record their responses into an electronic data capture device (i.e., 
tablet).  During remote visits, participants will record their responses on a paper copy, which 
will later be transcribed into the database by site personnel. 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3 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 throughout the study as described in the Schedule of 
Procedures – Part 1 and Schedule of Procedures – Part 2.  Assessment windows are presented 
in Table 3 and Table 4. 
7.3.1 Body Height, Weight, and BMI 
Body height (inches or centimeters) and weight (pounds or kilograms) will be measured at 
Screening Visit 1a to the nearest tenth, and BMI will be calculated automatically by the 
eCRF functionality (BMI [kg/m2] = body weight [kg] / height2 [m2]). Body weight will be 
subsequently measured as described in the Schedule of Procedures – Part 1 and Schedule of 
Procedures – Part 2. 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. 
7.3.2 Physical Examinations and Medical History 
A complete physical examination will be performed during Screening Visit 1a.  Brief 
physical examinations will subsequently be performed at the timepoints specified in the study 
Schedule of Procedures – Part 1 and Schedule of Procedures – Part 2.  
A complete physical examination 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 Screening Visit 1a will become part of medical 
history.  New physical examination findings observed after initiation of study drug will be 
classified as being in 1 of 3 categories: normal, abnormal but not clinically significant (NCS), 
or abnormal and clinically significant (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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Medical history, smoking and alcohol history, and demographic data will be recorded at Visit 
1a as specified in the Schedule of Procedures – Part 1. 
7.3.3 Vital Sign Measurements 
Vital sign measurements will include systolic blood pressure, diastolic blood pressure, and 
pulse rate and will be performed at the timepoints specified in the Schedule of Procedures – 
Part 1 and Schedule of Procedures – Part 2.  Respiratory rate and body temperature will be 
measured once at Screening Visit 1a. 
Participants will remain at rest in a seated position for a minimum of 5 minutes before vital 
sign 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 
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 should be recorded as medical history at Screening Visit 
1a and as an AE thereafter.  If other procedures are scheduled at the same timepoint, vital 
signs should be obtained first, before an ECG and/or blood draw. 
7.3.4 12-Lead ECGs 
Standard 12-lead ECGs will be performed at the timepoints specified in the study Schedule 
of Procedures – Part 1 and Schedule of Procedures – Part 2.     
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 timepoint, the ECG should be 
obtained after vital sign measurements and/or before the scheduled blood draw.   
ECGs will be transmitted electronically to the central ECG laboratory for analysis according 
to the instructions provided by the laboratory to be read by a cardiologist.  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 should be reported as medical history at 
Screening Visit 1a and as AEs thereafter. 
 
Additional ECGs may be performed if deemed medically appropriate. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.5 Clinical Laboratory Tests 
Blood and urine specimens will be collected for clinical laboratory determinations 
(hematology, clinical chemistry including serum sodium, liver chemistry and serum 
creatinine and serum cystatin C, serology, and urinalysis) by the central laboratory and local 
urine pregnancy tests (WOCBP only) at the timepoints specified in the study Schedule of 
Procedures – Part 1 and Schedule of Procedures – Part 2.  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.  All CS findings should be reported as 
medical history at Screening Visit 1a and as AEs thereafter. Repeat testing for abnormal liver 
chemistry tests is described in Section 7.3.7.1.  Any other repeat laboratory testing for values 
that are not CS should first be discussed with the medical monitor before such tests are 
ordered. All positive urine pregnancy testing results will be confirmed by a serum pregnancy 
test at the central laboratory.   
With the exception of participants’ at-home collection of urine specimen for measurement of 
urine osmolality by the central laboratory, laboratory tests required by the protocol do not 
require overnight fasting.  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 8. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Table 8. Clinical Laboratory Parameters 
Chemistry 
Hematology 
Urinalysis 
Albumin 
Hematocrit 
pH 
Blood urea nitrogen (urea) 
Hemoglobin 
Specific gravity 
Calcium 
Red blood cell count 
Protein 
Chloride 
Quantitative platelet count 
Glucose 
Carbon dioxide (CO2) 
Glucose 
White blood cell (WBC) count 
with differential (total and %) 
Ketones 
Phosphorous 
only if WBC count is abnormal: 
Bilirubin 
Potassium 
    Neutrophils 
Blood 
Protein 
    Lymphocytes 
Urobilinogen 
Sodium* 
Uric Acid 
 
Serum Creatinine 
Creatinine, enzymatic 
 
    Monocytes 
    Eosinophils 
    Basophils 
Leukocytes 
Nitrite 
Microscopic examination 
(if positive for blood, 
protein, nitrite, or 
leukocytes) 
Serum cystatin C 
 
 
 
Serology (Screening) 
Hepatitis B surface antigen 
Hepatitis C antibody (reflex 
HCV RNA for all Hepatitis C 
antibody positive or reactive 
results) 
 
 
Liver Chemistry 
Alkaline phosphatase 
ALT 
AST 
Bilirubin (Total and Direct) 
Other Tests 
Urine osmolality 
Urine or serum pregnancy 
test 
*Serum sodium will be assessed at all time-points specified in the Schedule of Procedures 
either as part of chemistry or liver chemistry testing.  
 
7.3.5.1 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. Participant age and year of 
birth will be collected at the time of sample collection and reported on the requisition form.  


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.6 Assessment of Tolerability During Placebo Run-in and Lixivaptan 
Titration Period 
In the pre-randomization phase of the study, tolerability will be assessed at the end of the 
Placebo Run-in Period (Visit 3), to maintain participant blinding and at each visit during the 
Lixivaptan Titration Period (Visits 4 to 9).  A single tolerability question will be asked: 
“Would you take the study drug for the next 24 months?”   If the participant confirms the 
dose can be tolerated, the participant will be titrated to the next dose level (i.e., the dose will 
be increased).  This assessment of tolerability will continue at weekly intervals until either 
the maximum dose level is reached (Level 4 [200 mg BID]) or until the participant confirms 
the dose cannot be tolerated for a 24-month period.  In that case, the dose will be reduced by 
one dose level as described in the Lixivaptan Titration Period (Part 1) — Lixivaptan Titration 
Flowchart. 
7.3.7 Assessment of Liver Symptoms, Signs, or Test Abnormalities 
Testing for hepatic aminotransferases (ALT/AST), alkaline phosphatase, and total bilirubin 
will be performed at the timepoints as specified in the Schedule of Procedures – Part 1 and 
Schedule of Procedures – Part 2. Management of hepatic and liver chemistry test 
abnormalities are discussed below.  The appearance of any suspicious symptoms or signs of 
liver dysfunction as described in Appendix 2 (Section 13.2) in a participant at any time 
during the study should trigger prompt testing of liver chemistry tests (i.e., within 48 hours). 
7.3.7.1 Management of Liver Chemistry Test Abnormalities and Signs or 
Symptoms of Liver Dysfunction Occurring During Study 
Treatment 
Elevations of liver aminotransferase levels >3 x ULN or total bilirubin levels >2 x ULN 
should prompt immediate retesting within 48 hours.  Although central laboratory testing is 
preferred, local laboratory testing is acceptable, ideally with a concurrent central laboratory 
sample for confirmation.  After the Investigator consults with the medical monitor and 
sponsor, temporary reduction in dose or interruption of study drug administration must be 
instituted if liver aminotransferase levels >3 x ULN or total bilirubin levels >2 x ULN are 
observed during the Lixivaptan Titration or Double-Blind Randomized Treatment Periods of 
Part 1 or the Lixivaptan Re-Titration or Maintenance Treatment Periods of Part 2. 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.  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. 
Similarly, the appearance of any suspicious symptom or sign of liver dysfunction (see 
Appendix 2 (Section 13.2)) at any time during the study should trigger prompt testing of liver 
chemistry (i.e., within 48 hours) and consultation with the medical monitor and sponsor to 
discuss any changes to dosing with study drug. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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All elevations meeting these thresholds or confirmed symptoms or signs of liver dysfunction 
will be assessed for causality by an independent, blinded Hepatic Events Review Committee 
(HERC) (see Section 7.3.7.2). 
In the case of study drug interruption, re-starting study drug should be encouraged (see 
except under these circumstances 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. 
Treatment with study drug cannot be resumed in participants when: 
• aminotransferase levels >8 × ULN at any time, 
• aminotransferase levels >5 × ULN for more than 2 weeks, or 
• concurrent elevations of aminotransferase levels >3 × ULN and total bilirubin >2 × 
ULN 
except under these circumstances: 
Participants with these levels of abnormality may be re-challenged with study drug if 
abnormalities were adjudicated by the HERC as having a ≤50% likelihood of being 
related to study drug (per DILI Network [DILIN] probability criteria, modified, 
Appendix 4 (Section 13.4) (Fontana et al, 2009) 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 agree to study drug re-challenge. 
Liver chemistry test increases of a lesser extent (serum aminotransferase levels ≤3 × ULN or 
total bilirubin ≤2 × ULN) will be discussed with the medical monitor.  They may be related 
to the underlying variability of such test results in ADPKD patients (Watkins et al, 2015).  
Generally, dosing should continue during such lesser liver chemistry test increases; however, 
the frequency of laboratory testing should increase, particularly during the Double-Blind 
Randomized Treatment Period in Part 1 and the Maintenance Treatment Period in Part 2.  
Slowing of titration may also be considered if the abnormalities occur during the Lixivaptan 
Titration Period in Part 1 or Lixivaptan Re-Titration Period in Part 2. 
For participants exhibiting an increase during the Lixivaptan Titration or Lixivaptan Re-
titration Periods, follow the instructions in Section 7.3.7.1.2 (Liver Test Abnormalities during 
the Placebo Run-in and/or Lixivaptan Titration Period). 
7.3.7.1.1 Repeat Liver Testing in Participants with Abnormal Values at 
Screening 
Participants with aminotransferase or total bilirubin values above the values in the exclusion 
criteria (>1.2 × ULN) during Screening will not proceed further in the trial.  However, if 
evaluation indicates a reversible cause of abnormal values, such participants may be re-
screened when their liver chemistry tests return to values allowing entry into the trial. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.7.1.2 Liver Test Abnormalities during the Placebo Run-in and/or 
Lixivaptan Titration Period 
Serum aminotransferase or total bilirubin levels that are ≥1.2 × ULN to 2 × ULN during the 
Placebo Run-in and/or Lixivaptan Titration Period will require holding the dose constant and 
a discussion with the medical monitor.  Levels exceeding 2 × ULN during the Placebo Run-
in and/or Lixivaptan Titration Period will require reducing the dose or discontinuation of 
study drug (randomization will not occur) depending on the extent of the elevation and in 
consultation with the medical monitor.  Weekly monitoring of liver chemistry tests will be 
conducted until the values are below the ULN. In consultation with the medical monitor and 
sponsor, continuation of titration can resume if study drug was continued.  If study drug had 
been stopped, titration can be re-initiated at Level 1 (50 mg BID) with weekly monitoring of 
liver chemistry tests if the participant agrees to the increased monitoring, is informed of the 
potential risks, and agrees to re-initiating study drug. 
7.3.7.2 Hepatic Events Review Committee (HERC) – Special Reporting of 
Liver Events 
In order to adequately characterize the liver safety profile of lixivaptan, additional testing and 
data collection will be required for any participant who develops clinically significant liver 
chemistry test abnormalities and/or signs or symptoms of liver dysfunction during the study. 
This additional data will be reported on a liver dysfunction details eCRF.  The type of 
information needed to complete it is provided in Appendix 2 (Section 13.2).  The purpose of 
the liver dysfunction details eCRF and additional testing is to facilitate review and 
adjudication of each event of clinically significant 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 and adjudication will be performed by an independent, 
blinded HERC, a committee of 3 to 4 experts experienced in liver disease.  The HERC will 
use the modified DILIN probability criteria (0 to 5% = unrelated; 6 to 25% = unlikely, 25% 
to 50% = possibly, 51% to 75% = probably, 76% to 95% = very likely, >95% = definite; see 
Appendix 4: DILI Network Causality Criteria, modified) to assign attribution to each case of 
potential liver dysfunction. The HERC will independently decide attribution and will 
communicate in writing with the sponsor and the IDMC.  The IDMC reviews data at a study-
level and, as such, its recommendations will not be made known to the HERC so as not to 
bias the HERC when adjudicating participant cases.  These two committees are independent 
and will have a one-way line of communication from HERC to IDMC.  The results of the 
HERC review and adjudication will be incorporated into the reporting of the safety results of 
the trial.  The result of these analyses may be presented separately from the final clinical 
study report (CSR). 
The Investigator must complete and submit a copy of the liver dysfunction details eCRF with 
the SAE/AESI form within 24 hours of awareness through the SAE reporting pathway 
(described in Section 7.3.8.3) for any 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 ALT or AST levels >3 × ULN, 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• develops total bilirubin levels >2 × ULN,  
• develops any signs or symptoms of hepatic dysfunction (see Appendix 2 (Section 
13.2)), 
• discontinues treatment due to a liver-related AE, 
• reports a serious liver-related AE.  
The SAE/AESI report form should be updated as new information becomes available. 
7.3.8 Adverse Events 
7.3.8.1 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 study drug or their clinical significance, as outlined 
in Section 7.3.8.3 below. 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to study drug. 
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
study drug or any event already present that worsens in either intensity or frequency after 
exposure to study drug. 
An SAE is defined as any event that: 
• results in death,  
• is immediately life threatening,  
• requires in-participant 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. 
7.3.8.2 Eliciting and Documenting Adverse Events and Serious Adverse 
Events 
All AEs will be recorded from the time the participant signs the ICF until study completion. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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At every study visit, participants will be asked a standard nonleading 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, used 
acetaminophen/paracetamol, or changed concomitant medication regimens (both prescription 
and over-the-counter medications).  Tolerability issues including but not limited to aquaretic 
effects, difficulty swallowing capsules, and abnormal thirst, will be recorded as adverse 
events. 
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. 
7.3.8.3 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 drug treatment, dose, event term, date of onset, 
Investigator-specified assessment of severity and relationship to study drug, 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, 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.   
Any AE that meets SAE or AESI criteria will be reported to Premier Research Global 
Pharmacovigilance (Premier PV) immediately (i.e., within 24 hours) after site personnel first 
learn about the event.  Investigators should record all SAE details available, including 
Investigator causality assessment, on the SAE/AESI form and subsequently record the event 
on the Adverse Event eCRF within 24 hours of becoming aware of the event.  Investigators 
should record all AESI details available, including Investigator causality assessment, on the 
SAE/AESI form and subsequently record the event on the Adverse Event eCRF within 24 
hours of becoming aware of the event. 
Completed SAE/AESI Report Forms should be submitted to Premier PV as an email 
attachment to the email address below.  
 
 


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Premier PV 
Investigative sites in North America PVDS-NA@premier-research.com 
Investigative sites in Rest of World 
PVDS-ROW@premier-research.com 
Should the site have questions or concerns regarding SAE/AESI report submission, the site 
may elect to call the site Clinical Research Associate (CRA) or contact the medical monitor. 
The site will be asked to provide the following information: protocol number, site number, 
participant identifiers, event term, study drug information, and relationship of the event to 
study drug. 
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 (24/7) via a Premier Research 
Call-Center:  
Investigative Sites in North America: +1 510 722 8910 
Investigative Sites in South America: +54 911 5479 8678 
Investigative Sites in Europe and Middle East Region: +44 118 936 4096 
Investigative Sites in Australia, New Zealand: +61 3921 39875 
For the purpose of this study, Adverse Events of Special Interest are liver events as described 
in Section 7.3.7.2. 
The sponsor (or Premier Research) will determine whether the SAE must be reported to 
regulatory authorities in compliance with local and regional regulations and law (i.e., within 
7 or 15 days).  If so, the sponsor (or Premier Research) will report the event to the 
appropriate regulatory authorities and investigators.  The investigator will report SAEs to the 
IRB/IEC per their IRB/IEC policy. 
7.3.8.4 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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.8.5 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 study drug itself caused 
or contributed to an AE. 
If the final determination of causality is unknown and the Investigator does not know 
whether the study drug caused the event, then the event will be handled as “possibly related 
to study drug” for reporting purposes.  If the Investigator’s causality is “unknown, but not 
related to study drug”, this should be clearly documented on study records. 
The relationship of an AE to the administration of the study drug will be assessed and 
recorded on the eCRF.  Terms used to describe the degree of causality between a study 
drug/investigational product and an AE are: definitely, probably, possibly, unlikely, or not 
related.  The best 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 9. 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Table 9. Guideline for Assessment of Adverse Event Causality 
Relationship to 
Study Drug 
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 study drug and the AE could exist 
(i.e., the possibility cannot be excluded), but the AE is most likely 
explained by causes other than the study drug (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 study drug 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 study drug (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 study drug are reasonably related in time 
and/or follow a known pattern of response, and the AE is more likely 
explained by study drug than other causes. 
Definitely 
Related 
The AE and administration of study drug are related in time, and a 
direct association can be demonstrated (e.g., disappears or decreases 
with reduction in dose or cessation of drug/investigational product and 
recurs with re-exposure). 
7.3.8.6 Procedure for Breaking the Blind 
The investigator is encouraged to contact the medical monitor or sponsor to discuss their 
rationale for unblinding. However, to prevent delays to the investigator or medical personnel 
responding to a potentially emergent situation, unblinding of study drug will not be 
dependent upon the investigator receiving approval from the medical monitor or sponsor. If 
the blind is broken, the medical monitor will be notified immediately or as soon as 
reasonably possible (but within 24 hours of unblinding) to provide an explanation.  
The treatment assignment for the participant can be determined by designated site personnel 
logging into the IRT system via role-based and password-protected access.  Documentation 
of breaking the blind should be recorded in the participant’s medical record with the date and 
time the blind was broken, and the names of the personnel involved. Once the blind is broken 
for a given participant, that participant may not reinitiate treatment with study drug. 
7.3.8.7 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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.8.8 Overdose Management 
An overdose is any dose of study drug given to a participant or taken by a participant that 
exceeds the dose described in the protocol.  Participants must be instructed to immediately 
report any overdoses to the Investigator.  The Investigator must then promptly report the 
overdose, irrespective of whether it was associated with an AE.  Additionally, ingestion of 
study drug by anyone other than the participant should immediately be 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.  Overdoses associated with an SAE must additionally be reported to Premier PV 
within 24 hours of awareness via the SAE Reporting Form.  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. 
7.3.8.9 AE/SAEs Experienced by Nonparticipants Exposed to Study 
Treatment 
Nonparticipants exposed to study treatment are persons who are not enrolled in the study but 
have been exposed to study treatment, including instances of diversion of study 
treatment.  All such AE/SAEs occurring in nonparticipants from such exposure will be 
reported to Premier PV personnel on the SAE Reporting Form regardless of whether the 
event was serious or not.  Instructions for completing the form for events experienced by 
nonparticipants will be provided.  SAEs occurring in nonparticipants exposed to study 
treatment will be processed with the same SAE reporting timelines as described in Section 
7.3.8.3.  Additionally, the drug accountability source documentation at the site should reflect 
this occurrence.  
7.3.8.10 Pregnancy 
Pregnancy is not regarded as an AE unless there is a medical/surgical complication.  Any 
pregnancy of a participant or the female partner of a male participant that occurs during study 
participation must be reported using a Pregnancy Data Collection Form to Premier PV 
through the SAE reporting pathway.  To ensure participant safety, each pregnancy must be 
reported through this mechanism to Premier PV within 24 hours of learning of its occurrence.  
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 Premier PV. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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7.3.9 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. 
7.3.10 Independent Data Monitoring Committee 
In order to ensure the safety of participants, the sponsor will use an IDMC.  An IDMC 
charter will be written to describe the IDMC objectives, schedule for data reviews, and 
general responsibilities in respect to the study.  The IDMC will meet on a regular basis as 
specified in the Charter. In addition to the pre-determined data review meetings, the IDMC 
may meet on an ad hoc basis in the face of an emerging safety issue.  The Committee will 
have access to unblinded data and will report any findings or make recommendations to the 
sponsor without revealing participant treatment assignment.  Adjudication results as 
determined by the HERC will be reported to the IDMC on an agreed frequency (see Section 
7.3.7.2).  All IDMC recommendations will be documented in writing, and where required, 
submitted to the IRB/Ethics Committees (ECs) and respective regulatory/CAs for their 
review or information.    
7.4 Population Pharmacokinetic Assessments 
Blood samples will be obtained from all participants at designated timepoints as described in 
the Schedule of Procedures – Part 1 and Schedule of Procedures – Part 2.  Sparse sampling 
will be used to support PopPK analysis of lixivaptan using a validated assay. 
7.4.1 Pharmacokinetic Blood Sampling 
Sparse samples will be taken for determination of plasma lixivaptan concentrations.  A single 
plasma sample will be collected at the timepoints specified in the Schedule of Procedures – 
Part 1 and Schedule of Procedures – Part 2, further described below.  Visit scheduling on PK 
sampling days should take into account the PK measurement time requirements relative to 
the last dose of study drug taken.  Note: At Visit 3, dosing should occur in the clinic to allow 
for PK sampling following the first dose of single-blind lixivaptan. Visits 12 and 32 should 
ideally be scheduled in the morning to accommodate pre-dose sampling without a lapse in 
dosing.  At all other visits, the morning dose should not be withheld.  Note: At Visit 9 and 
Visit 38 PK samples can be obtained at any time post-dose.  Participants who have taken 
their morning dose at home should not receive a second dose in the clinic for the purposes of 
PK sampling.     
Part 1: 
• Screening – Visit 2 (any time) 
• After first dose of lixivaptan – Visit 3 (0.5 to 1.5 hours post-dose) 


Palladio Biosciences PA-ADPKD-301                                                                                   
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• After dose titration – Visit 9 (any time post-dose) 
• During the Double-blind, Randomized Treatment Period – Visit 12 (pre-dose); Visit 
15 (1 to 6 hours post-dose); Visit 18 (6 to 10 hours post-dose) 
Part 2: 
• 
After lixivaptan dose re-titration – Visit 29 (1 to 6 hrs post dose)  
• 
During the Maintenance Treatment Period – Visit 32 (pre-dose); Visit 35 (6 to 10 
hours post-dose); Visit 38 (any time post-dose) 
The date and time of collection of the PK sample and the date and time of administration of 
the last preceding dose of study drug must be recorded in the eCRF for all samples.  
All plasma samples will be shipped frozen to the central clinical laboratory for storage, until 
analyzed. Detailed handling and shipping instructions are in the laboratory manual. 
Blood samples for the PopPK analysis of lixivaptan will be collected and handled according 
to the specifications in the laboratory manual.   


Palladio Biosciences PA-ADPKD-301                                                                                   
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8 STATISTICAL PROCEDURES 
The statistical and analytical plan for this clinical trial is summarized below.  Further details 
are provided separately in the Statistical Analysis Plan (SAP). 
8.1 Sample Size 
Part 1: 
Based on the results of the REPRISE trial with tolvaptan, (Torres et al, 2017) it is assumed 
that the standard deviation for the primary efficacy endpoint, change from baseline to post-
treatment follow-up in mean eGFR, is 6.20 mL per minute per 1.73 m2.  Assuming a 
between-treatment group difference of -1.40 mL per minute per 1.73 m2 and a randomization 
ratio of 2:1 for lixivaptan to placebo, a sample size estimate of 1314 participants (438 
placebo-treated participants and 876 lixivaptan-treated participants) is required to achieve 
90% power at a significance level of 0.01.  In order to compensate for possible dropouts, this 
estimate has been adjusted up to 1350 participants (450 placebo participants and 900 
lixivaptan participants).  It is estimated that approximately 2250 participants will need to be 
screened in order to randomize 1350 participants. 
A blinded sample size re-estimation (BSSR) to estimate the variance corresponding to the 
primary efficacy estimand is planned after at least 20% of the total randomized participants 
have completed Part 1 of the study or before screening for the study has ended (Section 8.2). 
Part 2:  
This is a convenience sample based on the number of participants who elect to continue into 
Part 2.  It is estimated that approximately 1350 participants will be randomized in Part 1.  All 
participants except those who discontinue due to an adverse event or withdraw consent will 
continue into Part 2.  Approximately 90% (1215) of Part 1 participants are anticipated to 
continue into Part 2. 
8.2 Blinded Sample Size Re-estimation 
After at least 20% of the randomized participants (i.e., 270 participants) complete Part 1 of 
the study (Visit 25) or before screening for the study has ended, a BSSR will be performed by 
a blinded statistician.  Based on this interim data set of blinded eGFR values, the variance 
corresponding to the primary efficacy estimand will be estimated and the total sample size re-
estimated by a blinded statistician.  If the BSSR estimates that the standard deviation of the 
primary efficacy estimand is less than or equal to 6.20 mL per minute per 1.73 m2, then the 
sample size will remain at 1350 randomized participants.  If the BSSR estimates that the 
standard deviation is greater than 6.20 mL per minute per 1.73 m2, then the total sample size 
will be re-estimated based on this new estimate of the standard deviation by the sponsor or 
designee.  The BSSR will be based on the original, assumed between-treatment group 
difference, i.e., there will be no change to the estimate of the between-treatment group 
difference based on the BSSR. Since a BSSR does not inflate the type 1 error of the primary 
efficacy analysis, the significance level for the final efficacy analysis will remain at 0.01. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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8.3 Populations for Analysis 
Part 1: 
The following populations will be used for analyzing the data from Part 1: 
Treated Safety Set:  The Treated Safety Set consists of all participants who received at least 1 
dose of study drug in Part 1.   
Randomized Safety Set:  The Randomized Safety Set consists of all participants in the 
Treated Safety Set who are randomized and receive at least 1 dose of randomized study drug.   
Primary Efficacy Analysis Set (PEAS):  The PEAS consists of all participants in the 
Randomized Safety Set who have both baseline and at least 1 valid assessment of eGFR in 
the Follow-up Period. 
Secondary Efficacy Analysis Set (SEAS):  The SEAS consists of all participants in the 
Randomized Safety Set who have both baseline and at least 1 on-treatment assessment of 
eGFR. 
Part 2: 
The following populations will be used for analyzing the data from Part 2: 
Long-term Safety Set:  The Long-term Safety Set consists of all participants in the 
Randomized Safety Set of Part 1 who receive at least 1 dose of lixivaptan during Part 2. 
Long-term Full Analysis Set:  The Long-term Full Analysis Set consists of all participants in 
the Long-term Safety Set who have at least 1 on-treatment measurement of eGFR in Part 2. 
Long-term Efficacy Analysis Set:  The Long-term Efficacy Analysis Set consists of all 
participants in the Long-term Full Analysis Set who were randomized to lixivaptan in Part 1.  
8.4 Primary Efficacy Analysis 
8.4.1 Primary Endpoint Analysis 
The primary endpoint analysis is based on the eGFR calculated from the CKD-EPIcr_R 
equation. Baseline eGFR is defined as the mean of the 3 eGFR determinations obtained 
during the Screening and Placebo Run-in Periods.  The primary efficacy analysis will utilize 
the change from this baseline eGFR to the post-treatment follow-up eGFR, annualized by 
each participant’s treatment duration.  The post-treatment follow-up eGFR is defined as the 
mean of 3 eGFR assessments obtained during the Follow-up Period I or the equivalent off-
therapy eGFR determinations if a participant discontinues study drug earlier. 
The estimand corresponding to the primary objective is the between-treatment group 
difference in the change from baseline in eGFR if all the participants in the PEAS had 
tolerated and adhered to their treatment for 52 weeks.  For randomized participants 
prematurely discontinuing from double-blind treatment, the primary analysis will be handled 
by annualizing the changes from baseline by multiplying each participant’s change from 
baseline by 365.25 days divided by the duration (days) from the median of the baseline eGFR 
assessments to the median of the 3 eGFR assessments obtained during the post-treatment, 
follow-up period immediately following study drug discontinuation. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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The primary efficacy endpoint, the annualized change from baseline to post-treatment 
follow-up in mean eGFR, will be analyzed by means of an analysis of covariance model with 
fixed effects for treatment group and the randomization stratification factors (CKD stage 
[CKD2 versus CKD3/4] and Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]) and 
the baseline eGFR as a covariate.  This analysis assumes that data are missing at random.  
The stratification by CKD stage (Section 8.4.1) will be based on the baseline eGFR 
creatinine equation in effect at the time of randomization.  However, all efficacy analyses of 
change in eGFR will be based on the CKD-EPIcr_R equation. 
The primary efficacy analysis will be performed at the 1% level of significance (p<0.01). 
8.4.2 Sensitivity Analysis of the Primary Efficacy Analysis 
In particular, in order to address the impact of missing data on the results from the primary 
efficacy analysis, a number of sensitivity analyses will be performed.  The detailed sensitivity 
analyses for the primary efficacy analysis will be described in the statistical analysis plan 
(SAP). 
 
Amongst these sensitivity analyses, the main sensitivity analysis of the primary efficacy 
analysis will use the mean of eGFR values obtained pretreatment and the mean of eGFR 
values obtained off treatment after the end of the 52-week treatment period, regardless of 
adherence to randomized treatment and/or withdrawal for all randomized participants, i.e., 
Intent-To-Treat participants. Missing values at Week 52 will be imputed using multiple 
imputations (assuming missing at random). Tipping point analyses will be included using a 
pattern-mixture model to impute missing data at Week 52 (assuming missing not at random) 
by systematically varying assumptions about the missing outcomes on the two treatment 
arms – these tipping point analyses will be bi-dimensional, i.e., allow the assumptions about 
the missing outcomes in the two arms to vary independently, and will include scenarios 
where the dropouts on the lixivaptan arm have worst outcome compared to placebo dropouts. 
 
8.5 Secondary Efficacy Analyses. 
If the primary efficacy analysis is statistically significant at the 1% level of significance, then 
the secondary efficacy endpoints of (1) annualized rate of change (slope) in eGFR based on 
all on-treatment eGFR determinations during the Double-blind, Randomized Treatment 
Period calculated from the CKD-EPIcr_R equation for serum creatinine; and (2) annualized 
change in TKV as measured by MRI will be analyzed.  Each will be tested at the 1% level of 
significance in sequential order using a closed testing procedure on the SEAS.  The details of 
the testing procedure will be provided in the SAP for the study. 
8.5.1 Annualized Rate of Change (Slope) in eGFR on Treatment 
In order to assess the linear effect (slope) of lixivaptan based on the on-treatment eGFR data 
in all randomized participants, an analysis utilizing a mixed-effects model for repeated 
measures (MMRM) will be performed on the observed changes in eGFR from baseline 
(mean of the 3 eGFR determinations obtained during the Screening and Placebo Run-in 
Periods) to all Double-Blind Treatment Period visits up to Week 52.  The MMRM will 
include treatment group, visit, treatment group-by-visit, and randomization stratification 


Palladio Biosciences PA-ADPKD-301                                                                                   
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factors as fixed effects baseline as a covariate, and the baseline-by-visit interaction.  An 
unstructured variance-covariance matrix is assumed for the repeated measures.  A linear 
contrast of the treatment slope differences for these 12 monthly visits will be used for this 
analysis. 
8.5.2 Annualized Change in TKV 
The 2nd secondary efficacy endpoint is the change in height-adjusted TKV (normalized as a 
percentage) from baseline for lixivaptan relative to placebo.  In order to handle the variability 
in the time of post-baseline MRI acquisition, time to post-baseline MRI from randomization 
will be treated as a continuous variable, expressed as years from date of randomization to 
date of MRI visit (date of MRI visit – date of randomization + 1, Baseline MRI will have a 
time of 0).  In addition, in order to reduce heterogeneity in variance and achieve linearity 
over time, log10 transformation will be applied to the total kidney volume data.  
 ANCOVA will be used to analyze the log transformed TKV data.  Further details will be 
provided in the statistical analysis plan. 
A significance level of 0.01 (two-sided) will be used to declare statistical significance at the 
final analysis.  In addition, estimate of the contrast and its 99% CI will be obtained.  Anti-log 
of these statistics will provide an estimate of the ratio of the geometric means of annual 
percent changes (expressed as a ratio of the predicted one-year TKV divided by the predicted 
baseline TKV) from baseline for the 2 treatment groups and its 99% CI. 
8.6 Key Comparison Analysis 
8.6.1 Key Comparison Endpoint Analysis 
Baseline eGFR in Part 2 is defined as the mean of the 3 eGFR assessments obtained during 
Follow-up Period I.  
Descriptive statistics will be presented for the annualized changes from this baseline (Follow-
up Period I in Part 1) to the mean of the 3 eGFR measurements during Follow-up Period II in 
Part 2 for participants in the Long-term Efficacy Analysis Set.  The mean annualized change 
from baseline for Part 2 will be compared to corresponding mean annualized change in eGFR 
for Part 1 for the same analysis set. 
In addition, 2 supportive analyses will be performed for Part 2: 
To assess the transition from treatment with placebo in Part 1 to treatment with lixivaptan in 
Part 2, the same quantity will be calculated for participants in the Long-term Full Analysis 
Set who were randomized to placebo in Part 1 to be compared to the corresponding quantity 
in Part 1 for participants randomized to placebo.      
In addition to assess the effect of delaying treatment, the same quantity will be calculated for 
participants in the Long-term Full Analysis Set who were randomized to placebo in Part 1 to 
be compared to the corresponding quantity in Part 1 for participants randomized to 
lixivaptan. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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8.6.2 Sensitivity Analysis of the Key Comparison Analysis 
In order to assess the effect of missing data on the key comparison analysis in Part 2, 
sensitivity analyses for the descriptive statistics will be performed for all available annualized 
changes from baseline (the mean of the 3 eGFR assessments obtained during Follow-up 
Period I in Part 1) to the mean of the 3 off-treatment eGFRs after Week 104. 
8.7 Other Comparison Analyses 
8.7.1 Annualized Rate of Change (Slope) in eGFR on Treatment 
In order to assess the linear effect (slope) of lixivaptan based on the on-treatment eGFR data 
in Part 2, an analysis utilizing a MMRM will be performed on the observed changes from 
baseline (mean of the 3 eGFR assessments obtained during Follow-up Period I) to Weeks 52 
to 104 (Visit 29 to Visit 42) of the Maintenance Treatment Period in eGFR.  The MMRM will 
include visit, and randomization stratification factors as fixed effects, and baseline (Follow-
up Period I in Part 1) as a covariate, and the baseline-by-visit interaction.  An unstructured 
variance-covariance matrix is assumed for the repeated measures.  The estimated annualized 
rate of change (slope) from this analysis will be compared to the corresponding results in Part 
1. 
8.7.2 Annualized Change in TKV 
The height-adjusted TKV measurements at Follow-up Periods I and II will be log10 
transformed.  The mean and 99% CI of the difference of the log10-transformed value at 
Follow-up Period II from the log10-transformed value at Follow-up Period I will be 
calculated for all participants in the Long-term Efficacy Analysis Set.  Anti-log of these 
statistics will provide an estimate of the geometric mean of annual percent changes 
(expressed as a ratio of the predicted one-year TKV divided by the predicted baseline TKV) 
from baseline of the 2 treatment groups and its 99% CI.  This will be compared to the 
corresponding quantity from Part 1 for the same participants.  
8.8 Population Pharmacokinetics Analyses 
Plasma concentrations of lixivaptan will be used for PopPK analysis that will be described in 
a separate report. 
8.9 Health Outcomes Analyses 
8.9.1 Medical Resource Utilization 
A detailed description of the analysis for the medical resource utilization and health 
economics assessments will be specified in a prospective health outcomes analysis plan. 
8.9.2 ADPKD-IS, ADPKD-PDS, and ADPKD-UIS 
Detailed descriptions of analyses of these questionnaires will be specified in the SAP. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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8.10 Exploratory Analyses 
8.10.1 Annualized Change in LV 
The between-treatment group difference in LV for Part 1 and 2 will be examined using 
appropriate statistical methods.  Details for the planned analyses will be provided in the SAP. 
8.10.2 Urinary Osmolality 
Descriptive statistics for the change from baseline in morning spot urine osmolality will be 
presented by treatment group for the Treated Safety Set in Part 1 and overall, for the Long-
term Safety Analysis Set in Part 2 at each scheduled time point.  The number (%) of 
participants who show suppressed urine osmolality in each treatment group, defined by 2 
levels of spot urine osmolality – ≤250 mOsm/kg and ≤300 mOsm/kg – will be summarized 
descriptively at each time point. 
8.10.3 Annualized Change in eGFR Assessed by Serum Creatinine and 
Cystatin-C (CKD-EPIcr-cys_R) 
This analysis is based on the change from the baseline eGFR to the post-treatment follow-up 
eGFR calculated from the CKD-EPIcr-cys_R equation, annualized by each participant’s 
treatment duration. Baseline eGFR is defined as the mean of the 3 eGFR determinations 
obtained during the Screening and Placebo Run-in Periods.  The post-treatment follow-up 
eGFR is defined as the mean of 3 eGFR assessments obtained during the Follow-up Period I 
or the equivalent off-therapy eGFR determinations if a participant discontinues study drug 
earlier. 
This annualized change from baseline to post-treatment follow-up in mean eGFR will be 
analyzed by means of an analysis of covariance model with fixed effects for treatment group 
and the randomization stratification factors and the baseline eGFR as a covariate. 
8.11 Subgroup Analyses 
Descriptive statistics will be presented for the primary and secondary efficacy analyses for 
age (≤50 years, >50 years), sex, race (White, non-White), region (US, non-US), baseline 
eGFR (≤median, >median), CKD stage (CKD2, CKD3/4), Mayo Clinic ADPKD Image 
Classification (1C, 1D, and 1E) and baseline TKV (≤median, >median).  
8.12 Analysis of Demographic and Baseline Characteristics 
Part 1: 
Descriptive statistics for demographic (e.g., sex, age, race, and ethnicity) and baseline (e.g., 
eGFR, TKV, and LV) characteristics will be presented by treatment group and for all 
participants for the Randomized Safety Set and PEAS.  
Part 2: 
Descriptive statistics for demographic and baseline characteristics will be presented for all 


Palladio Biosciences PA-ADPKD-301                                                                                   
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participants for the Long-term Safety and Long-term Full Analysis Sets. 
8.13 Safety Analyses 
All Safety Analyses will be performed separately for Parts 1 and 2 for the following: 
• Single-Blind Placebo Run-in Period for the Treated Safety Set (Part 1) 
• Lixivaptan Titration Period for the Treated Safety Set (Part 1) and Lixivaptan Re-
titration Period for the Long-term Safety Set (Part 2) 
• The Double-blind, Randomized Treatment and Follow-up I Periods for the 
Randomized Safety Set (Part 1) and the Maintenance Treatment and Follow-up II 
Periods for the Long-term Safety Set (Part 2) 
8.13.1 Liver Safety Analyses 
8.13.1.1 Liver Safety Analysis for Key Safety Endpoint 
The incidence of participants who develop serum ALT levels >3 times the ULN will be 
summarized by treatment group for Part 1 and for all participants for Part 2. Additional 
summaries of causality of such cases as determined by the HERC will be included. 
8.13.1.2 Additional Liver Safety Analyses 
The incidence of participants in Parts 1 and 2 who develop: 
• >5 x-, 10 x-, and 20 x ULN elevations for ALT  
• >3 x-, 5 x-, 10 x-, and 20 x ULN elevations for AST  
• >3 x-, 5 x-, 10 x-, and 20 x ULN elevations for either ALT or AST 
• Any elevation of bilirubin; elevated serum total bilirubin (TBL) to >2 x ULN 
• Any elevation of alkaline phosphatase >1.5 x ULN 
• Elevation of aminotransferase (>3 x ULN) accompanied by elevated bilirubin (>2 x 
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. 
8.13.2 Adverse Events 
For Part 1, the number and percentage of participants and the number of events will be 
presented by treatment group for treatment-emergent adverse events (TEAEs), serious 
adverse events (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 maximum 
severity and relationship to study drug.  Listings of deaths and serious TEAEs will be 


Palladio Biosciences PA-ADPKD-301                                                                                   
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provided.   
For Part 2, the number and percentage of participants and the number of events will be 
presented for all participants for TEAEs, SAEs, treatment-related TEAEs, and TEAEs 
leading to premature withdrawal according to the SOC and PT assigned to the event using 
MedDRA.  In addition, TEAEs will also be summarized by maximum severity and 
relationship to study drug.  Listings of deaths and serious TEAEs will be provided. 
For Part 1 and Part 2, 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 whether the adverse events are SAEs, AESIs, date of AEs, relationship to 
study drug, severity, and action taken for the AEs.  Adverse events with a relationship to 
study drug considered possibly, probably, or definitely related will be considered related.     
8.13.3 Clinical Laboratory Tests 
For Part 1, descriptive statistics (n, mean, standard deviation [SD], median, minimum, and 
maximum) for clinical laboratory data and changes from baseline at each post-baseline time 
point will be presented by treatment group.  
The baseline value is the last value observed prior to first administration of study drug and 
any information obtained after first administration of study drug is regarded as post-baseline 
information.  The change-from-baseline variables will be calculated as the post-baseline 
value minus the value at baseline.  Change from baseline on continuous data will be 
summarized using descriptive statistics at each post-baseline time point by treatment group.  
For categorical data, change from baseline will be summarized using frequency and 
proportion at each post-baseline timepoint by treatment group. 
For all continuous clinical laboratory variables, a shift table comparing the baseline value 
(normal, low, and high) to the last observation on treatment will be presented by treatment 
group. 
For urinalysis, a shift table comparing the baseline value to the maximum value will be 
presented by treatment group (using number of participants with results of negative, trace, or 
positive). 
For Part 2, descriptive statistics (n, mean, standard deviation [SD], median, minimum, and 
maximum) for clinical laboratory data and changes from baseline (last value observed during 
Follow-up Period I in Part 1) at each post-baseline time point will be presented for all 
participants for each scheduled time point. 
For all continuous clinical laboratory variables in Part 2, a shift table comparing the baseline 
(last value observed during Follow-up Period I in Part 1) value (normal, low, and high) to the 
last observation on treatment will be presented for all participants. 
For urinalysis in Part 2, a shift table comparing the baseline (last value observed during 
Follow-up Period I in Part 1) value to the maximum value will be presented for all 
participants (using number of participants with results of negative, trace, or positive). 
For Part 1 and Part 2, 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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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8.13.4 ECGs 
For Part 1, observed values and changes from baseline (last value observed prior to the first 
dose of study drug) at each post-baseline timepoint for continuous ECG parameters including 
heart rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), and QTcF 
interval will be summarized by treatment group using descriptive statistics (n, mean, SD, 
median, minimum, and maximum).  
A summary shift table comparing the baseline (last value observed prior to the first dose of 
study drug) interpretation (normal, abnormal - NCS, abnormal - CS) to the Investigator 
interpretation at each post-baseline time point will also be presented by treatment group. 
A listing will be provided for Investigator-identified ECG abnormalities from safety ECGs.  
The overall evaluation of safety ECGs will be summarized by treatment group using 
frequency counts and percentage of participants as normal or abnormal, and the relevance of 
the abnormality will be summarized as CS or NCS. 
For Part 2, observed values and changes from baseline (last value observed during Follow-up 
Period I in Part 1) at each post-baseline assessment timepoint for continuous ECG parameters 
including heart rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), 
and QTcF interval will be summarized for all participants using descriptive statistics (n, 
mean, SD, median, minimum, and maximum).   
A summary shift table comparing the baseline (last value observed during Follow-up Period I 
in Part 1) interpretation (normal, abnormal - NCS, abnormal - CS) to the Investigator 
interpretation at each post-baseline time point will be presented for all participants. 
A listing will be provided for Investigator-identified ECG abnormalities from safety ECGs.  
The overall evaluation of safety ECGs will be summarized for all participants using 
frequency counts and percentage of participants as normal or abnormal, and the relevance of 
the abnormality will be summarized as CS or NCS. 
8.13.5 Body Height, Weight and BMI 
For Part 1, changes in BMI from baseline (last value observed prior to the first dose of study 
drug) to end of the Double-blind, Randomized Period and to end of Follow-up Period I (last 
value observed) will be summarized by treatment group using descriptive statistics (n, mean, 
SD, median, minimum, and maximum).   
For Part 2, changes in BMI from baseline (last value observed during Follow-up Period I in 
Part 1) to end of Maintenance Treatment Period and to end of Follow-up Period II (last value 
observed) will be summarized for all participants using descriptive statistics (n, mean, SD, 
median, minimum, and maximum).   
For Part 1 and Part 2, the change from baseline is defined as the post-baseline value minus 
the baseline value.  There will not be any imputation for missing values.  Body height, 
weight and BMI data will be listed individually by each participant based on the respective 
analysis population. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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8.13.6 Vital Signs 
For Part 1, changes from baseline (last value observed prior to the first dose of study drug) in 
vital signs at each post-baseline timepoint will be summarized by treatment group using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).   
For Part 2, changes from baseline (last value observed during Follow-up Period I in Part 1) in 
vital signs at each post-baseline timepoint will be summarized for all participants using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).   
For Part 1 and Part 2, the change from baseline is defined as the post-baseline value minus 
the baseline value.  There will not be any imputation for missing values.  All vital sign data 
will be listed individually by each participant based on the respective analysis population. 
8.14 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, standard deviation (SD), median, minimum, and 
maximum.  Categorical variables will be summarized using the following descriptive 
statistics: frequency counts and percentages.  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. 
8.15 Data Quality Assurance 
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. 
Clinical data will undergo source document verification by the CRA in accordance with the 
Study-Specific Monitoring Plan and the principles of Risk-based Monitoring. Clinical data 
will be reviewed by Data Management in accordance with the Data Management Plan 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. 
8.15.1 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 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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 
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.  
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) 
standard. 
Clinical data management will be performed in accordance with applicable standards and 
data cleaning procedures of the 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 of 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 initials will not be 
collected or transmitted to the sponsor. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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 IRB/EC before participation 
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), Good Clinical Practice (GCP), and applicable local 
regulatory requirements and laws. 
9.3 Participant Information and Consent 
Written informed consents that meet the requirements of 21 Code of Federal Regulations 
(CFR) 50, local regulations, ICH guidelines, privacy and data protection laws applicable in 
the respective participating countries and the IRB/IEC or study center 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 participating 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.  Participants will be made aware that they may 


Palladio Biosciences PA-ADPKD-301                                                                                   
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withdraw from the study at any time for any reason. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the participant or legal guardian. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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, the CRO’s medical 
monitor, other sponsor and CRO personnel (Premier Research is the designated CRO), and 
other study 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 designees, the US Food and Drug Administration (FDA), 
European Medicines Agency (EMA) or other health or regulatory authority 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 and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  In addition, 
Investigators and sub-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 following the completion of the study. 
Neither the sponsor nor sponsor’s representatives are 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 are 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: 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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 (where applicable), and all updates on a new fully 
executed Form FDA 1572 
• Curriculum vitae for the Investigator and each Sub-Investigator  
• Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements to the appropriate regulatory 
authorities.  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. 
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/EC 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/EC 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 participating participants 


Palladio Biosciences PA-ADPKD-301                                                                                   
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(sufficient 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 drug.  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 study steering committee 
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 steering committee has final 
approval authority over all such issues. 
Data are the property of the sponsor, but data and publication thereof will not be unduly 
withheld. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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11 STUDY MANAGEMENT 
11.1 Monitoring 
11.1.1 Monitoring of the Study 
The Clinical Research Associate (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, EMA 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 participants can be enrolled into an amended protocol, and 
before the changes can be implemented. 
11.3 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, 


Palladio Biosciences PA-ADPKD-301                                                                                   
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the implemented deviation or change, the reasons for it, and any proposed protocol 
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 or not adhering to 
FDA regulations or ICH GCP guidelines, and will lead to the participant being withdrawn 
from the study (Section 4.2.5). 
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. 
11.4 Management of 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 his/her last 
visit. 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study report is prepared and provided to the regulatory agency as required by the 
applicable regulatory requirement(s).  The sponsor will also ensure that the clinical study 
report in marketing applications meet the standards of the ICH harmonized tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report.  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 clinical study report, 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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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12  REFERENCE LIST 
1. Antignac C, Calvet JP, Germino GG, Grantham JJ, Guay-Woodford LM, Harris PC, 
Hildebrandt F, Peters DJM, Somlo S, Torres VE, Walz G, Zhou J, Yu ASL. 2015. 
The Future of Polycystic Kidney Disease Research — As Seen By the 12 Kaplan 
Awardees. J Am Soc Nephrol (26):2081-2095. 
2. Belibi FA, Reif G, Gail R, Wallace DP, Yamaguchi T, Olsen L, Li H, Helmkamp 
GM, Grantham, JJ. 2004. Cyclic AMP promotes growth and secretion in human 
polycystic kidney epithelial cells. Kidney Int. 66(3):964-973. 
3. Boertien WE, Meijer E, Zittema D, van Dijk MA, Rabelink TJ, Breuning MH, Struck 
J, Bakken SJL, Peters DJM, de Jong PE, Gansevoort RT. 2012. Copeptin, a surrogate 
marker for vasopressin, is associated with kidney function decline in subjects with 
autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 27:4131-
4137. 
4. 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. 
5. Chapman AB, Devuyst O, Eckardt K-U, Gansevoort RT, Harris T, Horie S, Kasiske 
BL, Odland D, Pei YP, Perrone RD, Pirson Y, Schrier RW, Torra R, Torres VE, 
Watnick T, Wheeler, DC. 2015. Autosomal-dominant polycystic kidney disease 
(ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes 
(KDIGO) Controversies Conference.  Kidney Int. 88(1):17-27 
6. 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. 
7. Delgado, C., Baweja, M., Crews, D. C., Eneanya, N. D., Gadegbeku, C. A., Inker, L. 
A., Mendu, M. L., Miller, W. G., Moxey-Mims, M. M., Roberts, G. V., St Peter, W. 
L., Warfield, C., & Powe, N. R. 2021. A Unifying Approach for GFR Estimation: 
Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race 
in Diagnosing Kidney Disease.  J Am Soc Nephrol. 2021 Sep 23:ASN.2021070988. 
doi: 10.1681/ASN.2021070988. Epub ahead of print. 
8. Devuyst O, Chapman AB, Gansevoort RT, Higashihara E, Perrone RD, Torres VE, 
Blais JD, Zhou W, Ouyang J, Czerwiec FS. 2017. Urine osmolality, response to 
tolvaptan, and outcome in autosomal dominant polycystic kidney disease: results 
from the TEMPO 3:4 trial. J Am Soc Nephrol. 28(5):1592-1602. 
9. Di Mise A, Wang X, Ye H, Pellegrini L, Torres VE, Valenti G. 2021. Pre- clinical 
evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for 
autosomal dominant polycystic kidney disease. FASEB J 2021: 
2021;35:e21874..https://doi.org/10.1096/fj.20210 0774R  35(10): e21256 
10. 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. 


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11. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon 
J; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective 
study: rationale, design and conduct. Drug Saf. 2009;32(1):55-68.
12. Gattone II VH, Wang X, Harris PC, Torres VE. 2003. Inhibition of renal cystic 
disease development and progression by a vasopressin V2 receptor antagonist. Nat 
Med. 9(10):1323-1326.
13. Hogan MC, Abebe K, Torres VE, Chapman AB, Bae KT, Tao C, Sun H, Perrone RD, 
Steinman TI, Braun W, Winklhofer FT, Miskulin DC, Rahbari-Oskoui F, Brosnahan 
G, Masoumi A, Karpov IO, Spillane S, Flessner M, Moore CG, Schrier RW. 2015. 
Liver involvement in early autosomal dominant polycystic kidney disease.  Clin 
Gastroenterol Hepatol. 13(1):155-164.
14. Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE. Tolvaptan plus 
pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol. 2015; 
26(1): 39-47.
15. International Society of Nephrology. Kidney International Supplements. KDIGO 
2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic 
Kidney Disease. Kidney Int. 99(3S):S1-S87. DOI:
https://doi.org/10.1016/j.kint.2020.11.003.
16. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, Bae 
KT, Chapman AB, Grantham JJ, Mrug M, Hogan MC, El-Zoghby ZM, Harris PC, 
Erickson BJ, King BF, Torres VE; CRISP Investigators. 2015. Imaging classification 
of autosomal dominant polycystic kidney disease: a simple model for selecting 
patients for clinical trials. J Am Soc Nephrol. 26(1):160-172.
17. 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.
18. Oberdhan D, Cole JC, Krasa HB, Cheng R, Czerwiec FS, Hays RD, Chapman AB, 
Perrone RD. 2017. Development of the Autosomal Dominant Polycystic Kidney 
Disease Impact Scale: A New Health-Related Quality-of-Life Instrument. Am J 
Kidney Dis. 71(2):225-235.
19. Oberdhan D, Krasa H, Cheng R, Hays R, Cole J, Chapman A, Perrone R. 2013. Two 
New Instruments to Measure Autosomal Dominant Polycystic Kidney Disease
(ADPKD) Related Burden: ADPKD-Impact Scale (ADPKD-IS) and ADPKD-
Urinary Impact Scale (ADPKD-UIS). 10.13140/RG.2.2.34784.89607/1.
20. Oberdhan D, Palsgrove Andrew, Cole J, Blais J, Cheng R. 2015. Patient Experience 
with Pain Related to Autosomal Dominant Polycystic Kidney Disease (ADPKD). 
10.13140/RG.2.1.2771.4321/1.
21. Pei Y, Hwang YH, Conklin J, Sundsbak JL, Heyer CM, Chan W, Wang K, He N, 
Rattansingh A, Atri M, Harris PC, Haider MA. 2015. Imaging-based diagnosis of 
autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 26(3):746-753.


Palladio Biosciences PA-ADPKD-301                                                                                   
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22. Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, Parfrey P, Cramer B, 
Coto E, Torra R, San Millan JL, Gibson R, Breuning M, Peters D, Ravine D. 2009. 
Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 
20(1):205-212. 
23. Torres VE. 2005. Vasopressin antagonists in polycystic kidney disease. Kidney Int. 
68(5):2405-2418. 
24. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, 
Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. 
2012. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N 
Engl J Med. 367(25):2407-2418. 
25. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, 
Ouyang J, Czerwiec FS, Blais JD; TEMPO 4:4 Trial Investigators. 2017a. 
Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety 
of early versus delayed treatment with tolvaptan in autosomal dominant polycystic 
kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant. 32(7):1262. 
26. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang 
J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. 2017. Tolvaptan in later-stage 
autosomal dominant polycystic kidney disease. N Engl J Med. 377:1930-1942. 
27. Wang X, Constans MM, Chebib FT, Torres VE, Pellegrini L.  Effect of a vasopressin 
V2 receptor antagonist on polycystic kidney disease development in a rat model. Am J 
Nephrol. 2019; 49(6): 487-493. 
28. Wang X, Gattone V, 2nd, Harris PC, Torres VE.  2005. Effectiveness of vasopressin 
V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease 
development in the PCK rat. J Am Soc Nephrol. 16(4):846-851. 
29. Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. 2008. Vasopressin directly 
regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2008 Jan; 
19(1):102-108. 
30. Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, 
Ouyang J, Torres VE, Czerwiec FS, Zimmer CA. 2015. Clinical Pattern of Tolvaptan-
Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney 
Disease: Analysis of Clinical Trials Database. Drug Saf 38:1103-1113.KDIG 
31. 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. 
32. 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. 
33. 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. 


Palladio Biosciences PA-ADPKD-301                                                                                   
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13 APPENDICES 
13.1 Appendix 1: Chronic Kidney Disease Classification Criteria 
As of protocol Version 2, this study will replace measurement of eGFR as calculated by the 
2009 CKD-EPI creatinine equation1 with the 2021 CKD-EPI equation refit without race 
variable (CKD-EPIcr_R) (Delgado et al, 2021), which is recommended by the National 
Kidney Foundation-American Society of Nephrology Task Force. 
The CKD-EPIcr_R equation is: 
𝑒𝐺𝐹𝑅= 142 ×  min (𝑆𝑐𝑟
κ , 1)
α
× max (𝑆𝑐𝑟
κ , 1)
−1.200
× 0.9938Age × 1.012 (if female) 
Abbreviations/Units 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
Scr (standardized serum creatinine) = mg/dL 
 = 0.7 (females) or 0.9 (males) 
α = -0.241 (females) or -0.302 (males) 
min = indicates the minimum of Scr / or 1 
max = indicates the maximum of Scr / or 1 
age = years 
 
 
 
1  
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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Serum Creatinine and Cystatin C (CKD-EPIcr-cys_R): 
 
In this study eGFR will also be assessed from a novel serum creatinine and serum cystatin C 
equation refit without the race variable (CKD-EPIcr-cys_R) (Delgado et al, 2021).  To reduce 
potential decision errors, eGFR calculated from this equation will not be shared with sites as 
all eligibility and treatment decisions will be based on eGFR calculated from the CKD-
EPIcr_R equation. 
 
The CKD-EPIcr-cys_R equation is: 
eGFR = 135 × min (
𝑆𝑐𝑟
𝑘,  1)
𝛼
× max (
𝑆𝑐𝑟
𝑘,  1)
−0.544
× min (
𝑆𝑐𝑦𝑠
0.8 ,  1)
−0.323
×
max (
𝑆𝑐𝑦𝑠
0.8 ,  1)
−0.778
× 0.9961𝑎𝑔𝑒× 0.963 [if female] 
Abbreviations/Units 
 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
Scr (serum creatinine) = mg/dL 
Scys (serum cystatin C) = mg/L 
 = 0.7 (females) or 0.9 (males) 
α = -0.219 (females) or -0.144 (males) 
min = indicates the minimum of Scr/k or 1 OR Scys/0.8 or 1 
max = indicates the maximum of Scr/k or 1 OR Scys/0.8 or 1 
age = years  
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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13.2 Appendix 2: Liver Dysfunction Checklist 
The following items will be included in a checklist to be completed by the site (Part 1- 
Symptoms and Part 2- Signs) when directed by the protocol.     
 
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 
 
The Investigator is responsible for adverse event reporting of any symptoms, signs, or 
associated diagnosis deemed clinically significant based on information entered in this 
checklist. The Investigator will determine whether a constellation of symptoms and signs in 
the context of all available information including laboratory data indicate the potential 
presence of liver dysfunction.  Otherwise, individual symptoms and signs need to be 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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 7.3.7.1 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 study drug, either 
temporarily or permanently? 
• What is the participant’s nationality? 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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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) 
• 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 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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13.4 Appendix 4: 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. 
 
 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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13.5 Appendix 5: Minimization of Missing Data: Study and Study 
Treatment Modification 
In all cases of impending study drug discontinuation or withdrawal of consent, Investigators 
should meet and discuss with the participant the options for continuing in the study, 
preferably on therapy.  The Investigator should ensure understanding and documentation of 
the reasons for the participants’ desire to withdraw consent. 
If a participant wishes to withdraw from the study (Part 1 or Part 2) at any time following 
randomization: 
1) The Investigator should seek to understand the participant’s motivation and wherever 
possible make accommodations to prevent treatment discontinuation or complete withdrawal 
of consent and maintain compliance with the protocol assessments (e.g., provide necessary 
travel reimbursement, in-home visits, alternate visit scheduling including during weekends). 
If the participant’s wish is to discontinue study drug only, proceed to Step 2. 
2) Ask the participant, “Are you willing to continue if your dose of study drug is lowered?” If 
the answer is “Yes”, titrate the dose down one level.  Repeat this step if the participant 
continues to request withdrawal of consent.  If the answer is “No” or if, once the Level 1 
dose is reached, the participant continues to request withdrawal of consent, go to Step 3. 
3) Ask the participant, “If we temporarily interrupt your study drug would you be willing to 
later resume medication and continue with regular visits?” If the answer is “Yes”, interrupt 
study drug but continue to follow all other trial procedures for the participant until the 
participant restarts treatment.  If the participant does not resume treatment with study drug 
after 7 days, perform the treatment interruption assessments and follow-up specified in 
Section 4.2.3, and then resume study drug and continue with all other monthly assessments to 
the end of the trial.  If the answer is “No” and the participant still wishes to withdraw from 
the trial, go to Step 4. 
4) Ask the participant, “If we discontinue your study drug permanently, would you continue 
with all visits and sample collections?” The Investigator should discuss the scientific value of 
continued data collection even in the absence of study treatment.  If the answer is “Yes”, the 
participant is willing to continue with all visits and sample collections, discontinue study 
drug, perform an ET visit (Visit 22/ET if in Part 1 or Visit 42/ET if in Part 2), complete the 
Follow-up Period assessments, and continue with all other monthly assessments to the end of 
the trial to reduce missing data.  If the answer is “No” go to Step 5. 
5) If the above steps including interruption or permanent discontinuation of study drug do not 
resolve the participant’s issues, further accommodations such as less frequent visits or blood 
draws may be used (as long as adequate safety monitoring can be ensured for participants 
continuing study drug).  Less frequent visits or procedures must be offered only if they are 
required to maintain access to the participant’s medical information and/or to encourage the 
participant to continue in the trial. 
 
 


Palladio Biosciences PA-ADPKD-301                                                                                   
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13.6 Appendix 6: Procedures to Prevent Loss to Follow-up 
The Investigator must make every effort to contact participants who fail to return for 
scheduled visits to prevent participants from being “lost to follow-up”. The following 
procedures should be followed at a minimum, with additional measures taken if 
unsuccessful. 
 
1) Contact all numbers for the participant and their listed contacts (to be collected in source 
document at the participant’s entry into the trial). This includes making calls after normal 
business hours or on holidays and weekends.  Notify the CRA and/or medical monitor 
promptly after participant fails to return for a scheduled visit. 
 
2) Contact the participant’s primary care physician, referring specialist, pharmacist or other 
health-care professional (using the contacts provided by the participant at entry to the 
trial). 
3) Send a text, e-mail and postal mail with certified (return-receipt requested) letters to 
all the participant’s addresses and all contacts (as provided by the participant at entry to the 
trial). 
4) In-home visit at last address given. 
5) Review available medical records/notes for details of hospitalizations, clinic visits or 
other procedures which may indicate the status of participants (as allowed through 
release of medical record forms to be completed by participant at trial entry). 
6) Conduct an internet search for additional contact information (e.g., reverse directory 
for phone numbers or new address information; social media outlets (e.g., Facebook, 
LinkedIn or other social media for status updates). 
7) Check local, regional and national public records to locate the participant or search for 
mortality status as allowed by law. 
Once all these actions have been exhausted (and documented), then the CRA or medical 
monitor should be contacted for additional guidance. 


Overview of Changes in the Conduct of the Study  
 
Due to the staggered nature of regulatory submissions and approvals around the world, two 
versions of the protocol were active and being used at the time of early termination. The design 
in Version 3.0 was being used in two countries (Bulgaria and Poland) and Version 1.0 (original 
protocol) was being used in all other countries.  After Version 2.0 was completed and released, 
but before implementation anywhere in the world, it was realized that additional clarifications 
and improvements to the text would result in an enhanced protocol. Thus, Version 3.0 was 
created from Version 2.0, and, in particular, details about the primary endpoint analyses, more 
typically provided only in the Statistical Analysis Plan, were incorporated into the main body of 
the study protocol. The major changes from V1.0 to V3.0 are provided below. Details of all the 
changes are provided in the subsequent 2 documents. 
1) 
to increase study power from 85% to 90% resulting in a sample size increase from 
1200 randomized to 1350 randomized participants, to meet the mainstream industry 
standard for powering phase 3 studies, and a direct result of the merging of Palladio 
into the newly formed Centessa Pharmaceuticals. This was decided before any 
participant had enrolled into the ACTION study. 
2) 
to update the equation used in the calculation of the primary endpoint from the 2009 
CKD-EPI equation to the 2021 CKD-EPIcr_R equation. This updated equation 
removes the race variable from the calculation of eGFR, per the recent update to this 
standard.    
3) 
to add exploratory endpoints for eGFR calculated from a combination of serum 
creatinine and serum cystatin C based on the 2021 CKD-EPIcr-cys_R equation in 
recognition of the potential for this to be the standard equation in the future.    
4) 
to increase frequency of serum sodium assessments to enhance safety monitoring as 
recommended by members of the Steering Committee based on the experience in the 
REPRISE study of tolvaptan. 
5) 
to remove suppression of post-randomization eGFR results to facilitate the Blinded 
Sample Size Re-estimation process and enhance safety monitoring.  
6) 
to add a benefit/risk paragraph.  
7) 
to incorporate additional guidance about the importance of study participants staying 
on study drug or continuing in the study off study drug. 


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Study PA-ADPKD-301: The ACTION Study 
Clinical Study Protocol Version 3.0, Dated 14 February 2022 
Summary of Changes 
This Summary of Changes document reflects revisions incorporated into Protocol Amendment 02, Version 3.0 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 3 are shown in Track Changes.  Minor editorial and document 
formatting revisions have not been summarized. 
 
The amendment is a substantial amendment because these changes affect 1) the safety or rights of the participant and 2) the 
reliability and robustness of the data generated in the clinical trial.  
 
The main reasons for this amendment are clarification and/or codification of text to clarify activities and/or to reduce variance; and 
providing further insight into the statistical analyses that will be conducted. 
 
Administrative Changes 
 
There are no Administrative Changes to this version of the protocol.  
 
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 2.0, Dated 01 Feb 2022 
Version 3.0; Dated 14 Feb 2022 
Explanation 
Multiple Global 
Maintenance Period 
Maintenance PeriodMaintenance Treatment 
Period 
For consistency of 
‘Maintenance Treatment 
Period’ throughout the 


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protocol 
Multiple Global 
Lixivaptan Dose Titration Period 
Lixivaptan Dose Titration Period 
For consistency of 
‘Lixivaptan Titration Period’ 
throughout the protocol 
20 
Synopsis, Study 
Design: 
At the beginning of Part 2, participants 
will start lixivaptan during the Lixivaptan 
Re-titration Period to re-establish the 
dose level that was tolerated during Part 
1. 
At the beginning of Part 2, all participants 
will start lixivaptan during the Lixivaptan Re-
titration Period to re-establish the dose level 
that was tolerated during Part 1 
To clarify re-establishment 
of dose level applies to all 
participants (both 
lixivaptan-treated 
participants in Part 1 and 
placebo treated participants 
in Part 1) 
20 
Synopsis, Study 
Period Description and 
Estimated Duration: 
Screening Period (Visits 1a, 1b, and 2): 
To obtain informed consent and 
determine initial participant eligibility, 
screening assessments will be performed 
at Visit 1a 
Screening Period (Visits 1a, 1b, and 2): To 
After obtaining informed consent screening 
assessments will be performed at Visit 1a to 
and determine initial participant eligibility, 
screening assessments will be performed at 
Visit 1a.   
To clarify that informed 
consent will be obtained 
prior to any assessments at 
Screening Visit 1a. 
23 
Synopsis, Study 
Period Description and 
Estimated Duration: 
Part 2, Lixivaptan Re-titration Period 
(Visits 26 to 29): 
….For participants randomized to 
placebo in Part 1, lixivaptan dosing will 
be titrated to the final blinded dose level 
achieved during the Double-Blind 
Treatment Period in accordance with 
Table 2. 
Part 2, Lixivaptan Re-titration Period (Visits 
26 to 29): 
…..For participants randomized to placebo 
in Part 1, lixivaptan dosing will be titrated to 
the final blinded inferred dose level (the 
dose level equal to the active dose level had 
the participant been randomized to the 
active arm) achieved during the Double-
Blind Treatment Period in accordance with 
Table 2. 
To clarify the target dose 
level that participants 
randomized to placebo in 
Part 1 during re-titration in 
Part 2. 
25 
Synopsis, Study Drug, 
Dosage, and Route of 
Administration: 
In an effort to minimize missing data, 
wherever practicable, participants who 
experience a study drug interruption of 7 
or more days should be scheduled to 
have 3 separate serum creatinine 
samples obtained (minimally 24 hrs. 
apart between 8 and 28 days after their 
last dose) for determination of eGFR. 
In an effort to minimize missing data, 
wherever practicable, participants who 
experience a study drug interruption of 7 or 
more days should will be scheduled to have 
3 separate serum creatinine samples 
obtained (minimally 24 hrs. apart between 8 
and 28 days after their last dose) for 
determination of eGFR. 
To strengthen the protocol 
emphasis on obtaining 
blood draws for eGFR 
determinations at the same 
clock time during baseline 
eGFR and off-treatment 
timepoints; important 
primary efficacy endpoints. 
26 
Synopsis, Table 2, 
footnote * 
Periodic attempts should be made to re-
establish dosing at Level 2 (100 mg BID) 
during the open-label phase 
Periodic aAttempts should will be made 
every 4 to 8 weeks to re-establish dosing at 
To clarify and codify the 
frequency of attempts to re-
establish dose level 2 


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Level 2 (100 mg BID) during the open-label 
phase. 
during open-label phase in 
Part 2 for participants who 
had a reduction in dose to 
level 1. 
34 
Table 3. Schedule of 
Procedures – Part 1, 
footnote e 
e. As participants transition into the 
Double-Blind Randomized Treatment 
Period, with visits scheduled every 4 
weeks, participant follow-up via a 
telephone contact is strongly 
encouraged.  Telephone contacts should 
be repeated throughout the study as 
needed.  Any contact with the participant 
via telephone will be recorded in the 
source document 
e. As participants transition into the Double-
Blind Randomized Treatment Period, with 
visits scheduled every 4 weeks, participant 
follow-up via a telephone contact is 
strongly encouraged. To encourage study 
compliance, Dduring the Double-Blind 
Randomized Treatment Period, tTelephone 
contacts willshould be made 2 weeks (± 5 
days) after every scheduled visit.repeated 
throughout the study as needed.  Any All 
telephone contacts with the participant via 
telephone will be recorded in the source 
document. 
 
To clarify and codify the 
frequency and schedule of 
follow-up telephone 
contacts in order to 
encourage study 
compliance. 
38 
Table 4. Schedule of 
Procedures – Part 2, 
footnote l 
l.   Participant follow-up via a telephone 
contact between study visits is strongly 
encouraged.  Telephone contacts 
should be repeated throughout the 
study as needed.   
     Any contact with the participant via 
telephone will be recorded in the 
source document 
l.   During the Maintenance Treatment Period, 
pParticipant follow-up via a telephone 
contact will be made 2 weeks (± 5 days) 
after every scheduled visit between study 
visits is strongly encouraged.  Telephone 
contacts should be repeated throughout the 
study as needed.  Any All telephone 
contacts with the participant via telephone 
will be recorded in the source document 
To clarify and codify the 
frequency and schedule of 
telephone contacts. 
58 
3.1.2 Detailed Study 
Design; Part 2: 
 
Lixivaptan Re-Titration Period (Visits 26 to 
29): 
Note: during the Re-titration Period of Part 
2, all participants are re-titrated with 
lixivaptan to the last actual dose level if 
they had received lixivaptan during the 
Double-blind, Randomized Treatment 
Period, or, if they had received placebo 
during the Double-blind, Randomized 
Treatment Period, to the last inferred dose 
level (the dose level equal to the active 
Relocated text from 
Maintenance Treatment 
Period section of protocol to 
the more appropriate 
location in the Lixivaptan 
Re-titration Period section. 


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dose level had the participant been 
randomized to the active arm). Re-titration 
will be performed by the IRT, and the site, 
participant, and sponsor maintain a 
blinded status to the prior treatment 
assignment in Part 1. If no adjustment is 
made to the inferred dose during the 
Double-Blind, Randomized Treatment 
Period, the last inferred dose for a 
participant randomized to placebo will be 
equal to the maximal tolerated lixivaptan 
dose established during the Titration 
Period in Part 1. 
59 
3.1.2 Detailed Study 
Design; Part 2: 
Maintenance Treatment Period (Visits 30 
to 42): 
  Note: during the Re-titration Period of 
Part 2, all participants are re-titrated with 
lixivaptan to the last actual dose level if 
they had received lixivaptan during the 
Double-blind, Randomized Treatment 
Period, or, if they had received placebo 
during the Double-blind, Randomized 
Treatment Period, to the last inferred 
dose level (the dose level equal to the 
active dose level had the participant 
been randomized to the active arm). This 
will be performed by the IRT and the site, 
participant, and sponsor maintain a 
blinded status to the prior treatment 
assignment in Part 1. If no adjustment is 
made to the inferred dose during the 
Double-Blind, Randomized Treatment 
Period, the last inferred dose for a 
participant randomized to placebo will be 
equal to the maximal tolerated lixivaptan 
dose established during the Titration 
Period in Part 1. 
 
Relocated text from 
Maintenance Treatment 
Period section of protocol to 
the more appropriate 
location in the Lixivaptan 
Re-titration Period section. 


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65 
4.2.3 Treatment 
Interruption 
If a study drug interruption is expected to 
last 7 or more consecutive days, the 
participant should be scheduled to have 
3 separate serum creatinine and serum 
cystatin C samples obtained (minimally 
24 hrs. apart) beginning on Day 8 after 
the last dose of study drug for 
determination of eGFR in the event the 
study drug interruption leads to 
permanent discontinuation of treatment.  
In such cases, the 3rd sample should be 
collected up to Day 28 (± 3 days) after 
the last dose of study drug.  If, in the 
Investigator’s opinion, the treatment 
interruption is expected to be prolonged 
(i.e., >4 weeks in duration) or permanent, 
then a postbaseline MRI should also be 
obtained. 
If a study drug interruption is expected to 
last 7 or more consecutive days, the 
participant willshould be scheduled to have 
3 separate serum creatinine and serum 
cystatin C samples obtained (minimally 24 
hrs. apart) beginning on Day 8 after the last 
dose of study drug for determination of 
eGFR in the event the study drug 
interruption leads to permanent 
discontinuation of treatment.  In such 
cases, the 3rd sample willshould be 
collected up to Day 28 (± 3 days) after the 
last dose of study drug.  If, in the 
Investigator’s opinion, the treatment 
interruption is expected to be prolonged 
(i.e., >4 weeks in duration) or permanent, 
then a postbaseline MRI willshould also be 
obtained. 
To clarify if the interruption 
is expected to last 7 or 
more days, the per protocol 
mandate to obtain 3 blood 
draws for determination of 
serum creatinine and serum 
cystatin C (used for eGFR 
calculations) at least 24 
hours apart beginning on 
Day 8 after the last dose of 
study drug. If interruption is 
expected to last > 4 weeks, 
an MRI will be obtained. 
67 
4.2.4 Treatment 
Discontinuation 
Participants may elect to stop treatment 
permanently before the end of the study 
for various reasons. 
Participants may elect to stop treatment, 
(i.e., stop taking their study drug), 
permanently before the end of the study for 
various reasons.  This is separate and 
distinct from study discontinuation and/or 
withdrawal (,Section 4.2.5), although the 
reason(s) for study drug discontinuation 
may be identical and/or similar to reason(s) 
for study discontinuation.   
To clarify and distinguish 
between Treatment 
Discontinuation, i.e., 
cessation of study drug 
treatment, and study 
discontinuation and/or study 
withdrawal. 
78 
 
79 
80 
81 
83 
 
90 
 
91 
6. Timing of Study 
Procedures; 
6.1.1 Visit 1a; 
6.1.2 Visit 1b; 
6.1.3 Visit 2; 
6.2 Placebo Run-in 
Period and Visit 3; 
6.4.2 Visit 22/Early 
Termination; 
6.5.1 Visit 23 and Visit 
24; 
For a given participant, every attempt 
should be made to draw blood samples 
for eGFR determinations at 
approximately the same clock time during 
Visits 1a/1b, 2, and 3 and Visits 23, 24, 
and 25, and again at Visits 43, 44, and 
45.  
 
For a given participant, every attempt 
willshould be made to draw blood samples 
for eGFR determinations at approximately 
the same clock time during Visits 1a/1b, 2, 
and 3 and Visits 23, 24, and 25, and again 
at Visits 43, 44, and 45.  
 
To strengthen the protocol 
emphasis on obtaining 
blood draws for eGFR 
determinations at the same 
clock time during baseline 
eGFR and off-treatment 
timepoints; important 
primary efficacy endpoints. 


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92 
97 
 
98 
99 
101 
6.5.2 Visit 25; 
6.7.2 Visit 42/Early 
Termination (Part 2); 
6.8.1 Visit 43 and 44; 
6.8.2 Visit 45; 
7.1.1 eGFR 
Determination 
 
122 
8.5.1 Annualized Rate 
of Change (Slope) in 
eGFR on Treatment 
A linear contrast of the treatment 
differences for these 12 monthly visits will 
be used for this analysis. 
 
A linear contrast of the treatment slope 
differences for these 12 monthly visits will 
be used for this analysis. 
 
To clarify that the treatment 
slope difference will be 
used for the analysis. 
136 
11.4 Study 
Termination 
11.4 Study Termination 
11.4 Management of Study Termination 
Section heading revised to 
reflect the content of the 
section. 
 
 
 


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Clinically-relevant Changes 
This section describes changes that affect safety or study conduct. 
Page 
Section 
Version 2.0, Dated 01 Feb 2022 
Version 3.0; Dated 14 Feb 2022 
Rationale 
Multiple 
Global 
Note: In the event of newly emerging 
tolerability issues at any time during 
the study, dosing may be decreased 
or temporarily stopped.  During the 
Double-Blind Treatment Period, 
periodic attempts should be made to 
re-establish the previously achieved 
dose level from Visit 9, if medically 
appropriate. 
Note: In the event of newly emerging 
tolerability issues at any time during 
the study, dosing may be decreased 
or temporarily stopped.  If dosing is 
resumed during the Double-Blind 
Treatment Period at a dose level less 
than that achieved at Visit 9 During 
the Double-Blind Treatment Period, 
periodic attempts should will be made 
every 4 to 8 weeks to re-establish the 
previously achieved dose level from 
Visit 9, if medically appropriate. If 
study drug is interrupted for longer 
than 8 weeks, then study drug 
treatment will be permanently 
discontinued. 
To clarify and codify 1) the 
frequency of attempts to re-
establish end-of-titration dose 
level and 2) the maximum 
duration of a temporary drug 
interruption is 8 weeks after 
which study drug treatment will 
be permanently discontinued. 
Multiple 
Global 
As participants transition into the 
Double-Blind Randomized Treatment 
Period, with visits scheduled every 4 
weeks, participant follow-up via a 
telephone contact is strongly 
encouraged.  Telephone contacts 
should be repeated throughout the 
study as needed.  Any contact with 
the participant via telephone will be 
recorded in the source document 
As participants transition into the 
Double-Blind Randomized Treatment 
Period, with visits scheduled every 4 
weeks, participant follow-up via a 
telephone contact is strongly 
encouraged. To encourage study 
compliance, Dduring the Double-Blind 
Randomized Treatment Period, 
tTelephone contacts willshould be 
made 2 weeks (± 5 days) after every 
scheduled visit.repeated throughout 
the study as needed.  Any All 
telephone contacts with the participant 
via telephone will be recorded in the 
source document. 
 
To codify the frequency and 
schedule of telephone contacts 
and clarify that all telephone 
contacts will be documented. 


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Multiple 
Global 
Note: In the event of newly emerging 
tolerability issues at any time during 
the study including the Part 2 
Lixivaptan Re-titration Period or 
during the Maintenance Period, 
dosing may be decreased or 
temporarily stopped.  Periodic 
attempts should be made to re-
establish the previously achieved 
dose level from Part 1, if medically 
appropriate. 
 
Note: In the event of newly emerging 
tolerability issues at any time during 
the study including the Part 2 
Lixivaptan Re-titration Period or during 
the Maintenance PeriodMaintenance 
Treatment Period, dosing may be 
decreased or temporarily stopped.  
Periodic aAttempts should will be 
made every 4 to 8 weeks to re-
establish the previously achieved dose 
level at the end of the Double-blind, 
Randomized Treatment Period offrom 
Part 1, if medically appropriate. If 
study drug is interrupted for longer 
than 8 weeks, then study drug 
treatment will be permanently 
discontinued. 
To clarify and codify 1) during 
the Maintenance Treatment 
Period, the frequency of 
attempts to re-establish the dose 
level at the end of the Double-
blind, Randomized Treatment 
Period and 2) the maximum 
duration of a temporary drug 
interruption, after which study 
drug treatment will be 
permanently discontinued. 
Multiple 
Global 
 
If study drug is interrupted for longer 
than 8 weeks, then study drug 
treatment will be permanently 
discontinued. 
Text added to establish a 
maximum duration of study drug 
interruption, after which study 
drug treatment will be 
permanently discontinued. 
17 
 
 
62 
Synopsis, Study 
Population, Inclusion 
Criteria 
 
4.1.1, Inclusion Criteria 
7.b. …Note: in women with severe 
polycystic liver disease, 
contraceptives containing 
estrogen (and hormone 
replacement therapy) may be 
involved in the development and 
growth of liver cysts and 
polycystic liver disease 
progression and should be 
discussed between the 
Investigator and the potential 
participant. 
7.b. .. Note: in women with severe 
polycystic liver disease, 
contraceptives containing 
estrogen (and hormone 
replacement therapy) may be 
involved in the development and 
growth of liver cysts and 
polycystic liver disease 
progression; the supplemental risk 
of initiating or continuing estrogen 
treatment, as well as potential 
alternative contraceptives for 
WOCBP will should be discussed 
between with the Investigator and 
the potential participant. 
 
To elaborate the discussion with 
women of child-bearing potential 
(WOCBP) participants with 
severe polycystic liver disease 
(PLD) regarding estrogen and 
potential effects on development 
and growth of liver cysts and 
progression of PLD disease. 
The investigator is inherent on 
all activities of the protocol so 
unnecessary to state it. 


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28 
Synopsis, Statistical 
Methods: 
 
 
Primary Efficacy Analysis: Part 1: 
Sensitivity analyses of the primary 
efficacy analysis will include the use of 
the mean of eGFR values obtained 
pretreatment and the mean of eGFR 
values obtained off treatment after the 
end of the 52-week treatment period, 
regardless of adherence to 
randomized treatment and/or 
withdrawal for all randomized 
participants, i.e., Intent-To-Treat 
participants. Week 52 missing values 
will be imputed using multiple 
imputations (assuming missing at 
random). Bi-directional tipping point 
analyses will be included using a 
pattern-mixture model to impute 
missing data at Week 52 (assuming 
missing not at random); allowing 
varying assumptions about the 
missing outcomes on the two 
treatment arms. 
Text added to describe planned 
sensitivity analyses of the 
primary efficacy analysis. 
49 
1.9, Benefit/Risk 
Assessment 
Safety data gathered to date in 
participants with ADPKD are 
consistent with the robust safety 
experience from studies in earlier 
indications investigated for 
lixivaptan—congestive heart failure, 
liver cirrhosis with ascites, or 
syndrome of inappropriate 
antidiuretic hormone secretion. The 
primary adverse effects of lixivaptan 
are related to the exaggerated 
pharmacology of blockade of the 
renal concentrating mechanism. This 
results in urinary dilution with the 
production of increased amounts and 
frequency of urine output and, 
secondarily, the stimulation of thirst. 
No adverse effects on other body 
Safety data gathered to date in 
participants with ADPKD are 
consistent with the robust safety 
experience from lixivaptan treatment 
in studies in earlier indications 
investigated for lixivaptan—congestive 
heart failure, liver cirrhosis with 
ascites, or syndrome of inappropriate 
antidiuretic hormone secretion. The 
most common (≥> 2%)primary 
adverse effects of lixivaptan are 
related to the exaggerated 
pharmacology of blockade of the renal 
concentrating mechanism. This results 
in urinary dilution with the production 
of increased amounts and frequency 
of urine output and, secondarily, the 
stimulation of thirst. No adverse 
To clarify and elaborate the 
risks, specifically of the potential 
risk for drug-induced liver injury 
(DILI) and the associated 
redundancy, by design, of 
safety monitoring. 


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systems have been noted. 
Additionally, pharmacodynamic data 
generated for vasopressin V2 
receptor antagonists that assess the 
mechanism of action, primarily 
through the development program for 
tolvaptan, have been confirmed in 
Phase 2 studies with lixivaptan and 
support continued development of 
lixivaptan for this indication. As there 
additionally remains a large unmet 
medical need to address chronic 
treatment in patients with ADPKD, 
particularly those who have 
experienced liver chemistry 
abnormalities leading to 
discontinuation of treatment with 
tolvaptan, continued investigation of 
this drug for ADPKD is warranted. 
Based on the totality of evidence 
generated to date on lixivaptan, the 
benefit/risk assessment of lixivaptan 
remains favorable. 
 
effects on other body systems have 
been noted. Lixivaptan as a 
vasopressin V2 receptor antagonist is 
in the same pharmacological class as 
tolvaptan.  Drug-induced liver injury 
(DILI) has been observed during the 
use of tolvaptan for ADPKD and 
JINARC / Jynarque® (brand names for 
tolvaptan) have boxed warnings for 
DILI in their Summary of Product 
Characteristics/US Prescribing 
Information label.  Although there 
have been no reports of DILI related to 
lixivaptan to-date, the potential risk of 
DILI during lixivaptan treatment exists; 
this protocol has been designed to 
frequently monitor the participants for 
liver test abnormalities, has 
established an Independent Data 
Monitoring CommitteeIDMC for safety 
oversight and has established an 
independent Hepatic Event Review 
Committee to monitor and review any 
participant’s signs, symptoms, and/ 
laboratory tests that meet hepatic 
criteria, and described procedures to 
prevent liver toxicity.   One of the two 
primary objectives of this study is to 
determine the risk of DILI as a result 
of lixivaptan treatment for ADPKD. 
56 
3.1.2 Detailed Study 
Design; Part 1: 
Participants who were originally 
enrolled based on the 2009 CKD-EPI 
equation (Appendix 1 (Section 13.1)) 
will not be discontinued from the 
study should their recalculated 
baseline eGFR, based on the CKD-
EPIcr_R equation, yield a mean 
eGFR value outside of the range of 
25 to 90 mL/min/1.73 m2 
Participants who were originally 
enrolled based on the 2009 CKD-EPI 
equation ((referenced in Appendix 1 
(Section 13.1)) will not be 
discontinued from the study should 
their recalculated baseline eGFR, 
based on the CKD-EPIcr_R equation, 
yield a mean eGFR value outside of 
the range of 25 to 90 mL/min/1.73 m2.  
The stratification by CKD stage 
Clarification that the CKD 
stratification at time of 
randomization will be based on 
the baseline eGFR creatinine 
equation (CKD-EPIcr or CKD-
EPIcr_R) at the time of 
randomization.  All efficacy 
assessments will be based on 
eGFR based on CKD-EPIcr_R 
equation. 


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(Section 8.4.1) will be based on the 
baseline eGFR creatinine equation in 
effect at the time of randomization.  
However, all efficacy analyses of 
change in eGFR will be based on the 
CKD-EPIcr_R equation. 
59 
3.1.2 Detailed Study 
Design; Part 2: 
Maintenance Treatment Period 
(Visits 30 to 42): 
If the participant’s dose was 
decreased during the Lixivaptan Re-
Titration Period, periodic attempts 
should be made to re-establish the 
previously achieved dose level from 
Part 1 
 
Maintenance Treatment Period (Visits 
30 to 42): 
If the participant’s dose was 
decreased during the Lixivaptan Re-
Titration Period, periodic attempts 
should will be made every 4 to 8 
weeks to re-establish the previously 
achieved dose level (actual or 
inferred) at the end of the Double-
blind, Randomized Treatment Period 
offrom Part 1. 
To codify and clarify 1) that 
attempts to re-establish end-of-
titration dose level every 4-8 
weeks and 2) the target dose is 
actual or inferred dose at the 
end of the Double-blind, 
Randomized Treatment Period 
of Part 1. 
65 
4.2.3 Treatment 
Interruption 
If a participant’s study drug must be 
interrupted for medical or surgical 
reasons, liver chemistry test 
abnormalities, tolerability issues, 
temporary use of a prohibited 
concomitant medication, life 
situations, e.g., airplane travel, etc. 
or other reasons; the participant’s 
study drug should be resumed as 
early as the situation allows and the 
interruption recorded as a “Treatment 
Interruption” on the eCRF. 
If a participant’s study drug must be 
interrupted for medical or surgical 
reasons, liver chemistry test 
abnormalities, tolerability issues, 
temporary use of a prohibited 
concomitant medication, life situations, 
e.g., airplane travel, etc... or other 
reasons, the interruption should be 
recorded as a “Treatment Interruption” 
on the eCRF.; the The participant’s 
study drug should be resumed as 
early as the situation allows, e.g., 
airplane travel ends or recovery from 
surgery allows re-initiation/re-
establishment of study drug treatment, 
and the interruption recorded as a 
“Treatment Interruption” on the eCRF.  
The maximum duration of an 
interruption is 8 weeks; if interruption 
To clarify resumption of study 
drug after a treatment 
interruption and to establish a 
maximum duration of study drug 
interruption of 8 weeks, after 
which study drug treatment will 
be permanently discontinued. 


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is greater than 8 weeks, study drug 
will be permanently discontinued.  
66 
4.2.3 Treatment 
Interruption 
Participants with a prolonged study 
drug interruption (i.e., greater than 4 
weeks in duration), who are re-
initiating treatment are required to re-
establish their last tolerated dose 
over a 2-week interval.   
Participants with a prolonged study 
drug interruption (i.e., greater than 4 
weeks in duration) equal to or less 
than 8 weeks), who are re-initiating 
treatment are required to re-establish 
their last tolerated dose over a 2-week 
interval.   
To establish a maximum 
duration of study drug 
interruption of 8 weeks. 
67 
4.2.3 Treatment 
Interruption 
 
Participants with a prolonged study 
drug interruption of greater than 8 
weeks will not be allowed to re-initiate 
and/or re-establish study drug 
treatment i.e., study drug treatment 
will be permanently discontinued.  
These participants should be 
encouraged to continue their 
participation in the study following the 
procedures described in Section 4.2.7 
and Appendix 5 (Section 13.5). 
 
Text added to establish a 
maximum duration of study drug 
interruption of 8 weeks after 
which study drug treatment will 
be discontinued.  Study 
participants should be 
encouraged to continue in the 
study. 
73 
5.2 Dose Administered 
 
The participant’s study drug should be 
resumed as early as the situation 
allows, e.g., airplane travel ends or 
recovery from surgery allows re-
initiation/re-establishment of study 
drug treatment.  The maximum 
duration of an interruption is 8 weeks; 
if interruption is greater than 8 weeks, 
study drug treatment will be 
permanently discontinued (Section 
4.2.3). 
 
Text added to clarify resumption 
of study drug administration 
after a temporary interruption 
and to establish a maximum 
duration of study drug 
interruption. 


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74 
5.4 Treatment 
Compliance 
If the participant is not ≥ 80% 
compliant with the prescribed study 
drug doses during the study overall, 
it will be noted as a significant 
protocol deviation. 
If the participant is not ≥ 80% 
compliant with the prescribed study 
drug doses during the study overall, it 
will be noted as a significant protocol 
deviation. 
To clarify the protocol deviation 
of study drug treatment 
compliance is <80% during the 
study overall. 
75 
5.5 Prior and Concomitant 
Therapy 
Note: in female participants with 
severe polycystic liver disease, 
contraceptives (and hormone 
replacement therapy) containing 
estrogen may be involved in the 
development and growth of liver 
cysts and polycystic liver disease 
progression and should be discussed 
between the Investigator and the 
potential participant 
Note: in female participants with 
severe polycystic liver disease, 
contraceptives (and hormone 
replacement therapy) containing 
estrogen may be involved in the 
development and growth of liver cysts 
and polycystic liver disease 
progression; the supplemental risk of 
initiating or continuing estrogen 
treatment, as well as potential 
alternative contraceptives for WOCBP  
and should will be discussed between 
thewith  Investigator and the potential 
participant. 
To elaborate, with regards to, 
the discussion with women of 
child-bearing potential 
(WOCBP) participants with 
severe polycystic liver disease 
(PLD) regarding estrogen and 
potential effects on 
development and growth of liver 
cysts and progression of PLD 
disease. The investigator is 
inherent on all activities of the 
protocol so unnecessary to 
state it. 
76 
5.5.1.2 Prohibited 
Therapy 
strong or moderate CYP3A4 or 
CYP2C8 inhibitors, including…. 
strong or moderate CYP3A4 or 
CYP2C8 inhibitors, including…. 
voriconazole, 
Voriconazole added to the list of 
strong or moderate CYP3A4 or 
CYP2C8 inhibitors 
109 
7.3.7.1 Management of 
Liver Chemistry Test 
Abnormalities and Signs 
or Symptoms of Liver 
Dysfunction Occurring 
During Study Treatment 
Liver chemistry test increases of a 
lesser extent (serum 
aminotransferase levels ≤3 × ULN or 
total bilirubin ≤2 × ULN) should be 
discussed with the medical monitor.  
They may be related to the 
underlying variability of such test 
results in ADPKD patients (Watkins 
et al, 2015).   
Liver chemistry test increases of a 
lesser extent (serum aminotransferase 
levels ≤3 × ULN or total bilirubin ≤2 × 
ULN) willshould be discussed with the 
medical monitor.  They may be related 
to the underlying variability of such 
test results in ADPKD patients 
(Watkins et al, 2015).    
To mandate, by protocol, 
discussion of liver chemistry 
test abnormalities with the 
medical monitor. 


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112 
7.3.8.2 Eliciting and 
Documenting Adverse 
Events and Serious 
Adverse Events 
 
Tolerability issues including but not 
limited to aquaretic effects, difficulty 
swallowing capsules, and abnormal 
thirst, will be recorded as adverse 
events. 
Text added to clarify and 
provide examples of tolerability 
issues. 
119 
8.2 Blinded Sample Size 
Re-estimation 
After at least 20% of the randomized 
participants (i.e., 270 participants) 
complete Part 1 of the study (Visit 
25) or before screening for the study 
has ended, a BSSR will be 
performed by a blinded, independent 
statistician.  Based on this interim 
data set, the variance corresponding 
to the primary efficacy estimand will 
be estimated and the total sample 
size re-estimated.  If the BSSR 
estimates that the standard deviation 
of the primary efficacy estimand is 
less than or equal to 6.20 mL per 
minute per 1.73 m2, then the sample 
size will remain at 1350 randomized 
participants.  If the BSSR estimates 
that the standard deviation is greater 
than 6.20 mL per minute per 1.73 m2, 
then the total sample size will be re-
estimated based on this new 
estimate of the standard deviation 
and the resulting revised sample size 
estimate will be provided to the 
sponsor for consideration.  The 
BSSR will be based on the original, 
assumed between-treatment group 
difference, i.e., there will be no 
change to the estimate of the 
between-treatment group difference 
based on the BSSR. Since it is felt 
that the impact of the BSSR on the 
significance level will be negligible, 
After at least 20% of the randomized 
participants (i.e., 270 participants) 
complete Part 1 of the study (Visit 25) 
or before screening for the study has 
ended, a BSSR will be performed by a 
blinded, independent statistician.  
Based on this interim data set of 
blinded eGFR values, the variance 
corresponding to the primary efficacy 
estimand will be estimated and the 
total sample size re-estimated by a 
blinded statistician.  If the BSSR 
estimates that the standard deviation 
of the primary efficacy estimand is 
less than or equal to 6.20 mL per 
minute per 1.73 m2, then the sample 
size will remain at 1350 randomized 
participants.  If the BSSR estimates 
that the standard deviation is greater 
than 6.20 mL per minute per 1.73 m2, 
then the total sample size will be re-
estimated based on this new estimate 
of the standard deviation and the 
resulting revised sample size estimate 
will be conducted by the sponsor 
provided to by the sponsor or 
designeefor consideration.  The BSSR 
will be based on the original, assumed 
between-treatment group difference, 
i.e., there will be no change to the 
estimate of the between-treatment 
group difference based on the BSSR. 
Since it is felt that the impact of the a 
To clarify that the BSSR will be 
performed by a blinded 
statistician using blinded eGFR 
values and that the BSSR does 
not inflate the type 1 error of the 
primary efficacy analysis. 


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the significance level for the final test 
will remain at 0.01. 
BSSR does not inflate the type 1 error 
of the primary efficacy analysison the 
significance level will be negligible, the 
significance level for the final test 
efficacy analysis will remain at 0.01. 
120 
8.4.1 Primary Endpoint 
Analysis 
The estimand corresponding to the 
primary objective is the between-
treatment group difference in the 
change from baseline in eGFR if all 
the participants in the PEAS had 
tolerated and adhered to their 
treatment for 52 weeks.  Potential 
bias due to randomized participants 
prematurely discontinuing from 
double-blind treatment will be 
handled by annualizing the changes 
from baseline by multiplying each 
participant’s change from 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. 
 
The estimand corresponding to the 
primary objective is the between-
treatment group difference in the 
change from baseline in eGFR if all 
the participants in the PEAS had 
tolerated and adhered to their 
treatment for 52 weeks.  Potential bias 
due toFor randomized participants 
prematurely discontinuing from 
double-blind treatment, the primary 
analysis will be handled by 
annualizing the changes from baseline 
by multiplying each participant’s 
change from baseline by 365.25 days 
divided by the duration (days) from the 
median of the baseline eGFR 
assessments to the median of the 3 
eGFR assessments made obtained 
during the post-treatment, follow-up 
period immediately following study 
drug discontinuationassessments in 
days. 
For participants who prematurely 
discontinue study drug prior to Week 
52, the follow-up data from the period 
immediately following study drug 
discontinuation will be used for the 
primary efficacy endpoint. 
 
To clarify the method of primary 
analysis for randomized 
participants who discontinue 
from study drug treatment 
during the double-blind 
treatment period. 


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121 
8.4.1 Primary Endpoint 
Analysis 
 
The stratification by CKD stage 
(Section 8.4.1) will be based on the 
baseline eGFR creatinine equation in 
effect at the time of randomization.      
However, all efficacy analyses of 
change in eGFR will be based on the 
CKD-EPIcr_R equation. 
Text added to clarify that CKD 
stage stratification will be based 
on whichever baseline eGFR 
equation was used at the time 
of randomization. To clarify that 
all efficacy analyses will be 
based on eGFR calculated 
using the 2021 CKD-EPIcr-R 
equation. 
121 
8.4.2 Sensitivity Analysis 
of the Primary Efficacy 
Analysis 
In order to address the impact of 
missing data on the results from the 
primary efficacy analysis, a number 
of sensitivity analyses will be 
performed.  The sensitivity analyses 
for the primary efficacy analysis will 
be described in the statistical 
analysis plan (SAP). 
 
In particular, in order to address the 
impact of missing data on the results 
from the primary efficacy analysis, a 
number of sensitivity analyses will be 
performed.  The detailed sensitivity 
analyses for the primary efficacy 
analysis will be described in the 
statistical analysis plan (SAP). 
 
Amongst these sensitivity analyses, 
the main sensitivity analysis of the 
primary efficacy analysis will use the 
mean of eGFR values obtained 
pretreatment and the mean of eGFR 
values obtained off treatment after the 
end of the 52-week treatment period, 
regardless of adherence to 
randomized treatment and/or 
withdrawal for all randomized 
participants, i.e., Intent-To-Treat 
participants. Missing values at Week 
52 will be imputed using multiple 
imputations (assuming missing at 
random). Tipping point analyses will 
be included using a pattern-mixture 
model to impute missing data at Week 
52 (assuming missing not at random) 
by systematically varying assumptions 
about the missing outcomes on the 
two treatment arms – these tipping 
point analyses will be bi-dimensional, 
Text added to elaborate 
planned sensitivity analyses of 
the primary efficacy analysis of 
the Intent-To-Treat population. 
Multiple imputations will be 
used to impute missing values 
at Week 52 (assuming missing 
at random) and tipping point 
analysis will be used to impute 
missing value at Week 52 
(assuming missing not at 
random). 


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i.e., allow the assumptions about the 
missing outcomes in the two arms to 
vary independently, and will include 
scenarios where the dropouts on the 
lixivaptan arm have worst outcome 
compared to placebo dropouts. 
 
123 
8.6.2 Sensitivity Analysis 
of the Key Comparison 
Analysis 
In order to assess the effect of 
missing data on the key comparison 
analysis in Part 2, sensitivity 
analyses for the descriptive statistics 
described in the corresponding 
section of Section 8.6.1, will be 
performed.  The sensitivity analyses 
for the key comparison analysis in 
Part 2 will be described in the SAP. 
 
In order to assess the effect of missing 
data on the key comparison analysis 
in Part 2, sensitivity analyses for the 
descriptive statistics described in the 
corresponding section of Section 
8.6.1, will be performed for all 
available annualized changes from 
baseline (the mean of the 3 eGFR 
assessments obtained during Follow-
up Period I in Part 1) to the mean of 
the 3 off-treatment eGFRs after Week 
104..  The sensitivity analyses for the 
key comparison analysis in Part 2 will 
be described in the SAP. 
To clarify the endpoints that will 
be used for the key comparison 
analyses. 
 


Summary of Changes 
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Study PA-ADPKD-301: The ACTION Study 
Clinical Study Protocol Version 2.0, Dated 01 February 2022 
Summary of Changes 
This Summary of Changes document reflects revisions incorporated into Protocol Amendment 01, 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 amendment is a substantial amendment because these changes affect 1) the safety or rights of the participant and 2) the 
reliability and robustness of the data generated in the clinical trial.  
The main reasons for this substantial amendment are as follows:  
1) to increase study power to 90% resulting in a sample size increase from 1200 randomized to 1350 randomized participants;  
2) to update the equation used in the calculation of the primary endpoint from the 2009 CKD-EPI equation to the 2021 CKD-
EPIcr_R . This updated equation removes the race variable from the calculation of eGFR;  
3) to add exploratory endpoints for eGFR calculated from a combination of serum creatinine and serum cystatin C based on the 
2021 CKD-EPIcr-cys_R equation;  
4) to increase frequency of serum sodium level assessment to enhance safety monitoring;  
5) to remove suppression of post-randomization eGFR results to facilitate safety monitoring and allow the sponsor to conduct the 
Blinded Sample Size Re-estimation (BSSR);  
6) to add a benefit/risk section;  
7) to incorporate additional messaging about the importance of study participants staying on study drug or continuing in the study 
off of study drug; and  
8) to incorporate protocol administrative letters #1 (06-Jul-2021) and #2 (04-Aug-2021). 
 
 
 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 01 February 2022 
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Administrative Changes 
 
This section lists administrative changes, including changes of names or roles of companies or personnel and/or contact 
information. There are no changes included that affect clinical decision making or consent. 
 
Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Rationale 
1, 4, 14 
 
 
  
Title Page: Sponsor, 
Palladio Logo, 
Sponsor Contact, 
  
Protocol Approval 
Signature Page, 
 
Protocol Synopsis 
Palladio Biosciences, Inc., a Centessa 
Pharmaceuticals Company 
Palladio Biosciences, Inc., a Centessa 
Pharmaceuticals Company 
Clarified that Palladio 
Biosciences, Inc is the legal 
entity. This update 
incorporates the change noted 
in Protocol Administrative 
Letter 01 (06-Jul-2021). 
The logo has been revised to 
only show Palladio 
Biosciences. 
1, 115 
 
 
 
 
 
 
 
Title Page: Emergency 
Telephone Number 
 
 
 
 
 
Protocol, Section, 
7.3.8.3, Reporting 
Adverse Events, 
Serious Adverse 
Events, and Adverse 
Events of Special 
Interest 
 
 
North America: +1 510 722 8910 
South America: +54 911 5479 8678 
Europe, South Africa: +44 118 936 
4096 
Australia: +61 3921 39875 
 
 
 
Investigative Sites in North America: 
+1 510 722 8910 
Investigative Sites in South America: 
+54 911 5479 8678 
Investigative Sites in Europe, South 
Africa: +44 118 936 4096 
Investigative Sites in Australia: +61 
3921 39875 
 
North America: +1 510 722 8910 
South America: +54 911 5479 8678 
Europe, South Africa and Middle East 
Region: +44 118 936 4096 
Australia, New Zealand: +61 3921 
39875 
 
 
      Investigative Sites in North 
America: +1 510 722 8910 
Investigative Sites in South America: 
+54 911 5479 8678 
Investigative Sites in Europe, South 
Africa and Middle East Region: +44 118 
936 4096 
Investigative Sites in Australia, New 
Zealand: +61 3921 39875 
 
List of country/regional 
emergency telephone 
numbers have been updated 
to reflect current study regional 
locations.  
41 
List of Abbreviations 
 
CKD-EPIcr_R Chronic Kidney Disease 
Epidemiology Collaboration eGFR 
creatinine equation refit without the race 
variable 
Added abbreviations for the 
updated equations for eGFR 
which will be used in the 
primary and exploratory 


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Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Rationale 
 
CKD-EPIcr-cys_R 
Chronic Kidney 
Disease Epidemiology Collaboration 
eGFR creatinine and cystatin C equation 
refit without the race variable. 
endpoints. 
112 
Protocol Section, 
7.3.7.2. Hepatic 
Events Review 
Committee (HERC)- 
Special Reporting of 
Liver Events 
The Investigator must complete the 
liver dysfunction details eCRF within 24 
hours of awareness through the SAE 
reporting pathway (described in Section 
7.3.8.3) for any participant who 
develops an Adverse Event of Special 
Interest (AESI) related to abnormal liver 
chemistry test results or clinical signs or
symptoms…. 
….The AESI report form should be 
updated as new information becomes 
available. 
The Investigator must complete and 
submit a copy of the liver dysfunction 
details eCRF with the SAE/AESI form 
within 24 hours of awareness through the 
SAE reporting pathway (described in 
Section 7.3.8.3) for any participant who 
develops an Adverse Event of Special 
Interest (AESI) related to abnormal liver 
chemistry test results or clinical signs or 
symptoms…. 
….The SAE/AESI report form should be 
updated as new information becomes 
available. 
Clarified the procedures for 
AESI reporting. 
Updated the name of the 
report form to SAE/AESI report 
form. 
114 
Protocol, Section, 
7.3.8.3, Reporting 
Adverse Events, 
Serious Adverse 
Events, and Adverse 
Events of Special 
Interest 
Any AE that meets SAE or AESI criteria 
will be reported to Premier Research 
Global Pharmacovigilance (Premier PV) 
immediately (i.e., within 24 hours) after 
site personnel first learn about the 
event.  Investigators should record all 
SAE details available, including 
Investigator causality assessment, on 
the SAE form and subsequently record 
the event on the Adverse Event eCRF 
within 24 hours of becoming aware of 
the event.   Investigators should record 
all AESI details available, including 
Investigator causality assessment, on 
the AESI form and subsequently record 
the event on the Adverse Event eCRF 
Any AE that meets SAE or AESI criteria 
will be reported to Premier Research 
Global Pharmacovigilance (Premier PV) 
immediately (i.e., within 24 hours) after 
site personnel first learn about the event.  
Investigators should record all SAE details 
available, including Investigator causality 
assessment, on the SAE/AESI form and 
subsequently record the event on the 
Adverse Event eCRF within 24 hours of 
becoming aware of the event. 
Investigators should record all AESI 
details available, including Investigator 
causality assessment, on the SAE/AESI 
form and subsequently record the event 
on the Adverse Event eCRF within 24 
hours of becoming aware of the event. 
Text revised to reflect that 
there is a combined SAE/AESI 
form for event reporting. 


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Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Rationale 
within 24 hours of becoming aware of 
the event. 
Completed SAE Report Forms and 
AESI Report Forms should be submitted 
to Premier PV as an email attachment to
the email address below. 
…. 
Should the site have questions or 
concerns regarding SAE report 
submission, the site may elect to call the 
site Clinical Research Associate (CRA) 
or contact the medical monitor. The site 
will be asked to provide the following 
information: protocol number, site 
number, participant identifiers, event 
term, study drug information, and 
relationship of the event to study drug. 
Completed SAE/AESI Report Forms  and 
AESI Report Forms should be submitted 
to Premier PV as an email attachment to 
the email address below. 
 
…. 
Should the site have questions or 
concerns regarding SAE/AESI report 
submission, the site may elect to call the 
site Clinical Research Associate (CRA) or 
contact the medical monitor. The site will 
be asked to provide the following 
information: protocol number, site number, 
participant identifiers, event term, study 
drug information, and relationship of the 
event to study drug. 
139 
Reference List 
 
7. 
Delgado, C., Baweja, M., Crews, D. 
C., Eneanya, N. D., Gadegbeku, C. A., 
Inker, L. A., Mendu, M. L., Miller, W. G., 
Moxey-Mims, M. M., Roberts, G. V., St 
Peter, W. L., Warfield, C., & Powe, N. R. 
2021. A Unifying Approach for GFR 
Estimation: Recommendations of the 
NKF-ASN Task Force on Reassessing the 
Inclusion of Race in Diagnosing Kidney 
Disease.  J Am Soc Nephrol. 2021 Sep 
23:ASN.2021070988. doi: 
10.1681/ASN.2021070988. Epub ahead 
of print. 
Updated the reference list with 
the reference for the 2021 
CKD-EPI equation refit without 
race variable (CKD-EPIcr_R). 
Reference List renumbered as 
a result of this change. 
139 
Reference List 
8.Di Mise A, Wang X, Ye H, Pellegrini L, 
Torres VE, Valenti G: Dual Targeting of 
the G Protein-Coupled Receptors CaSR 
and V2R for Treating Autosomal 
8.9. Di Mise A, Wang X, Ye H, Pellegrini 
L, Torres VE, Valenti G. 2021. Pre- clinical 
evaluation of dual targeting of the GPCRs 
CaSR and V2R as therapeutic strategy for 
Updated the Di Mise reference 
from the abstract to the full 
manuscript. 


Summary of Changes 
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Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Rationale 
Dominant Polycystic Kidney Disease 
(ADPKD) [Abstract]. J Am Soc Nephrol. 
30, 2019: Page 628. 
autosomal dominant polycystic kidney 
disease. FASEB J 2021: 
2021;35:e21874.. 
https://doi.org/10.1096/fj.202100774R  
35(10): e21256 
8.Di Mise A, Wang X, Ye H, Pellegrini L, 
Torres VE, Valenti G: Dual Targeting of 
the G Protein-Coupled Receptors CaSR 
and V2R for Treating Autosomal 
Dominant Polycystic Kidney Disease 
(ADPKD) [Abstract]. J Am Soc Nephrol. 
30, 2019: Page 628. 
140 
Reference List 
14. International Society of Nephrology. 
Kidney International Supplements. 
KDIGO. 2012. KDIGO Clinical Practice 
Guideline for the Management of Blood 
Pressure in Chronic Kidney Disease. 
2(5). Available at: http://www.kidney-
international.org. 
14. 
International Society of Nephrology. 
Kidney International Supplements. 
KDIGO. 2012. KDIGO Clinical Practice 
Guideline for the Management of Blood 
Pressure in Chronic Kidney Disease. 2(5). 
Available at: http://www.kidney-
international.org. 
14. 15.International Society of 
Nephrology. Kidney International 
Supplements. KDIGO 2021 Clinical 
Practice Guideline for the Management of 
Blood Pressure in Chronic Kidney 
Disease. Kidney Int. 99(3S):S1-S87. DOI: 
https://doi.org/10.1016/j.kint.2020.11.003. 
Updated the reference list with 
the KDIGO 2021 guideline for 
blood pressure control to align 
with Inclusion Criterion #5. 
 
 
 


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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 30JUN2021 
Version 2.0, Dated 01FEB2022 
Explanation 
Multiple Global 
KDIGO 
the 2021 KDIGO guideline 
Clarified version of the 
KDIGO blood pressure 
guideline used. 
Multiple Global 
Mayo Clinic ADPKD Classification 
Mayo Clinic ADPKD Image Classification. 
Clarified that ADPKD 
classification is based on 
MRI imaging. 
Multiple Global 
 
Note: In the event of newly emerging 
tolerability issues at any time during the study, 
dosing may be decreased or temporarily 
stopped.  During the Double-Blind Treatment 
Period, periodic attempts should be made to 
re-establish the previously achieved dose 
level from Visit 9, if medically appropriate.  
Clarified that dosing may 
be reduced or temporarily 
stopped at any time during 
the study with the caveat 
that the dose should be re-
established only if 
medically appropriate. 
Multiple Global 
 
Note: In the event of newly emerging 
tolerability issues at any time during the study 
including the Part 2 Lixivaptan Re-titration 
Period or during the Maintenance Period, 
dosing may be decreased or temporarily 
stopped.  Periodic attempts should be made 
to re-establish the previously achieved dose 
level from Part 1, if medically appropriate 
Clarified that dosing may 
be reduced or temporarily 
stopped at any time during 
the study, including the 
Lixivaptan Re-titration or 
Maintenance Periods of 
Part 2 with the caveat that 
the dose should be re-
established only if 
medically appropriate. 
Multiple Global 
Visit 24 must be scheduled to occur 12 
to 24 days after the last dose of double-
blind study drug and a minimum of 24 
hours apart from either Visit 23 or Visit 
25.   
 
Visit 24 must be scheduled to occur at least 
24 hours after Visit 23 and at least 24 hours 
prior to Visit 25 12 to 24 days after the last 
dose of double-blind study drug and a 
minimum of 24 hours apart from either Visit 23 
or Visit 25.   
Changed visit timing to 
increase operational 
efficiency. 
Multiple Global 
Visit 44 must be scheduled to occur 12 
to 24 days after the last dose of study 
drug and a minimum of 24 hours apart 
Visit 44 must be scheduled to occur at least 
24 hours after Visit 43 and at least 24 hours 
prior to Visit 45. 12 to 24 days after the last 
Changed visit timing to 
increase operational 
efficiency. 


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Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Explanation 
from either Visit 43 or Visit 45. 
dose of study drug and a minimum of 24 hours
apart from either Visit 43 or Visit 45. 
 
Multiple Global 
Schedule participant for the post-
baseline MRI for assessment of TKV 
and LV to occur 28 ± 3 days after the 
last dose; the MRI should occur up to 3 
days prior to or on the same day as 
Visit 25. 
Schedule participant for the post-baseline MRI 
for assessment of TKV and LV to occur 
between 25 days and 31 28 ± 3 days after the 
last dose of study drug; the MRI should occur 
up to 3 days must be completed prior to or on 
the same day as all other Visit 25 study 
procedures 
Text regarding timing of 
MRI at Visit 25 was 
revised for clarity. 
Multiple Global 
Schedule participant for the post-
baseline MRI for assessment of TKV 
and LV to occur 28 ± 3 days after the 
last dose; the MRI should occur up to 3 
days prior to or on the same day as 
Visit 45. 
Schedule participant for the post-baseline MRI 
for assessment of TKV and LV to occur 
between 25 days and 31 28 ± 3 days after the 
last dose of study drug; the MRI should occur 
up to 3 days must be completed prior to or on 
the same day as all other Visit 45 study 
procedures 
Text regarding timing of 
MRI at Visit 45 was 
revised for clarity. 
Multiple Global 
…The baseline MRI, which may be 
completed before, at, or after Visit 1b, is 
to be completed minimally 2 weeks prior 
to Visit 2 to allow for receipt of the Mayo 
Clinic ADPKD classification from the 
central imaging vendor… 
 
 
 
 
Participants who do not require 
modification to medical treatment should 
be scheduled for the baseline MRI and 
should proceed to Visit 2 in 3 to 5 weeks 
following Visit 1a. Note: Visit 2 should 
be scheduled minimally 2 weeks 
following completion of the MRI to allow 
for receipt of the Mayo Clinic ADPKD 
classification from the central imaging 
vendor… 
…The baseline MRI, which may be completed 
before, at, or after Visit 1b, is to be completed 
minimally 2 weeks approximately 1 week prior 
to Visit 2 to allow for receipt of the Mayo Clinic 
ADPKD Image classification from the central 
imaging vendor (Note: Visit 2 should be 
scheduled approximately 1 week after the 
baseline MRI and approximately 2 weeks after 
completion of Visit 1b, whichever occurs 
later)… 
Participants who do not require modification to 
medical treatment should be scheduled for the 
baseline MRI and should proceed to Visit 2 in 
3 to 5 weeks following Visit 1a. Note: Visit 2 
should be scheduled minimally 2 weeks 
approximately 1 week following completion of 
the MRI to allow for receipt of the Mayo Clinic 
ADPKD Image classification Classification 
from the central imaging vendor.  Participants 
must have adequate BP control for a minimum 
of 3 weeks prior to enrollment (Visit 2)…  
Timing of Visit 2 relative to 
the completion of Visit 1b 
for participants requiring 
blood pressure/blood 
pressure medication 
optimization has been 
revised for operational 
efficiency, including time 
for determination of Mayo 
Image Classification. 
 
 
 
Timing of Visit 2 relative to 
the completion of Visit 1b 
for participants requiring 
blood pressure/blood 
pressure medication 
optimization has been 
revised for operational 
efficiency, including time 


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Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Explanation 
for determination of Mayo 
Image Classification. 
Multiple Global 
Designated visits may be done 
remotely by a home healthcare clinician 
(HHC) (where available and locally 
approved by the Competent Authority 
(CA) and/or IRB/EC) and telehealth 
(e.g., telemedicine virtual visit, 
telephone or video call (without 
recording)) with the study site, as 
applicable. 
If agreeable to the participant and at the 
discretion of the investigator, designated visits 
may be done remotely by a home healthcare 
clinician (HHC) (where available and locally 
approved by the Competent Authority (CA) 
and/or IRB/EC). Some remote visits and may 
also include telehealth (e.g., telemedicine 
virtual visit, telephone or video call (without 
recording)) with the study site, as applicable.  
Remote visits may also be conducted by 
qualified site personnel who have been 
delegated the authority to carry out the 
procedures required at remote visits by the 
Investigator. 
Added framework around 
permitting remote visits 
and indicated that some 
visits will include telehealth 
with the Investigator. 
 
Clarified that remote visits 
may also be conducted by 
qualified site staff, where 
available and approved. 
16, 53 
Protocol Synopsis, 
Objectives 
 
Protocol Section, 2.1.2 
Objectives of the 
Open-label Phase 
(Part 2/Year 2) 
 
   
The population pharmacokinetics (PopPK)    
objective of Part 2 is: 
 
To further characterize the PK profile of 
lixivaptan utilizing PopPK based on 
sparse plasma sampling. 
For completeness, an 
objective related to 
population PK has been 
added to Part 2 of the 
study. 
17 
Protocol Synopsis, 
Inclusion Criteria  
2. Diagnosis of ADPKD by modified 
Pei criteria: 
3.  For participants with family 
history of ADPKD, by ultrasound: 
 18-39 years: ≥3 cysts, unilateral 
or bilateral;   
 40-59 years: ≥2 cysts in each 
kidney; 
 60 years: ≥4 cysts in each 
kidney…. 
 
2. Diagnosis of ADPKD by modified Pei 
criteria: 
3. For participants with family history of 
ADPKD, by ultrasound: 
 18-39 years: ≥3 cysts, unilateral or 
bilateral;   
 40-59 years: ≥2 cysts in each kidney; 
 60 years: ≥4 cysts in each kidney… 
 
Corrected from a 
separately numbered 
inclusion criterion to a sub-
bullet. This update 
incorporates the change 
noted in Protocol 
Administrative Letter 2 
(04-Aug-2021) and 
harmonizes with 
numbering of criteria. 
As a result, all inclusion 
criteria after Inclusion 
Criterion 2 appearing in 


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Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Explanation 
the protocol synopsis were 
renumbered. 
17, 64 
Protocol Synopsis, 
Study Population 
 
Protocol Section 4.1.1, 
Inclusion Criteria 
 
5.   eGFR ≥25 mL/min/1.73 m2 
and ≤90 mL/min/1.73 m2 based 
on the mean of 2 eGFR 
determinations…Note: This 
criterion will preliminarily be 
reviewed at Visit 2 based on Visit 
1a or Visit 1b results (if Visit 1b is 
required).  The criterion must be 
re-evaluated no later than Visit 3 
when results for Visits 1a and 2 or 
Visits 1b and 2 are available. 
 
5   4.eGFR ≥25 mL/min/1.73 m2 and 
≤90 mL/min/1.73 m2 based on the mean 
of 2 eGFR determinations… Note: This 
criterion will preliminarily be reviewed at 
Visit 2 based on Visit 1a or Visit 1b 
results (if Visit 1b is required).  The 
criterion must be re-evaluated no later 
than Visit 3 when results for Visits 1a 
and 2 or Visits 1b and 2 are available to 
confirm that the participant remains 
eligible for participation.  
Clarification added that 
eligibility based on eGFR 
should be re-evaluated 
once Visit 2 lab results 
become available by Visit 
3. 
19, 65 
Protocol Synopsis, 
Study Population 
 
Protocol, Section 
4.1.2, Exclusion 
Criteria. 
4 
4. History of infection with human 
immunodeficiency virus (HIV) 
unless the participant is stable 
and doing well on a non-CYP 
interacting ART regimen and the 
participant has not required more 
than 2 changes in their ART 
regimen since treatment 
inception. 
4. History of infection with human 
immunodeficiency virus (HIV) unless the 
participant is clinically stable and doing 
well on a non-CYP interacting ART 
regimen and the participant has not 
required more than 2 changes in their 
ART regimen since treatment inception 
“Clinically” added to 
criterion for clarity 
21 
Protocol Synopsis, 
Study Period 
Description and 
Estimated Duration: 
 
Participants with appropriate blood 
pressure control…and not receiving 
a diuretic will have a baseline MRI 
exam scheduled and will proceed to 
Visit 2, 3 to 5 weeks after Visit 1a 
and after completion of the baseline 
MRI. (Screening may be extended 
to a maximum of 8 weeks, in the 
event of extenuating circumstances. 
Prior approval from the medical 
monitor is required.) 
 
 
Participants who need to be 
discontinued from diuretic therapy 
and/or have their anti-hypertensive 
 Participants with appropriate blood 
pressure control…and not receiving a 
diuretic will have a baseline MRI exam 
scheduled and will proceed to Visit 2, 3 to 5 
weeks after Visit 1a, and after completion 
of the baseline MRI (allow approximately 1 
week after completion of the MRI, however, 
a 3-week minimum between Visit 1a and 
Visit 2 is required). (Screening may be 
extended to a maximum of 8 weeks, in the 
event of extenuating circumstances. Prior 
approval from the medical monitor is 
required.) 
 
Clarified visit timing during 
the Screening Period for 
participants who do not 
require optimization of 
blood pressure/blood 
pressure medications as 
well as for those requiring 
optimization of blood 
pressure/blood pressure 
medication. 
 
Clarified that optimization 
of blood pressure/blood 
pressure medications for 
those who require it should 


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Explanation 
therapy optimized due to 
inadequate BP control (as defined 
by KDIGO) will return for Visit 1b to 
have additional serum chemistry 
testing once their treatment and 
blood pressure have been stable for 
a minimum of 3 weeks.  The 
baseline MRI exam should be 
scheduled after completion of Visit 
1a but may be performed before, at, 
or after Visit 1b (but prior to Visit 2) 
depending on scheduling. Upon 
attaining stability of antihypertensive 
therapy and completion of the 
baseline MRI, the participant will be 
scheduled for Visit 2 (a minimum of 
2 weeks following the MRI and a 
minimum of 1 week following Visit 
1b.)  The total duration of the 
Screening Period may be extended 
up to 8 weeks, including the time to 
completion of Visit 2. 
 
Participants who meet all of the 
inclusion criteria…will have Visit 2 end-
of-screening assessments and eligibility 
determination (final eGFR eligibility will 
be delayed until Visit 2 
serum creatinine results are obtained). 
Participants who fail inclusion/exclusion 
criteria… 
 
Participants who need to be discontinued 
from diuretic therapy and/or have their anti 
hypertensive therapy optimized due to 
inadequate BP control (as defined by the 
2021 KDIGO guideline) will return for 
unscheduled visits for blood pressure 
monitoring following Visit 1a.  Once their 
treatment and blood pressure have been 
stable for a minimum of 3 weeks, they will 
return for Visit 1b to have additional serum 
chemistry testing once their treatment and 
blood pressure have been stable for a 
minimum of 3 weeks.The baseline MRI 
exam should be scheduled after 
completion of Visit 1a but may be 
performed before, at, or after Visit 1b (but 
prior to Visit 2) depending on scheduling. 
Upon attaining stability of antihypertensive 
therapy and completion of the baseline 
MRI, the participant will be scheduled for 
Visit 2 (approximately 1 week minimum of 
2 weeks following the MRI and a minimum 
of approximately 1 2 weeks following Visit 
1b, whichever occurs later.) The total 
duration of the Screening Period may be 
extended up to 8 weeks, including the 
time to completion of Visit 2.  
 
Participants who meet all of the inclusion 
criteria…will have Visit 2 end-of-screening 
assessments and eligibility determination 
(final eGFR eligibility will be delayed until Visit 
2 serum creatinine results are obtained); 
fasting morning spot (i.e., discard first void 
and sample will be obtained from next void 
within 30 to 45 minutes) urine osmolality will 
also be measured. Participants who fail  
inclusion/exclusion criteria… 
occur at Unscheduled 
Visits prior to Visit 1b. 
 
Text added to clarify 
procedure for urine 
osmolality at Visit 2. 


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Version 2.0, Dated 01FEB2022 
Explanation 
22, 59 
Protocol Synopsis 
Study Period 
Description and 
Estimated Duration 
(Part 1) 
 
Protocol Section 3.1.2, 
Detailed Study Design 
(Part 1) 
Lixivaptan Dose Titration Period (Visits 
4 to 9):  During a period of 5 to 6 weeks, 
the lixivaptan dose will be increased in a 
single-blind fashion according to the 
titration schedule in Table 1 to achieve 
the maximally tolerated dose up to the 
maximum dose allowed (Level 4 [200 
mg BID]); as 4 capsules BID.  The 
minimum dose to enter the Double-
blind, Randomized Treatment Period is 
Level 2 (100 mg BID).  Once the 
maximally….  
Lixivaptan Dose Titration Period (Visits 4 to 
9):  During a period of 5 to 6 weeks for 
participants who complete the Placebo Run-
in Period, the lixivaptan dose will be 
increased in a single-blind fashion according 
to the titration schedule in Table 1 to achieve 
the maximally tolerated dose up to the 
maximum dose allowed (Level 4 [200 mg 
BID]); as 4 capsules BID.  The minimum 
dose to enter the Double-blind, Randomized 
Treatment Period is Level 2 (100 mg BID).  
Once the maximally….  
Text revised for clarity. 
23 
Protocol Synopsis 
Study Period 
Description and 
Estimated Duration 
(Part 2) 
Lixivaptan Re-titration Period (Visits 26 
to 29): Titration of lixivaptan will occur 
over a 2 to 4-week re-titration period 
and will start at a dose of 50 mg BID 
beginning at the conclusion of Visit 25. 
The dose will be increased at weekly 
intervals until the dose level from the 
end of the Double-blind, Randomized 
Treatment Period in Part 1 is achieved.  
In order to maintain blinding of the 
treatment assignment from Part 1, the 
dose level assignment for Part 2 will 
continue to be managed by the IRT. The 
dose-titration schedule for this part of 
the study is described in Table 2.   
 
Lixivaptan Re-titration Period (Visits 26 to 
29): Titration of lixivaptan will occur over a 2 
to 4-week re-titration period and will start at a 
dose of 50 mg BID beginning at the 
conclusion of Visit 25. The dose will be 
increased at weekly intervals until the dose 
level from the end of the Double-blind, 
Randomized Treatment Period in Part 1 is 
achieved.  For participants randomized to 
placebo in Part 1, lixivaptan dosing will be 
titrated to the final blinded dose level 
achieved during the Double-Blind Treatment 
Period in accordance with Table 2.  In order 
to maintain blinding of the treatment 
assignment from Part 1, the dose level 
assignment for Part 2 will continue to be 
managed by the IRT. The dose-titration 
schedule for this part of the study is 
described in Table 2.   
Text has been revised to 
provide clarity around re-
titration in Part 2, 
particularly for participants 
previously randomized to 
placebo in Part 1.  
24, 61 
 
 
 
 
Study Synopsis, Study 
Period Description and 
Estimated Duration: 
 
 
The total duration of participation in the 
study will be approximately 123 to 131 
weeks (up to 71 weeks in Part 1 and up 
to 60 weeks in Part 2) depending on the 
length of Screening (3 to 8 weeks), 
Titration (5 to 6 weeks), and Re-titration 
The total duration of participation in the study 
will be approximately 123 to 131 weeks (up 
to 71 weeks in Part 1 and up to 60 weeks in 
Part 2) depending on the length of Screening 
(3 to 8 weeks), Titration (5 to 6 weeks), and 
Re-titration (2 to 4 weeks).  Note that the 
Text clarified to reflect that 
the study may be 
interrupted at any time 
based on findings from the 
IDMC and the sponsor. 


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Page 
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Version 2.0, Dated 01FEB2022 
Explanation 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Section, 3.1.2 
Detailed Study Design 
(2 to 4 weeks).  Note that the study may 
be interrupted at any time if safety 
issues identified by an IDMC potentially 
compromise the safety of the 
participants. 
 
 
The maximum duration of participation 
in this study is 131 weeks (up to 71 
weeks in Part 1 and up to 60 weeks in 
Part 2) depending on the length of 
Screening (3 to 8 weeks), Titration (5 to 
6 weeks) and Re-titration (2 to 4 
weeks). Note that the study may be 
interrupted at any time if safety issues 
identified by an Independent Data 
Monitoring Committee potentially 
compromise the safety of the 
participants. 
 
study may be interrupted at any time if safety 
issues identified by an Independent Data 
Monitoring Committee (IDMC) and sponsor 
potentially compromise the safety of the 
participants. 
 
The maximum duration of participation in this 
study is 131 weeks (up to 71 weeks in Part 1 
and up to 60 weeks in Part 2) depending on 
the length of Screening (3 to 8 weeks), 
Titration (5 to 6 weeks) and Re-titration (2 to 
4 weeks). Note that the study may be 
interrupted at any time if safety issues 
identified by an Independent Data Monitoring 
Committee IDMC and sponsor potentially 
compromise the safety of the participants. 
25 
 
 
 
 
 
  75 
Protocol Synopsis, 
Study Drug, Dosage, 
and Route of 
Administration 
 
 
Protocol Section 5.2, 
Dose Administered 
Participants who are unable to tolerate 
the minimum dose for study entry (100 
mg BID/ Level 2) will be discontinued 
from the study. 
 
 
Once the maximum tolerated dose is 
achieved during the Lixivaptan Titration 
Period, participants will generally stay 
on that dose for 1 additional week to 
confirm tolerability.  As the maximum 
duration of the Lixivaptan Titration 
Period is 6 weeks, participants who 
require a dose reduction at Week 6, as 
a result of emerging tolerability issues, 
will proceed to the double-blind period 
on the newly assigned (reduced) dose 
level without extension of the titration 
Participants who are unable to tolerate the 
minimum dose for study entry into the 
Double-blind, Randomized Treatment Period 
(100 mg BID/ Level 2) will be discontinued 
from the study. 
 
Once the maximum tolerated dose is 
achieved during the Lixivaptan Titration 
Period, participants will generally stay on that 
dose for 1 additional week to confirm 
tolerability.  As the maximum duration of the 
Lixivaptan Titration Period is 6 weeks, 
participants who require a dose reduction at 
Week 6, as a result of emerging tolerability 
issues, will proceed to the double-blind 
period on the newly assigned (reduced) dose 
level without extension of the titration period.  
Participants who are unable to tolerate the 
Revised text for clarity. 


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Version 2.0, Dated 01FEB2022 
Explanation 
period.  Participants who are unable to 
tolerate the minimum dose for study 
entry (100 mg BID/ Level 2) will be 
discontinued from the study.   
minimum dose for study entry into the 
Double-Blind, Randomized Treatment 
Period, (100 mg BID/ Level 2) will be 
discontinued from the study.   
26 
 
Protocol Synopsis, 
Study Drug Dosage, 
and Route of 
Administration (Part 2) 
 
 
Part 2: During the Lixivaptan Re-
titration Period, dosing will start at 
Level 1 (50 mg BID) and will be 
increased weekly until the dose level 
taken at the end of the Double-blind, 
Randomized Treatment Period is 
achieved.  This is shown in Table 2.  
That dose will be continued for the 
remainder of Part 2…. 
Part 2: During the Lixivaptan Re-titration 
Period, dosing will start at Level 1 (50 mg 
BID) for all participants in Part 2 and will be 
increased weekly until the dose level taken 
at the end of the Double-blind, Randomized 
Treatment Period is achieved.  This is 
shown in Table 2.  That dose will be 
continued for the remainder of Part 2. 
Clarified that all 
participants (lixivaptan- 
and placebo-treated 
participants from Part 1 
who participate in Part 2) 
will initiate re-titration at 
lixivaptan (50 mg BID). 
 
35 
Table 3, Schedule of 
Procedures, Part 1  
(table note) 
Not all participants will need these visits
Visits 4 to 7, 10, 11, 13, 14, 16, 17, 19 
to 21, 23 and 24 may be conducted in 
the clinic or remotely by a home 
healthcare clinician 
Not all participants will need these visits 
Visits 4 to 7, 10, 11, 13, 14, 16, 17, 19 to 21, 
23 and 24 may be conducted in the clinic or 
remotely by a home healthcare clinician or 
qualified site personnel with the agreement of 
the participant and the discretion of the 
investigator, and where it is available and 
locally approved by the Competent Authority 
and/or Ethics Committee/Institutional Review 
Board. 
Clarified that remote visits 
may also be conducted by 
qualified site staff where 
available and approved. 
. 
39 
Table 4, Schedule of 
Procedures, Part 2  
(table note) 
Visits 26 to 28, 30, 31, 33, 34, 36, 37, 
39 to 41, 43, and 44 may be conducted 
in the clinic or remotely by a home 
healthcare clinician.  Remote visits may 
include a telehealth visit with the 
investigator as needed. 
Visits 26 to 28, 30, 31, 33, 34, 36, 37, 39 to 
41, 43, and 44 may be conducted in the clinic 
or remotely by a home healthcare clinician or 
qualified site personnel with the agreement of 
the participant and the discretion of the 
investigator, and where it is available and 
locally approved by the Competent Authority 
and/or Ethics Committee/Institutional Review 
Board. Remote visits may include a telehealth 
visit with the investigator as needed. 
 
39 
Table 4, Schedule of 
Procedures, Part 2, 
(footnote b) 
During the study drug-free Follow-up 
Period I, 3 visits will occur to obtain the 
3 serum creatinine values for 
During the study drug-free Follow-up Period I, 
3 visits will occur to obtain the 3 serum 
creatinine values for calculation of eGFR to 
Corrected endpoint for 
Part 2 of the study. 


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Explanation 
calculation of eGFR to determine the 
primary endpoint.  At the final…   
determine the primary endpoint key 
comparison endpoint.  At the final… 
54 
Protocol Section 
2.2.1.3, Secondary 
Efficacy Endpoint 
The annualized rate of change (slope) 
in on-treatment eGFR, based on all on-
treatment eGFR determinations during 
the Double-Blind, Randomized 
Treatment Period in Part 1, calculated 
from the CKD-EPI equation for serum 
creatinine; 
 
The annualized rate of change from 
baseline in TKV, determined by MRI, 
during Follow-up Period I. 
The annualized rate of change (slope) from 
baseline in on-treatment eGFR, based on all 
on-treatment eGFR determinations during the 
Double-Blind, Randomized Treatment Period 
in Part 1, calculated from the CKD-EPI 
equation (CKD-EPIcr_R) for serum creatinine. 
 
The annualized rate of change from baseline 
in TKV, determined by MRI, during Follow-up 
Period I. 
Clarified the method of 
calculating the eGFR for 
the primary endpoint. 
 
Removed reference to rate 
of change from baseline 
for TKV analysis. 
56 
Protocol Section 
2.2.2.6, Population 
Pharmacokinetics 
 
2.2.2.6 Population Pharmacokinetics 
 
Area under the plasma concentration-
time curve during the dosing interval. 
 
Maximum plasma concentration. 
 
For completeness, a 
population PK-related 
endpoint has been added 
for Part 2 of the study. 
57 
Protocol Section 3.1.1, 
Overview of Study 
Design 
Approximately 2000 participants with 
ADPKD  will be screened in order to 
randomize 1200 participants to lixivaptan 
or placebo in a 2:1 ratio in Part 1 of the 
study….. 
 
Approximately 2000 2250 participants with 
ADPKD will be screened in order to 
randomize 1200 1350 participants to 
lixivaptan or placebo in a 2:1 ratio in Part 1 of 
the study…. 
Participants who have not discontinued due to 
an adverse event or withdrawn consent will 
continue into the 2- to 4-week Lixivaptan Re-
titration Period to initiate Part 2 of the study. 
Dosing with lixivaptan will start at Level 1 
(50 mg BID) for all participants in Part 2 and 
will be increased weekly until the dose level 
taken at the end of the Double-blind, 
Randomized Treatment Period is achieved. 
Lixivaptan treatment will continue for 52 
weeks during the Maintenance Treatment 
Period after which study drug will be held, and 
final assessments obtained off-treatment over 
Text to briefly summarize 
Part 2 of the study has 
been added for 
completeness. 


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Explanation 
3 visits starting on the 8th day after the last 
dose of double-blind study drug through the 
28th day after the last dose of study drug. 
59 
Protocol Section 3.1.2, 
Detailed Study Design 
Placebo Run-in Period (Visit 3): During 
the 1-week Placebo Run-in Period, 
participants will receive single-blind 
placebo and take 4 capsules twice daily. 
At the end of the week, participants will 
attend Visit 3… 
Placebo Run-in Period (Visit 3): During the 1-
week Placebo Run-in Period, participants will 
receive single-blind placebo and take 4 
capsules twice daily. At the end of the 1-week 
Placebo Run-in Period, participants will attend 
Visit 3… 
Clarification of study 
period 
62 
Protocol Section 3.2, 
Rationale for Study 
Design 
A placebo-controlled, double-blind 
assessment of lixivaptan is the preferred 
study design for demonstrating the 
efficacy and safety of the drug in the 
treatment of patients with ADPKD.  This 
type of design was used both in the 
TEMPO 3:4 and REPRISE studies to 
assess the efficacy and safety of 
tolvaptan.  Furthermore, following the 
double-blind phase of the study with a 
52-week open label treatment phase 
allows for the demonstration of the 
durability of effect of lixivaptan….   
A placebo-controlled, double-blind 
assessment of lixivaptan is the preferred study 
design for demonstrating the efficacy and 
safety of the drug in the treatment of patients 
with ADPKD.  This type of design was used 
both in the TEMPO 3:4 and REPRISE studies 
to assess the efficacy and safety of tolvaptan.  
Furthermore, following the double-blind phase 
of the study with a 52-week open label 
treatment phase allows for the demonstration 
of the durability of effect of lixivaptan as well 
as assessment of long-term safety….   
Clarified that long term 
safety will also be 
assessed as part of Part 2 
of the study. 
67 
Protocol Section 4.2.2, 
Screening and Run-in 
Titration Failures 
4.2.2 Screening and Run-in/Titration 
Failures 
.… During the Screening Period, 
participants who withdraw their 
consent or fail to meet all of the 
entry criteria to participate in the 
study will be designated as 
“Screen failures.”  Screen failures 
will be recorded as such on the 
electronic Case Report Form 
(eCRF)... 
 
4.2.2 Screening and Placebo Run-
in/Lixivaptan Titration Failures 
.… During the Screening Period, 
participants who withdraw their consent 
or fail to meet all of the entry criteria to 
participate in the study will be 
designated as “Screen failures.” These 
participants will not complete an ET visit 
(Visit 22). Screen failures will be 
recorded as such on the electronic Case 
Report Form (eCRF)... 
 
Text revised to clarify that 
screen failures do not 
undergo early termination 
procedures. 
 
Text revised for 
consistency and to align 
with the case report form. 


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Explanation 
Participants who discontinue or are 
discontinued after screening but before 
randomization (i.e., during the Placebo 
Run-in Period or Lixivaptan Titration 
Period) will be considered “Run-
in/Titration failures.”  A participant may 
be considered a “Run-in/Titration 
failure” for the following reasons: 
 
Participant does not meet entry 
requirements (i.e., participant cannot 
tolerate study drug as specified for a 
particular pre-randomization period); or 
 
Participant decides to formally 
withdraw consent and/or fails to return 
for subsequent appointments at the trial 
site; or 
 
Participant experiences an AE or 
SAE that precludes further 
participation; or 
 
The Investigator considers the 
participant unsuitable for further 
participation. 
Run-in/Titration failures will be recorded
as such on the eCRF. Run-in/Titration 
Failures will complete an ET visit (Visit 
22) upon withdrawal from the trial and 
within 7 days of the last dose of study 
drug. The ET visit assessments for Part 
1 are delineated in the Schedule of 
Procedures – Part 1.  Run-in/Titration 
Failures are not required to complete 
Follow-up Period I, however, Run-
in/Titration failures with ongoing AEs 
will continue to be followed according 
to the instructions in Section 7.3.8.7. 
Participants who discontinue or are 
discontinued after screening but before 
randomization (i.e., during the Placebo Run-in 
Period or Lixivaptan Titration Period) will be 
considered “Placebo Run-in/Lixivaptan 
Titration failures.”  A participant may be 
considered a “Run-in/Titration failure” for the 
following reasons: 
 
Participant does not meet entry 
requirements (i.e., participant cannot tolerate 
study drug as specified for a particular pre-
randomization period); or 
 
Participant decides to formally withdraw 
consent and/or fails to return for subsequent 
appointments at the trial site; or 
 
Participant experiences an AE or SAE 
that precludes further participation; or 
The Investigator considers the participant 
unsuitable for further participation 
Run-in/Titration failures will be recorded as 
such on the eCRF. Placebo Run-in/Lixivaptan 
Titration Failures will complete an ET visit 
(Visit 22) upon withdrawal from the trial and 
within 7 days of the last dose of study drug. 
The ET visit assessments for Part 1 are 
delineated in the Schedule of Procedures – 
Part 1. Placebo Run-in/Lixivaptan Titration 
failures will not are not required to participate 
in complete Follow-up Period I, however, 
Placebo Run-in/Lixivaptan Titration failures 
with ongoing AEs will continue to be followed 
according to the instructions in Section 
7.3.8.7. 
 


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Version 2.0, Dated 01FEB2022 
Explanation 
81 
Protocol Section 6.1.1 
Visit 1a 
 
Collect body weight and height 
measurements; enter in the eCRF 
to calculate BMI. 
 
Collect body weight and height 
measurements; enter in the eCRF to 
calculate BMI will be auto-calculated by 
the EDC system. 
Text revised to reflect that 
height is not entered in the 
eCRF (entered in IRT); 
upon entering height in 
IRT and weight in the 
eCRF, BMI will be auto-
calculated by the EDC 
system. 
84 
Protocol Section 6.2, 
Placebo Run-in Period 
and Visit 3 
 
Review the mean eGFR from 
Visits 1a and 2 or Visits 1b and 2, 
if Visit 1b was required.  If less 
than 25 ml/min/1.73 m2 or greater 
than 90 ml/min/1.73 m2, complete 
procedures for ET visit (Visit 22) 
and contact the IRT to discontinue 
the participant from the study.  
Participant will not be required to 
complete the Follow-up Period. 
 
 
Review the mean eGFR (based on 
serum creatinine) from Visits 1a and 2 
or Visits 1b and 2, if Visit 1b was 
required.  If less than 25 ml/min/1.73 m2 
or greater than 90 ml/min/1.73 m2, 
complete procedures for ET visit (Visit 
22) and contact the IRT to discontinue 
the participant from the study and 
complete early termination procedures 
(Section 6.4.2).  Participant will not be 
required to complete participate in the 
Follow-up Period. 
 
Review ALT, AST, and total bilirubin 
from Visit 2.  If ALT, AST, or total 
bilirubin >1.2 x ULN complete 
procedures for ET visit (Visit 22) and 
contact the IRT to discontinue the 
participant from the study and complete 
early termination procedures (Section 
6.4.2).  Participant will not participate in 
the Follow-up Period. 
Text clarifications added 
regarding eGFR and liver 
enzyme-related eligibility 
criteria. 
 
Text added to clarify that 
participants discontinuing 
after enrollment, but prior 
to randomization undergo 
early termination 
procedures (V22) only, 
without subsequently 
entering the follow-up 
period. 
87 
Protocol Section 6.3.1, 
Visits 4 to 8 
(Lixivaptan Titration 
Period) 
At Visit 4, document CKD Stage based 
on mean eGFR calculated from Visits 
1a, 2, and 3 or Visits 1b, 2, and 3 (if 
Visit 1b was required). 
o 
CKD Stage 2: eGFR 60 to 89 
ml/min/1.73 m2 
 
At Visit 4, document CKD Stage based on 
mean eGFR calculated from Visits 1a, 2, and 
3 or Visits 1b, 2, and 3 (if Visit 1b was 
required). 
o 
CKD Stage 2: eGFR 60 to 89 90 
ml/min/1.73 m2 
Expand threshold for CKD 
Stage 2 to be inclusive of 
90 ml/min/1.73 m2 for 
stratification purposes. 


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Explanation 
98 
Protocol Section 6.7.2  
Visit 42/Early 
Termination (Part 2) 
Visit 42 is the end of the Maintenance 
Period and will also serve as the Early 
Termination visit for Part 2 of the study. 
For participants completing the 
Maintenance Period, the visit will occur 
at Week 52 ± 3 days.   
Visit 42 is the end of the Maintenance Period 
and will also serve as the Early Termination 
visit for Part 2 of the study. For participants 
completing the Maintenance Period, the visit 
will occur at Week 52 104 ± 3 days.   
Correction of typo 
104 
Protocol Section 7.1.2, 
MRI Assessment 
The MRI acquisition protocol will be 
detailed in the study imaging manual.  
MRI images will be sent to a central 
imaging vendor for a) quality control; b) 
determination of Mayo Clinic ADPKD 
classification (Screening only); and c) 
measurement of TKV and LV. 
The MRI acquisition protocol will be detailed in 
the study imaging manual.  MRI images will be 
sent to a blinded central imaging vendor for a) 
quality control; b) determination of Mayo Clinic 
ADPKD Image Classification (Class 1 [typical] 
or Class 2 [atypical] at Screening only); and c) 
measurement of TKV and LV. 
Text revised to clarify that 
central imaging vendor will 
be blinded to study 
treatment and to specify 
the Mayo Clinic ADPKD 
Image Classification that 
the central imaging vendor 
will provide. 
105 
Protocol Section 7.2.3 
ADPKD- Pain and 
Discomfort Scale 
Protocol Section 7.2.4, 
ADPKD- Urinary 
Impact Scale 
Protocol Section 7.2.4, 
ADPKD- Urinary 
Impact Scale 
 
In this study, participants will directly record 
their responses into an electronic data capture 
device (i.e., tablet).  During remote visits, 
participants will record their responses on a 
paper copy, which will later be transcribed into 
the database by site personnel. 
Added clarity regarding 
collection of patient-
reported outcome (PRO) 
measures. 
107 
Protocol Section 7.3.3, 
Vital Sign 
Measurements 
Any confirmed, clinically significant vital 
sign measurements must be recorded 
as medical history during the Screening 
and Baseline Periods and as an AE 
after the start of study drug. 
Any confirmed, clinically significant vital sign 
measurements must should be recorded as 
medical history during the at Screening Visit 
1a and Baseline Periods and as an AE 
thereafter the start of study drug. 
Clarified the guidance for 
recording clinically 
significant vital sign 
measurements as medical 
history vs. adverse events. 
108 
Protocol Section 7.3.4, 
12-Lead ECGs 
ECGs will be transmitted electronically 
to the central ECG laboratory for 
analysis according to the instructions 
provided by the laboratory to be read by 
a cardiologist….All CS findings will be 
reported as medical history during the 
Screening Period and as AEs after the 
start of study drug. 
ECGs will be transmitted electronically to the 
central ECG laboratory for analysis according 
to the instructions provided by the laboratory 
to be read by a cardiologist….All CS findings 
will should be reported as medical history 
during the at Screening Period Visit 1a and as 
AEs thereafter the start of study drug. 
Clarified the guidance for 
recording clinically 
significant events as 
medical history versus 
adverse events. 


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Explanation 
108 
Protocol Section 7.3.5, 
Clinical Laboratory 
Tests 
Blood and urine specimens will be 
collected for clinical laboratory 
determinations….  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…. 
Blood and urine specimens will be collected 
for clinical laboratory determinations… 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.  All CS findings should be 
reported as medical history at Screening Visit 
1a and as AEs thereafter…..  
Added guidance regarding 
reporting of clinically 
significant events as 
medical history versus 
adverse events 
109 
Protocol Section 
7.3.5.1, Sample 
Collections. 
 
Participant age and year of birth will be 
collected at the time of sample collection and 
reported on the requisition form. 
Clarified that participant 
age and year of birth will 
be collected and reported 
on each requisition form at 
the time of laboratory 
sample collection. 
112 
Protocol Section 
7.3.7.1.2, Liver Test 
Abnormalities during 
the Lixivaptan Titration 
Period 
7.3.7.1.2 Liver Test Abnormalities 
during the Lixivaptan Titration Period 
Serum aminotransferase or total 
bilirubin levels that are 1× ULN to 2 × 
ULN during the Lixivaptan Titration 
Period will require holding the dose 
constant and a discussion with the 
medical monitor. Levels exceeding 2 × 
ULN during the Lixivaptan Titration 
Period will require reducing the dose or 
discontinuation of study drug 
(randomization will not occur) 
depending on the extent of the elevation 
and in consultation with the medical 
monitor.... 
7.3.7.1.2 Liver Test Abnormalities during 
the Placebo Run-in and/or 
Lixivaptan Titration Period 
Serum aminotransferase or total bilirubin 
levels that are 1 ≥1.2× ULN to 2 × ULN during 
the Placebo Run-in and/or Lixivaptan Titration 
Period will require holding the dose constant 
and a discussion with the medical monitor. 
Levels exceeding 2 × ULN during the Placebo 
Run-in and/or Lixivaptan Titration Period will 
require reducing the dose or discontinuation of 
study drug (randomization will not occur) 
depending on the extent of the elevation and 
in consultation with the medical monitor... 
Text has been updated to 
clarify liver enzyme 
thresholds apply during 
the Placebo Run-in Period 
in addition to the 
Lixivaptan Titration Period. 
123 
Protocol Section 8.5.1, 
Annualized Rate of 
Change (Slope) in 
eGFR on Treatment 
In order to assess the linear effect 
(slope) of lixivaptan based on the on-
treatment eGFR data, an analysis 
utilizing a mixed-effects model for 
repeated measures (MMRM) will be 
performed on the observed changes 
from baseline (mean of the 3 eGFR 
determinations obtained during the 
In order to assess the linear effect (slope) of 
lixivaptan based on the on-treatment eGFR 
data in all randomized participants, an 
analysis utilizing a mixed-effects model for 
repeated measures (MMRM) will be 
performed on the observed changes in eGFR 
from baseline (mean of the 3 eGFR 
determinations obtained during the Screening 
The planned secondary 
analysis of the annualized 
rate of change (slope) in 
eGFR during treatment 
has been clarified. 


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Version 2.0, Dated 01FEB2022 
Explanation 
Screening and Placebo Run-in Periods) 
to Weeks 0 to 52 of the Double-Blind, 
Randomized Treatment Period in 
eGFR….   
and Placebo Run-in Periods) to Weeks 0 to all 
Double-Blind Treatment Period visits up to 
Week 52 of the Double-Blind, Randomized 
Treatment Period in eGFR….   
123 
Protocol Section 8.5.2, 
Annualized Rate of 
Change in TKV 
8.5.2 Annualized Rate of Change in 
TKV 
The 2nd secondary efficacy endpoint is 
the rate of change in TKV (normalized 
as a percentage) from baseline for 
lixivaptan relative to placebo….  
A linear mixed effect model will be fitted 
to the log transformed TKV data. 
Further detail will be provided in the 
statistical analysis plan.   
8.5.2 Annualized Rate of Change in TKV 
The 2nd secondary efficacy endpoint is the rate
of change in height-adjusted TKV (normalized 
as a percentage) from baseline for lixivaptan 
relative to placebo….  
A linear mixed effect model will be fitted to the 
log transformed TKV data ANCOVA will be 
used to analyze the log transformed TKV 
data.  Further details will be provided in the 
statistical analysis plan. 
Clarified that height-
adjusted TKV will be 
analyzed and clarified the 
analysis to be used for 
these data. 
125 
Protocol Section 8.7.1, 
Annualized Rate of 
Change (Slope) in 
eGFR on Treatment 
In order to assess the linear effect 
(slope) of lixivaptan based on the on-
treatment eGFR data in Part 2…. A 
linear contrast of the treatment 
differences for these 12 monthly visits 
will be used for this analysis. 
In order to assess the linear effect (slope) of 
lixivaptan based on the on-treatment eGFR 
data in Part 2…. A linear contrast of the 
treatment differences for these 12 monthly 
visits will be used for this analysis.The 
estimated annualized rate of change (slope) 
from this analysis will be compared to the 
corresponding results in Part 1. 
Text regarding analysis of 
annualized rate of change 
(slope) in eGFR treatment 
has been clarified. 
125 
Protocol Section 8.7.2, 
Annualized Rate of 
Change in TKV 
8.7.2 Annualized Rate of Change in 
TKV 
The TKV measurements at Follow-up 
Periods I and II will be log10 
transformed. 
8.7.2 Annualized Rate of Change in TKV 
The height-adjusted TKV measurements at 
Follow-up Periods I and II will be log10 
transformed. 
Corrected title/clarified 
analysis 
125 
Protocol Section 8.9.2, 
ADPKD-IS, ADPKD-
PDS, and ADPKD-UIS 
 
Detailed descriptions of analyses of 
these questionnaires will be specified in 
a prospective health outcomes analysis 
plan. 
Detailed descriptions of analyses of these 
questionnaires will be specified in a 
prospective health outcomes analysis plan the 
SAP. 
Clarified that the details 
surrounding the health-
related quality of life 
questionnaires will be 
included in the SAP. 
125 
Protocol Section 
8.10.1, Annualized 
Rate of Change in LV 
Protocol, Section 8.10.1, Annualized 
Rate of Change in LV 
Protocol, Section 8.10.1, Annualized Rate 
of Change in LV 
Corrected title/clarified 
analysis. 


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Explanation 
125 
Protocol Section 
8.10.2, Urine 
Osmolality 
Descriptive statistics for the change 
from baseline in morning spot urine 
osmolality will be presented by 
treatment group for the Safety Analysis 
Set in Part 1 and overall, for the Long-
term Safety Analysis Set in Part 2 at 
each scheduled time point.   
Descriptive statistics for the change from 
baseline in morning spot urine osmolality will 
be presented by treatment group for the 
Treated Safety Analysis Set in Part 1 and 
overall, for the Long-term Safety Analysis Set 
in Part 2 at each scheduled time point.   
Corrected name of the 
analysis set for 
consistency. 
126 
Protocol Section 8.11, 
Subgroup Analyses 
Descriptive statistics will be presented 
for the primary efficacy estimand for age 
(≤50 years, >50 years)….  
Descriptive statistics will be presented for the 
primary and secondary efficacy estimand 
analyses for age (≤50 years, >50 years)….  
Clarified that subgroup 
analyses will also be 
performed for secondary 
efficacy endpoints. 
 
 
 
 
 
 
 


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Clinically-relevant Changes 
This section describes changes that affect safety or study conduct. 
Page 
Section 
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Version 2.0, Dated 01FEB2022 
Rationale 
Multiple 
Global 
Visit 3 will occur at the end of the 
Placebo Run-in Period (± 3 days) 
Visit 3 will occur at the end of the 
Placebo Run-in Period (± 3 2 days) 
Visit windows for the Placebo 
Run-in Period were shortened 
to maintain consistency with 
visit windows for the Lixivaptan 
Titration period. 
Multiple 
Global 
Visits 4, 5, 6, 7, and 8 (Visit 8 only if 
needed) will occur weekly ± 3 days 
for titration… 
 
Visits 4, 5, 6, 7, and 8 (Visit 8 only if 
needed) will occur weekly ± 3 2 days 
for titration… 
 
Visit windows shortened for 
visits occurring at weekly 
intervals to ensure at least 5 
days of exposure per dose 
level, allowing more confidence 
in the assessment of tolerability 
at each dose. 
Multiple 
Global 
…Visits 26 to 29 will occur weekly ± 
3 days... 
 
…Visits 26 to 29 will occur weekly ± 
3 2 days... 
 
Visit windows shortened for 
visits occurring at weekly 
intervals to ensure a minimum 
of 5 days exposure at each 
dose level.  
Multiple 
Global 
… calculated by the Chronic Kidney 
Disease Epidemiology Collaboration  
equation (CKD-EPI) from serum 
creatinine values… 
… calculated by the 2021 Chronic 
Kidney Disease Epidemiology 
Collaboration (CKD-EPI) eGFR 
creatinine equation refit without the 
race variable (CKD-EPIcr_R) equation 
from serum creatinine values 
Updated the CKD-EPI equation 
for calculation of serum 
creatinine- based eGFR from 
the 2009 CKD-EPI equation to 
the 2021 CKD-EPIcr_R 
equation, without the race 
variable.  eGFR calculated 
from this revised equation will 
be used for eligibility 
determination as well as all 
efficacy analyses. 
Multiple 
Global 
Participants with appropriate blood 
pressure control (as defined by 
KDIGO) including those on ACEi or 
ARB treatment (unless not 
considered appropriate) and not 
receiving a diuretic will proceed to V2 
Participants with appropriate blood 
pressure control for a minimum of 3 
weeks prior to enrollment (Visit 2) (as 
defined by the 2021 KDIGO guideline) 
including those on stable ACEi or 
ARB treatment (unless not considered 
Added timeframe for 
appropriate blood pressure 
control for study eligibility for 
participants who do not require 
blood pressure medication 
optimization and clarified it for 


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Version 2.0, Dated 01FEB2022 
Rationale 
3 to 5 weeks after Visit 1a… 
Participants who need to be 
discontinued from diuretic therapy 
and/or have their anti-hypertensive 
therapy optimized due to inadequate 
BP control (as defined by KDIGO) will 
return for V1b… 
appropriate) and not receiving a 
diuretic will proceed to V2 3 to 5 
weeks after Visit 1a… 
 
Participants who need to be 
discontinued from diuretic therapy 
and/or have their anti-hypertensive 
therapy optimized due to inadequate 
BP control (as defined by the 2021 
KDIGO guideline) will return for 
unscheduled visits for blood pressure 
monitoring following Visit 1a.  Once 
their treatment and blood pressure 
have been stable for a minimum of 3 
weeks, they will return for V1b… 
those who require blood 
pressure medication 
optimization. 
 
Those participants requiring 
blood pressure medication 
optimization will attend 
Unscheduled Visits for blood 
pressure monitoring until blood 
pressure has been stable for a 
minimum of 3 weeks, at which 
time Visit 1b will be completed. 
Multiple 
Global 
 
serum cystatin C 
 
Part 1: Added serum cystatin C to 
blood samples collected during the 
Screening Period (V1a, V1b, V2), 
Placebo Run-in Period (V3), and 
during the Follow-up Period (V23, 
V24, and V25) to support exploratory 
efficacy analyses. 
Serum cystatin C will be assessed at 
the time-points specified in the 
Schedule of Procedures - Part 1 
(Table 3) of the study protocol. 
Protocol text has been updated 
globally to reflect collection of blood 
samples for serum cystatin C 
assessments as applicable.   
Part 2:  Added serum cystatin C to 
blood samples collected during 
Follow-up Period II (V43, V44, and 
V45) to support exploratory efficacy 
analyses. 
Collection of serum cystatin C, 
in addition to serum creatinine 
for the determination of eGFR 
for exploratory analyses based 
on a novel equation, CKD-
EPIcr-cys has been added to 
the study at Visits 1a, 1b, 2, 3, 
23, 24, 25, 43, 44, 45.  Serum 
cystatin C is also to be collected
at the same time-points as 
serum creatinine in the event of 
a treatment interruption 
expected to last 7 or more days 
(Protocol Section 4.2.3). 
 


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Version 2.0, Dated 01FEB2022 
Rationale 
Serum cystatin C will be assessed at 
the time-points specified in the 
Schedule of Procedures - Part 2 
(Table 4) of the study protocol. 
Protocol text has been updated to 
reflect collection of blood samples for 
serum cystatin C assessments as 
applicable. 
Multiple 
Global 
 
serum sodium 
 
Part 1: Added serum sodium to 
chemistry blood samples collected 
during the Screening Period (V1a, 
V1b, V2), Placebo Run-in Period (V3), 
Lixivaptan Titration Period (V9), 
Double-blind Randomized Treatment 
Period (V10-21 and V22), and during 
the Follow-up Period (V25). 
Serum sodium will be assessed at the 
time-points specified in the Schedule 
of Procedures - Part 1 (Table 3) of the 
study protocol either as part of 
chemistry or liver chemistry testing. 
Protocol text has been updated to 
reflect additional serum sodium 
assessments as applicable.   
Part 2:  Added serum sodium to blood 
chemistry samples collected during 
the Lixivaptan Re-titration Period 
(V29), during the Maintenance 
Treatment Period (V30-V41 and 
V42/ET), and during the Follow-up 
Period II (V45). 
Serum sodium will be assessed at the 
time-points specified in the Schedule 
of Procedures - Part 2 (Table 4) of the 
study protocol either as part of 
Serum sodium assessments 
have been added during 
additional study visits in Parts 1 
and 2 of the study for increased 
safety monitoring. 
 


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chemistry or liver chemistry testing. 
Protocol text has been updated to 
reflect additional serum sodium 
assessments as applicable 
Multiple 
Global 
1200 randomized, Part 1 (estimated 
1080 will continue into Part 2) 
12001350 randomized, Part 1 
(estimated 1080 1215 will continue 
into Part 2) 
Sample size increased as a 
result of increasing the power in 
the statistical analysis to 90%.  
14 
Protocol Synopsis, Study 
Sites 
 
Approximately 200 sites worldwide 
Approximately 200 250 sites 
worldwide 
Increase the number of sites to 
250 to meet increased sample 
size requirements 
16, 53, 54 Protocol Synopsis, 
Objectives [Exploratory] 
[Part 1 (Year 1)] 
 
Protocol Section 2.1.1, 
Objectives of the Double-
Blind Phase (Part 1/Year 
1) 
 
Protocol Synopsis, 
Objectives [Exploratory 
[Part 2 (Year 2)] 
 
Protocol Section 2.1.2, 
Objectives of the Open-
Label Phase (Part 2/Year 
2) 
 
To evaluate the effect of lixivaptan on 
kidney function as assessed by eGFR 
using a novel serum creatinine and 
serum cystatin C-based Chronic 
Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation refit 
without the race variable (CKD-EPIcr-
cys_R) compared with placebo. 
 
To evaluate the effect of lixivaptan on 
kidney function as assessed by eGFR 
using the CKD-EPIcr-cys_R equation 
following 52 weeks of open-label 
treatment. 
Exploratory objectives related to 
eGFR based on a novel 
equation utilizing serum 
creatinine and serum cystatin 
C, (CKD-EPIcr-cys) have been 
added to Parts 1 and 2 of the 
study.  
17, 63 
Protocol Synopsis, 
Inclusion Criteria 
 
Protocol Section 4.1.1, 
Inclusion Criteria 
4. Mayo Clinic ADPKD classification 
of 1C, 1D, or 1E based on age and 
height-adjusted total kidney volume as 
determined by kidney MRI obtained 
during Screening by the central 
imaging vendor. 
4 3. At risk for rapid progression of 
ADPKD as based on the Mayo Clinic 
Image ADPKD classification of 1C, 
1D, or 1E based on age and height-
adjusted total kidney volume (TKV) as 
determined by kidney MRI obtained 
during Screening, where class (class 
1 [typical] as assessed versus class 2 
[atypical]) and TKV are determined by 
This criterion has been clarified 
to include participants at risk of 
rapid progression of ADPKD, 
which in this study is being 
assessed by Mayo Image 
Classification (MIC). In MIC, 
class 1 is typical ADPKD and 
class 2 is atypical ADPKD.  The 
MIC and TKV are determined by


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the a central imaging vendor. 
 
a central imaging vendor.    
17, 64 
Protocol Synopsis,  
 
Protocol Section 4.1.1, 
Inclusion Criteria 
5.   eGFR ≥25 mL/min/1.73 m2 and 
≤90 mL/min/1.73 m2 based on the 
mean of 2 eGFR determinations 
(Visits 1a and 2 or Visits 1b and 2, if 
Visit 1b is required) calculated by the 
Chronic Kidney Disease 
Epidemiology Collaboration  equation 
(CKD-EPI) from serum creatinine 
values obtained during Screening… 
5 4.   eGFR ≥25 mL/min/1.73 m2 and 
≤90 mL/min/1.73 m2 based on the 
mean of 2 eGFR determinations 
(Visits 1a and 2 or Visits 1b and 2, if 
Visit 1b is required) calculated by the 
2021 Chronic Kidney Disease 
Epidemiology Collaboration (CKD-
EPI) eGFR creatinine equation refit 
without the race variable 
(CKD-EPIcr_R) equation from serum 
creatinine values obtained during 
Screening...  
Calculation of eGFR in the 
inclusion criteria updated from 
the CKD-EPI to the 
CKD-EPIcr_R, which removes 
the race variable from the 
calculation of eGFR. 
17, 64 
Protocol Synopsis,  
 
Protocol Section 4.1.1, 
Inclusion Criteria 
6. 
Appropriate control of 
hypertension including an 
angiotensin converting enzyme 
inhibitor or angiotensin receptor 
blocker (unless not considered 
appropriate for the participant) as 
suggested by the Kidney Disease 
Improving Global Outcomes (KDIGO) 
“Clinical Practice Guideline for the 
Management of Blood Pressure in 
Chronic Kidney Disease,” without the 
use of a diuretic. 
6.5. Appropriate control of 
hypertension for a minimum of 3 
weeks including the use of an 
angiotensin converting enzyme 
inhibitor or angiotensin receptor 
blocker (unless not considered 
appropriate for the participant) as 
suggested by the 2021 Kidney 
Disease Improving Global Outcomes 
(KDIGO) “Clinical Practice Guideline 
for the Management of Blood 
Pressure in Chronic Kidney Disease,” 
without the use of a diuretic. 
Added a 3-week minimum 
timeframe of BP control for all 
participants. 
18, 64, 77 
 
 
 
 
 
 
 
 
Protocol Synopsis,  
 
Protocol Section 4.1.1, 
Inclusion Criteria 
 
Protocol Section 5.5, 
Prior and Concomitant 
Therapy 
 
 
7. 
Female participants must: 
 
not be pregnant, lactating, or 
breastfeeding.   
 
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)… 
 
hormonal contraceptives: 
7. 
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-
Text added within the Inclusion 
Criteria and protocol body to 
highlight the potential risk of 
estrogen-containing 
contraceptives and hormone 
replacement therapy on the risk 
of cyst growth and polycystic 
liver disease progression. 
 
Criterion text in Protocol 


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combined (estrogen and progestogen 
containing) hormonal contraception 
associated with inhibition of ovulation 
(i.e., oral, intravaginal, transdermal) 
progestogen-only hormonal 
contraception (i.e., oral, injectable, 
implantable).  
 
 
 
 
 
 
 
 
 
 
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   (Section 5.5).  The 
Investigator is responsible… 
 
bearing    
      potential (WOCBP)… 
 
hormonal contraceptives: 
combined (estrogen and progestogen 
containing) hormonal contraception 
associated with inhibition of ovulation 
(i.e., oral, intravaginal, transdermal); 
progestogen-only hormonal 
contraception (i.e., oral, injectable, 
implantable). Note: in women with 
severe polycystic liver disease, 
contraceptives containing estrogen 
(and hormone replacement therapy) 
may be involved in the development 
and growth of liver cysts and 
polycystic liver disease progression 
and should be discussed between the 
Investigator and the potential 
participant. 
 
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 (Section 5.5).  Note: 
in female participants with severe 
polycystic liver disease, 
contraceptives (and hormone 
replacement therapy) containing 
estrogen may be involved in the 
development and growth of liver cysts 
and polycystic liver disease 
progression and should be discussed 
between the Investigator and the 
potential participant.  The Investigator 
is responsible… 
Section 4.1.1 has been 
harmonized with text for same 
criterion in the Protocol 
Synopsis. 
 
 
 


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20, 66 
Protocol Synopsis,  
Study Population  
 
Protocol, Section 4.1.2, 
Exclusion Criteria. 
 
16. Prior use of conivaptan, 
somatostatin analogs (e.g., 
lanreotide, pasireotide, octreotide, 
etc.), metformin (except for diabetes), 
nicotinamide, bardoxolone, 
demeclocycline, mTOR kinase 
inhibitors (e.g., everolimus, sirolimus, 
etc.) within the 2 months prior to 
Screening Visit 1a. 
 
16. Prior use of conivaptan, 
somatostatin analogs (e.g., lanreotide, 
pasireotide, octreotide, etc.), 
metformin (except for diabetes), 
nicotinamide, bardoxolone, 
demeclocycline, or mTOR kinase 
inhibitors (e.g., everolimus, sirolimus, 
etc.), or KetoCitra™ or any  beta-
hydroxybutyrate (BHB) containing 
supplements within the 2 months prior 
to Screening Visit 1a. 
Updated inclusion criterion to 
reflect additional supplements 
that may confound safety or 
efficacy assessments in this 
study. 
20, 57 
Protocol Synopsis,  
Study Design  
 
Protocol, Section 3.1.1, 
Overview of Study 
Design 
Approximately 2000 participants with 
ADPKD meeting the entry criteria will 
be screened in order to randomize 
1200 participants to lixivaptan or 
placebo in a 2:1 ratio in Part 1 of this 
study.   
Approximately 2000 2250 participants 
with ADPKD meeting the entry criteria 
will be screened in order to randomize 
12001350 participants to lixivaptan or 
placebo in a 2:1 ratio in Part 1 of this 
study.   
Sample size increased as a 
result of increasing the power in 
the statistical analysis to 90%.  
 
26 
Protocol Synopsis, Study 
Drug, Dosage, and Route 
of Administration 
(Table 2) 
 
 
Table 2 has been revised to 
clarify dose re-titration during 
the Lixivaptan re-titration Period 
in Part 2, for participants in 
either the lixivaptan treatment 
arm in Part 1 or the placebo 
treatment arm in Part 1. 
27 
Protocol Synopsis, Study 
Assessments 
Safety: Liver chemistry tests (ALT, 
AST, total bilirubin, direct bilirubin, 
alkaline phosphatase), clinical 
laboratory parameters (hematology, 
non-hepatic clinical chemistry, and 
Safety: Liver chemistry tests (ALT, 
AST, total bilirubin, direct bilirubin, 
alkaline phosphatase), clinical 
laboratory parameters (hematology, 
non-hepatic clinical chemistry, 
Added serum sodium as an 
additional safety assessment at 
designated visits. 


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urinalysis), 12 lead ECGs, vital signs, 
physical examinations, adverse 
events (AEs), and serious adverse 
events (SAEs) 
including serum sodium and 
urinalysis), 12-lead ECGs, vital signs, 
physical examinations, adverse 
events (AEs), and serious adverse 
events (SAEs) 
27 
Protocol Synopsis, Study 
Assessments 
Exploratory: LV by MRI, urine 
osmolality 
Exploratory: LV by MRI, urine 
osmolality, serum creatinine with 
cystatin C- based eGFR 
Added serum creatinine with 
cystatin C- based eGFR as 
additional exploratory 
assessments. 
27, 54 
Protocol Synopsis, 
Criteria for Evaluation 
[Primary Efficacy 
Endpoint] 
 
Protocol Section 2.2.1.1, 
Primary Efficacy 
Endpoint- 
Primary Efficacy Endpoint: 
Annualized change in eGFR 
calculated from the CKD-EPI 
equation for serum creatinine from 
baseline… 
 
The primary endpoint is the 
annualized change in eGFR 
calculated from the CKD-EPI 
equation for serum creatinine from 
baseline… 
Primary Efficacy Endpoint: 
Annualized change in eGFR 
calculated from the 2021 CKD-EPI 
equation (CKD-EPIcr_R) for serum 
creatinine from baseline… 
 
The primary endpoint is the 
annualized change in eGFR 
calculated from the CKD-EPI CKD-
EPIcr_R equation for serum creatinine 
from baseline… 
Updated the CKD-EPI equation 
for calculation of serum 
creatinine- based eGFR for the 
primary efficacy endpoint from 
the 2009 CKD-EPI equation to 
the 2021 CKD-EPIcr_R 
equation, without the race 
variable. 
27, 121 
Protocol Synopsis,  
Statistical Methods, 
Sample Size (Part 1) 
 
 
 
 
 
 
 
 
 
 
 
 
Assuming a between-treatment group 
difference of -1.40 mL per minute per 
1.73 m2 and a randomization ratio of 
2:1 for lixivaptan to placebo, a 
sample size estimate of 1155 
participants (385 placebo participants 
and 770 lixivaptan participants) is 
required to achieve 85% power at a 
significance level of 0.01.  In order to 
compensate for possible missing 
data, this estimate has been adjusted 
up to 1200 participants (400 placebo 
participants and 800 lixivaptan 
participants).  It is estimated that 
approximately 2000 participants will 
need to be screened in order to 
randomize 1200 participants. 
Assuming a between-treatment group 
difference of -1.40 mL per minute per 
1.73 m2 and a randomization ratio of 
2:1 for lixivaptan to placebo, a sample 
size estimate of 11551314 
participants (385 438 placebo 
participants and 770 876 lixivaptan 
participants) is required to achieve 85 
90% power at a significance level of 
0.01.  In order to compensate for 
possible missing data drop outs, this 
estimate has been adjusted up to 
12001350 participants (400 450 
placebo participants and 800 900 
lixivaptan participants).  It is estimated 
that approximately 2000 2250 
participants will need to be screened 
Sample size increased as a 
result of increasing the power in 
the statistical analysis to 90%.  
 


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Protocol Section 8.1, 
Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part I: 
Based on the results of the REPRISE 
trial with tolvaptan, (Torres et al, 
2017) it is assumed that the standard 
deviation for the primary efficacy 
endpoint, change from baseline to 
post-treatment follow-up in mean 
eGFR, is 6.20 mL per minute per 
1.73 m2.  Assuming a between-
treatment group difference of -1.40 
mL per minute per 1.73 m2 and a 
randomization ratio of 2:1 for 
lixivaptan to placebo, a sample size 
estimate of 1155 participants (385 
placebo-treated participants and 770 
lixivaptan-treated participants) is 
required to achieve 85% power at a 
significance level of 0.01.  In order to 
compensate for possible missing 
data, this estimate has been adjusted 
up to 1200 participants (400 placebo 
participants and 800 lixivaptan 
participants).  It is estimated that 
approximately 2000 participants will 
need to be screened in order to 
randomize 1200 participants. 
A blinded sample size re-estimation 
(BSSR) to estimate the variance 
corresponding to the primary efficacy 
estimand is planned after 20% of the 
total randomized participants have 
completed Part 1 of the study or 
before screening for the study has 
ended. (Section 8.1). 
Part 2:  
in order to randomize 12001350 
participants. 
 
 
Part I1: 
Based on the results of the REPRISE 
trial with tolvaptan, (Torres et al, 
2017) it is assumed that the standard 
deviation for the primary efficacy 
endpoint, change from baseline to 
post-treatment follow-up in mean 
eGFR, is 6.20 mL per minute per 1.73 
m2.  Assuming a between-treatment 
group difference of -1.40 mL per 
minute per 1.73 m2 and a 
randomization ratio of 2:1 for 
lixivaptan to placebo, a sample size 
estimate of 1155 1314 participants 
(385 438 placebo-treated participants 
and 770 876 lixivaptan-treated 
participants) is required to achieve 85 
90% power at a significance level of 
0.01.  In order to compensate for 
possible missing data drop outs, this 
estimate has been adjusted up to 
1200 1350 participants (400 450 
placebo participants and 800 900 
lixivaptan participants).  It is estimated 
that approximately 2000 2250 
participants will need to be screened 
in order to randomize 1200 1350 
participants. 
A blinded sample size re-estimation 
(BSSR) to estimate the variance 
corresponding to the primary efficacy 
estimand is planned after at least 20% 
of the total randomized participants 


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This is a convenience sample based 
on the number of participants who 
elect to continue into Part 2.  It is 
estimated that approximately 1200 
participants will be randomized in 
Part 1.  All participants except those 
who discontinue due to an adverse 
event or withdraw consent will 
continue into Part 2.  Approximately 
90% (1080) of Part 1 participants are 
anticipated to continue into Part 2. 
have completed Part 1 of the study or 
before screening for the study has 
ended. (Section 8.1). 
Part 2:  
This is a convenience sample based 
on the number of participants who 
elect to continue into Part 2.  It is 
estimated that approximately 1200 
1350 participants will be randomized 
in Part 1.  All participants except those 
who discontinue due to an adverse 
event or withdraw consent will 
continue into Part 2.  Approximately 
90% (1080 1215) of Part 1 
participants are anticipated to 
continue into Part 2. 
28, 54, 
122 
Protocol Synopsis, 
Statistical Methods 
[Primary Efficacy 
Analysis Part 1] 
 
 
 
 
 
 
 
 
 
Protocol Section 2.2.1.1, 
Primary Efficacy Endpoint 
 
 
 
 
Baseline eGFR is defined as the 
mean of the 3 eGFR assessments 
obtained during the Screening and 
single-blind, Placebo Run-in 
Periods... The post-treatment follow-
up eGFR is defined as the mean of 3 
eGFR assessments obtained during 
the Follow-up Period I or the 
equivalent off-therapy eGFR 
determinations if a participant 
discontinues study drug earlier. 
 
 
 
 
The primary endpoint is the 
annualized change in eGFR 
calculated from the CKD-EPI 
equation for serum creatinine from 
baseline (mean of 3 eGFR 
determinations obtained during 
Baseline eGFR is defined as the mean 
of the 3 eGFR assessments obtained 
during the Screening and single-blind, 
Placebo Run-in Periods… The post-
treatment follow-up eGFR is defined 
as the mean of 3 eGFR assessments 
obtained during the Follow-up Period I 
or the equivalent off-therapy eGFR 
determinations if a participant 
discontinues study drug 
earlier.  The eGFR for the primary 
analysis will be based on serum 
creatinine using the CKD-EPIcr_R 
equation. 
 
The primary endpoint is the 
annualized change in eGFR 
calculated from the CKD-EPI 
CKD-EPIcr_R equation for serum 
creatinine from baseline (mean of 3 
eGFR determinations obtained during 
Clarified that the primary 
endpoint analysis will be based 
on the CKD-EPIcr_R equation. 
 


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Protocol Section 8.4.1, 
Primary Endpoint 
Analysis 
 
 
Screening and Placebo Run-in 
Periods (Visits 1a/1b (if required), 
Visit 2, and Visit 3) to final 
assessment… 
Baseline eGFR is defined as the 
mean of the 3 eGFR determinations 
obtained during the Screening and 
Placebo Run-in Periods. The primary 
efficacy analysis will utilize… 
Screening and Placebo Run-in 
Periods (Visits 1a/1b (if required), Visit 
2, and Visit 3) to final assessment… 
 
 
The primary endpoint analysis is 
based on the eGFR calculated from 
the CKD-EPIcr_R equation.  Baseline 
eGFR is defined as the mean of the 3 
eGFR determinations obtained 
during the Screening and Placebo 
Run-in Periods. The primary efficacy 
analysis will utilize… 
33, 82, 83 Table 3. Schedule of 
Procedures – Part 1 
 
Protocol Section 6.1.2, 
Visit 1b  
 
Protocol Section 6.1.3, 
Visit 2 
 
 
 
 Collect and review any additional  
medical history since prior visit. 
Schedule of Procedures updated to 
remove Medical History review from 
visits 1b and 2. 
   Collect and review any additional  
medical history since prior visit. 
Removed collection of medical 
history from Visits 1b and 2 as 
all medical history should be 
collected at Visit 1a.. 
34, 36, 38, 
40, 89 
Table 3. Schedule of 
Procedures - Part 1 
(footnote e) 
 
 
 
 
 
 
 
 
 
 
 
V10-V21 
V10-V21e 
 
Telephone contact e 
 
e. As participants transition into the 
Double-Blind Randomized 
Treatment Period, with visits 
scheduled every 4 weeks, 
participant follow-up via a telephone 
contact is strongly encouraged.  
Telephone contacts should be 
repeated throughout the study as 
needed.  Any contact with the 
participant via telephone will be 
recorded in the source document 
 
Added optional telephone 
contacts as distinct study 
assessments at Visits 10 to 25. 
Telephone contacts are 
strongly encouraged 
throughout the study, as 
needed. 
 
Added footnote “e” to 
encourage sites to contact 
participants to assess 
tolerability as they transition into 
DBTP where visits are 4 weeks 
apart (and throughout the study 
as needed). 


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Table 4. Schedule of 
Procedures - Part 2 
(footnote l) 
 
 
 
 
 
 
 
 
 
Protocol Section 6.3.2 
Visit 9/Last Titration Visit 
 
 
 
 
 
 
 
 
 
Telephone contactl 
 
 
l.  Participant follow-up via a 
telephone contact between study 
visits is strongly encouraged. 
Telephone contacts should be 
repeated throughout the study as 
needed. Any contact with the 
participant via telephone will be 
recorded in the source document. 
 
 
Note: As participants transition into 
the Double-Blind Randomized 
Treatment Period with visits 
scheduled every 4 weeks, it is 
strongly encouraged to follow up with 
participants via a telephone contact to 
ascertain continued tolerability.  
Telephone contacts should be 
repeated throughout the study as 
needed and recorded in the source 
document. 
As result of this insertion, all 
subsequent footnotes have re-
ordered. 
 
Added optional telephone 
contacts as a distinct study 
assessments at Visits 26 to 44. 
Telephone contacts are 
strongly encouraged 
throughout the study, as 
needed. 
 
Added footnote “l” to Table 4 to 
encourage telephone contacts  
 
Corresponding text has been 
added for consistency to 
Section 6.3.2. 
 
 
 
 
 
 
 
 
 
36, 39, 68, 
92, 100 
 
Table 3. Schedule of 
Procedures – Part 1 
(footnote f) 
 
 
 
 
 
f. 
Participants who discontinue 
study drug or withdraw from the study 
at any time after the start of the 
Placebo Run-In Period should 
undergo V22/ET procedures within 7 
days of the last dose of study drug. 
Randomized participants should 
additionally continue into Follow-up 
Period I for final assessments of 
f. 
Participants who discontinue 
study drug or withdraw from the 
study at any time after the start of 
the Placebo Run-In Period should 
undergo V22/ET procedures 
within 7 days of the last dose of 
study drug. Randomized 
participants should additionally 
continue into Follow-up Period I 
Following Regulatory Authority 
feedback, MRI data to be 
collected for all participants with 
a study drug interruption 
expected to last 7 or more days. 
Relevant text for Parts 1 and 2 
of the study have been updated 
accordingly. 
 


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Table 4. Schedule of 
Procedures – Part 2 
(footnote c) 
 
 
 
 
 
 
 
 
Protocol Section 4.2.3 
Treatment Interruption 
 
 
 
 
 
 
 
 
 
 
Protocol Section 4.2.4 
Treatment 
Discontinuation 
 
 
safety and efficacy.  For participants 
who permanently discontinue 
treatment prior to Visit 12 (Week 12), 
the post-baseline MRI scheduled for 
Visit 25 is not required. 
 
 
c. 
Participants who discontinue 
from the study should undergo 
V42/ET procedures within 7 days of 
the last dose of lixivaptan and 
subsequently continue into Follow-up 
Period II for final assessments of 
safety and efficacy.  For participants 
who permanently discontinue study 
drug prior to Visit 32 (Week 64), the 
post-baseline MRI scheduled for Visit 
45 is not required. 
 
If a study drug interruption is expected 
to last 7 or more consecutive days… 
If, in the Investigator’s opinion, the 
treatment interruption is expected to 
be prolonged (i.e., >4 weeks in 
duration) or permanent, then a 
postbaseline MRI should also be 
obtained if the study drug interruption 
occurs at or after Visit 12 (Week 12) in 
Part 1 or at or after Visit 32 (Week 64) 
in Part 2. 
 
 
Participants may elect to stop 
treatment permanently before the end 
of the study for various 
reasons...Participants who 
permanently discontinue study drug 
prior to Visit 12 (Week 12 in Part 1) or 
Visit 32 (Week 64 in Part 2) will forego 
for final assessments of safety 
and efficacy.  For participants who 
permanently discontinue 
treatment prior to Visit 12 (Week 
12), the post-baseline MRI 
scheduled for Visit 25 is not 
required. 
c.    Participants who discontinue 
from the study should undergo 
V42/ET procedures within 7 days of 
the last dose of lixivaptan and 
subsequently continue into Follow-
up Period II for final assessments of 
safety and efficacy.  For participants 
who permanently discontinue study 
drug prior to Visit 32 (Week 64), the 
post-baseline MRI scheduled for 
Visit 45 is not required. 
 
If a study drug interruption is 
expected to last 7 or more 
consecutive days…If, in the 
Investigator’s opinion, the treatment 
interruption is expected to be 
prolonged (i.e., >4 weeks in 
duration) or permanent, then a 
postbaseline MRI should also be 
obtained if the study drug 
interruption occurs at or after Visit 
12 (Week 12) in Part 1 or at or after 
Visit 32 (Week 64) in Part 2. 
 
 
Participants may elect to stop 
treatment permanently before the end 
of the study for various 
reasons...Participants who 
permanently discontinue study drug 
 


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Protocol Section 6.4.2   
Visit 22/Early 
Termination  
 
 
 
 
 
 
 
 
 
 
Protocol Section 6.7.2 
Visit 42/Early Termination 
(Part 2) 
the postbaseline MRI scheduled for 
Visit 25 or Visit 45, in Part 1 and Part 
2, respectively. Those discontinuing at 
or after Visit 12 in Part 1 or Visit 32 in 
Part 2 should complete the 
postbaseline 
MRI either up to 3 days prior to or on 
the same day as the other Visit 25 or 
Visit 45 study assessments. 
 
…. 
 Schedule participant for the post-
baseline MRI for assessment of 
TKV and LV to occur 28 ± 3 days 
after the last dose; the MRI 
should occur up to 3 days prior to 
or on the same day as Visit 25 
(Note: Participants who 
permanently discontinue 
treatment prior to Visit 12 (Week 
12) are not required to undergo a 
post-baseline MRI).  
 
 
 Schedule participant for the post-
baseline MRI for assessment of 
TKV and LV to occur 28 ± 3 days 
after the last dose… (Note: 
Participants who permanently 
discontinue treatment prior to Visit 
32 (Week 64) are not required to 
undergo a post-baseline MRI).  
 
prior to Visit 12 (Week 12 in Part 1) or 
Visit 32 (Week 64 in Part 2) will forego 
the postbaseline MRI scheduled for 
Visit 25 or Visit 45, in Part 1 and Part 
2, respectively. Those discontinuing at 
or after Visit 12 in Part 1 or Visit 32 in 
Part 2 should complete the 
postbaseline 
MRI either up to 3 days prior to or on 
the same day as the other Visit 25 or 
Visit 45 study assessments. 
 
…. 
 
Randomized Participants: 
Schedule participant for the 
post-baseline MRI for 
assessment of TKV and LV to 
occur between 25 days and 31 
days post last dose of study 
drug and must be completed 
prior to or on the same day as 
all other Visit 25 study 
procedures (Note: Participants 
who permanently discontinue 
treatment prior to Visit 12 
(Week 12) are not required to 
undergo a post-baseline MRI).  
 
Schedule participant for the 
post-baseline MRI for 
assessment of TKV and LV to 
occur between 25 days and 31 
days after the last dose… 
(Note: Participants who 
permanently discontinue 
treatment prior to Visit 32 
(Week 64) are not required to 
undergo a post-baseline MRI).  


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37 
Table 3, Schedule of 
Procedures, Part 1, 
(footnote k) 
k. Liver chemistry includes alkaline 
phosphatase; ALT; AST; bilirubin 
(total and direct). Blood samples for 
serum creatinine will be collected… 
Although serum creatinine results will 
be provided to Investigators as part 
of the chemistries to allow safety 
evaluation, eGFRs derived from the 
serum creatinine results post-
randomization (Visit 9) will NOT be 
shared with the participant, the 
investigator, the clinical sites, the 
sponsor, or the contract research 
organization (CRO) because of the 
potential for unblinding. Laboratory 
test results from samples collected as 
specified in Table 3 will be reviewed 
and assessed. 
k l. Liver chemistry includes alkaline 
phosphatase; ALT; AST; bilirubin 
(total and direct). Blood samples for 
serum creatinine and serum cystatin 
C will be collected…Although serum 
creatinine results will be provided to 
Investigators as part of the 
chemistries to allow safety evaluation, 
eGFRs derived from the serum 
creatinine results post-randomization 
(Visit 9) will NOT be shared with the 
participant, the investigator, the 
clinical sites, the sponsor, or the 
contract research organization (CRO) 
because of the potential for 
unblinding…… Laboratory test results 
from  samples collected as specified 
in Table 3 will are to be reviewed and 
assessed. 
To facilitate safety oversight of 
participants, and to enable the 
Sponsor to conduct the Blinded 
Sample Size Re-estimation, 
eGFR values will be provided to 
sites post-randomization. 
37 
Table 3, Schedule of 
Procedures – Part 1, 
(footnote m) 
 
Serology (HBsAg, Anti-HCV) 
Serology (HBsAg, Anti-HCV)m 
Participants with positive test results 
for hepatitis C (HCV) antibody (Anti-
HCV), will require a negative HCV 
RNA titer reflex test prior to 
enrollment.  
HCV seropositive participants will 
undergo reflex testing at an 
Unscheduled Visit prior to Visit 2. 
Added clarification that retest 
after a positive HCV antibody 
should be performed at an 
unscheduled visit before Visit 2. 
51 
Protocol Section 1.9 
Benefit/Risk Assessment 
 
Safety data gathered to date in 
participants with ADPKD are 
consistent with the robust safety 
experience from studies in earlier 
indications investigated for 
lixivaptan—congestive heart 
failure, liver cirrhosis with ascites, or 
syndrome of inappropriate antidiuretic 
hormone secretion. The primary 
A benefit/risk assessment has 
been included for Investigators’ 
reference. 


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adverse effects of lixivaptan are 
related to the exaggerated 
pharmacology of blockade of the renal 
concentrating mechanism. This 
results in urinary dilution with the 
production of increased amounts and 
frequency of urine output and, 
secondarily, the stimulation of thirst. 
No adverse effects on other body 
systems have been noted. 
Additionally, pharmacodynamic data 
generated for vasopressin V2 receptor 
antagonists that assess the 
mechanism of action, primarily 
through the development program for 
tolvaptan, have been confirmed in 
Phase 2 studies with lixivaptan and 
support continued 
development of lixivaptan for this 
indication. As there additionally 
remains a large unmet medical need 
to address chronic treatment in 
patients with ADPKD, particularly 
those who have experienced liver 
chemistry abnormalities leading to 
discontinuation of treatment with 
tolvaptan, continued investigation of 
this drug for ADPKD is warranted. 
Based on the totality of evidence 
generated to date on lixivaptan, the 
benefit/risk assessment of lixivaptan 
remains favorable. 
54, 56 
Protocol Section 2.2.1.4 
Secondary Safety 
Endpoints  
 
Protocol Section 2.2.2.4, 
Secondary Safety 
Clinical laboratory findings (clinical 
chemistry including additional 
analyses of liver chemistry, 
hematology and urinalysis); 
 
Clinical laboratory findings (clinical 
chemistry including additional 
analyses of liver chemistry, and serum 
sodium, hematology and urinalysis); 
 
Added serum sodium clinical 
laboratory findings as part of 
secondary safety endpoints to 
Parts 1 and 2 of the study. 
 


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Endpoints 
55, 56 
Protocol Section 2.2.1.7, 
Exploratory Endpoints 
 
Protocol Section 2.2.2.7 
Exploratory Endpoints 
[Part 2/Year 2] 
 
The annualized rate of change from 
baseline in LV determined by MRI 
during Follow-up Period I; 
 
… 
The annualized rate of change from 
baseline in LV determined by MRI 
during Follow-up Period I;  
 
… 
The annualized change in eGFR 
calculated from the CKD-EPIcr-cys_R 
equation from baseline to final 
assessment. 
 
 
 
Clarified endpoint related to 
liver volume (LV)  
  
Added additional exploratory 
endpoint.  
 
55 
Protocol Section 2.2.2.1, 
Key Comparison 
Endpoint 
The primary endpoint of Part 2 is the 
annualized change in eGFR 
calculated from the CKD-EPI 
equation for serum creatinine from 
baseline… 
The primary endpoint of Part 2 is the 
annualized change in eGFR 
calculated from the CKD-EPI equation 
(CKD-EPIcr_R) for serum creatinine 
from baseline… 
Clarified the method of 
calculating the eGFR for the 
key comparison endpoint 
55 
Protocol Section 2.2.2.3, 
Other Comparison 
Endpoints 
The annualized rate of change in 
eGFR (calculated from the CKD-EPI 
equation for serum creatinine) from 
baseline (mean of 3 eGFR 
determinations obtained during 
Follow-up Period I) to Follow-up 
Period II;  
The annualized rate of change in 
TKV determined by MRI. 
The annualized rate of change (slope) 
from baseline (mean of 3 eGFR 
determinations obtained during 
Follow-up Period I) in on-treatment 
eGFR, based on all on-treatment 
eGFR determinations during the 
Maintenance Treatment Period in Part 
2, calculated from the CKD-EPI 
equation (CKD-EPIcr_R) for serum 
creatinineThe annualized rate of 
change in eGFR (calculated from the 
CKD-EPI equation for serum 
creatinine) from baseline (mean of 3 
eGFR determinations obtained during 
Follow-up Period I) to Follow-up 
Period II;  
The annualized rate of change in TKV 
determined by MRI. 
Clarified the method of 
calculating the rate of change in 
eGFR and change in TKV for 
other comparison endpoint 


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58 
Protocol Section 3.1.2, 
Detailed Study Design, 
Part 1  
 
 
Participants are eligible for 
enrollment if they are between the 
ages of 18 to 60 years (inclusive)… 
and meet all other study entry criteria 
(Section 4.1). Participants who fail 
inclusion/exclusion criteria due to 
temporary or correctable reasons…  
Participants are eligible for 
enrollment if they are between 
the ages of 18 to 60 years 
(inclusive)…and meet all other 
study entry criteria (Section 
4.1).  Participants who were 
originally enrolled based on the 
2009 CKD-EPI equation 
(Appendix 1 (Section 13.1)) will 
not be discontinued from the 
study should their recalculated 
baseline eGFR, based on the 
CKD--EPIcr_R equation, yield a 
mean eGFR value outside of 
the range of 25 to 90 
mL/min/1.73 m2.  Participants 
who fail inclusion/exclusion 
criteria due to temporary or 
correctable reasons...  
Clarified that any participants 
enrolled under the eGFR 
criterion of the original protocol 
(Version 1.0), would remain in 
the study, if their recalculated 
baseline eGFR based on the 
CKD-EPIcr_R equation yielded 
a value outside the range for 
study enrollment. 
 
 
59 
Protocol Section 3.1.2 
Detailed Study Design 
Part 1: 
Tolerability will be assessed at each 
titration visit (Visit 4 to Visit 9, as 
applicable). If the participant confirms 
the dose can be tolerated, the 
participant will be titrated to the next 
dose level (i.e., the dose will be 
increased). This assessment of 
tolerability will continue at weekly 
intervals until either the maximum 
dose level is reached (Level 4 [200 
mg BID]) or until the participant 
confirms the dose cannot be 
tolerated for a 24-month period. If the 
dose cannot be tolerated, it will be 
reduced by one dose level as 
described in the… 
Tolerability will be assessed at each 
titration visit (Visit 4 to Visit 9, as 
applicable). If the participant confirms 
the dose can be tolerated, the 
participant will be titrated to the next 
dose level (i.e., the dose will be 
increased). This assessment of 
tolerability will continue at weekly 
intervals until either the maximum 
dose level is reached (Level 4 [200 
mg BID]) or until the participant 
confirms the dose cannot be 
tolerated for a 24-month period. If the 
dose cannot be tolerated, it will be 
reduced by one dose level per 
titration visit as described in the… 
To clarify that reduction of one 
dose level is per titration visit. 
 
61 
Protocol Section 3.1.2, 
Detailed Study Design 
Maintenance Period (Visits 30 to 42): 
Following completion of the Lixivaptan 
Re-titration Period, participants will 
Maintenance Period (Visits 30 to 42): 
Following completion of the 
Lixivaptan Re-titration Period, 
Text has been revised for clarity 
on dosing during Part 2 of the 
study. including an explanation 


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continue to receive lixivaptan in the 
Maintenance Period for 52 weeks at 
the same dose achieved at the end of 
the Re-titration Period in Part 2. Visits 
will be performed every 4 weeks 
during this period. Assessments at 
each visit are detailed in the Schedule 
of Procedures – Part 2. 
participants will continue to receive 
lixivaptan in the Maintenance Period 
for 52 weeks at the same dose 
achieved at the end of the Re-
titration Period in Part 2.  If the 
participant’s dose was decreased 
during the Lixivaptan Re-Titration 
Period, periodic attempts should be 
made to re-establish the previously 
achieved dose level from Part 1. 
Visits will be performed every 4 
weeks during this period.  
Assessments at each visit are 
detailed in the Schedule of 
Procedures – Part 2.  Note: during 
the Re-titration Period of Part 2, all 
participants are re-titrated with 
lixivaptan to the last actual dose level 
if they had received lixivaptan during 
the Double-blind, Randomized 
Treatment Period, or, if they had 
received placebo during the Double-
blind, Randomized Treatment Period, 
to the last inferred dose level (the 
dose level equal to the active dose 
level had the participant been 
randomized to the active arm). This 
will be performed by the IRT and the 
site, participant, and sponsor 
maintain a blinded status to the prior 
treatment assignment in Part 1. If no 
adjustment is made to the inferred 
dose during the Double-Blind, 
Randomized Treatment Period, the 
last inferred dose for a participant 
randomized to placebo will be equal 
to the maximal tolerated lixivaptan 
of re-titration with emphasis on 
participants who had been 
assigned to the placebo 
treatment arm during Part 1 of 
the study. 
 
 


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dose established during the Titration 
Period in Part 1…. 
63 
Protocol Section 4.1, 
Selection of Study 
Population 
Approximately 2000 participants will 
be screened in order to randomize 
1200 participants at approximately 
200 sites globally.   
Approximately 2000 2250 participants 
will be screened in order to randomize 
1200 1350 participants at 
approximately 200 250 sites globally.   
Sample size increased as a 
result of increasing the power in 
the statistical analysis to 90%.  
67 
Protocol Section 4.2.3, 
Treatment Interruption 
The participant should immediately 
inform the Investigator of any missed 
doses reaching or expected to reach 
2 days or more so that the 
Investigator can continue to monitor 
the participant’s treatment and 
prepare for a possible extended 
study drug interruption... 
 
 
 
 
 
 
 
 
 
…In the event of a prolonged study 
drug interruption (i.e., greater than 4 
weeks in duration), participants re-
initiating treatment are required to re-
titrate to their last tolerated dose over 
2 weeks.  Re-initiation of treatment 
will begin with study drug at Level 2 
for one week and will then be 
increased to the highest level the 
participant was receiving prior to the 
The participant should be instructed to 
immediately inform the Investigator of 
any missed doses reaching or 
expected to reach 2 days or more so 
that the Investigator can continue to 
monitor the participant’s treatment 
and prepare for a possible extended 
study drug interruption.  The 
Investigator and/or site staff will notify 
the CRA and/or medical monitor of a 
potential interruption within 24 
hours…  
 
Participants with a study drug 
interruption 4 weeks or less in 
duration should resume study 
treatment at their last dispensed dose 
(or at a lower dose, if medically 
appropriate) without the need for 
stepwise dose re-establishment.  
Participants with In the event of a 
prolonged study drug interruption (i.e., 
greater than 4 weeks in duration), 
participants who are re-initiating 
treatment are required to re-titrate  re-
establish their last tolerated dose over 
a 2-week intervals.  Re-initiation of 
treatment will begin with study drug at 
Level 2 for one week and will then be 
increased to the highest level the 
Included notification of the CRA 
and/or medical monitor in the 
treatment interruption 
procedures in an effort to 
mitigate potential missing 
data... 
 
Clarified that drug interruptions 
4 weeks or less in duration do 
not require stepwise dose re-
establishment, unless 
medically necessary. 
 
Changed terminology from “re-
titrate” to “re-establish” in text 
and title of Table 6. 
 
Included a reference to the 
pharmacy manual for additional 
details related to dispensing 
study drug following a 
prolonged study drug 
interruption. 
Added a footnote to Table 6 
that specifies that a lower dose 
than that shown in the table 
may be assigned during Week 
2 of dose re-establishment if 
clinically indicated. 
 
 


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study drug interruption during the 
second week as described in Table 
6.  Re-titrations will be managed by 
the IRT system. 
 
 
 
 
 
 
 
Table 6. Dose Re-titration Following a 
Prolonged (> 4-week) Study Drug 
Interruption 
 
 
 
 
 
 
 
 
participant was receiving prior to the 
study drug interruption during the 
second week as described in Table 6  
(see pharmacy manual for further 
details related to study drug 
dispensing following a prolonged drug 
interruption.) The IRT system will be 
used to manage re-establishment of 
dose. The dose level assigned during 
Week 2 may be lowered based on 
Investigator discretion and clinical 
need. Re-titrations will be managed by 
The IRT system will be used to 
manage re-establishment of dose. 
 
Table 6. Dose Re-titration-
establishment Following a Prolonged 
(> 4-week) Study Drug Interruption 
 
69 
Protocol Section 4.2.4, 
Treatment 
Discontinuation 
Participants may elect to stop 
treatment permanently before the 
end of the study for various reasons.  
Every effort should be made to keep 
randomized participants in the study 
and offer them options for continued 
treatment and participation to the 
Participants may elect to stop 
treatment permanently before the end 
of the study for various reasons.  
Every effort should be made to keep 
randomized participants in the study 
and offer them options for continued 
treatment and, at a minimum, 
continued study participation to the 
Added text to emphasize 
retention of participants in the 
study even after treatment 
discontinuation in an effort to 
minimize missing data.  A 
reference to the protocol 
appendix related to minimizing 


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degree possible as described in 
Section 4.2.7 in order to minimize 
missing data.  Participants who 
permanently discontinue study drug 
will be recorded as study drug 
discontinuations on the eCRF.  They 
will have an ET visit (Visit 22 if in Part 
1 or Visit 42 if in Part 2), which 
should be scheduled within 7 days of 
the participant’s last dose of study 
drug, to collect data listed in the 
Schedule of Procedures – Part 1 and 
Schedule of Procedures – Part 2.  
Participants will immediately proceed 
into the 4-week Follow-up Period and 
will complete the 3 visits in the 
Follow-up Period…   
degree possible as described in 
Section 4.2.7 and Appendix 5 (Section 
13.5) in order to minimize missing 
data.  Participants who permanently 
discontinue study drug will be 
recorded as have the reason for study 
drug discontinuations (e.g., adverse 
event) recorded on the eCRF.  They 
will have an ET visit (Visit 22 if in Part 
1 or Visit 42 if in Part 2), which should 
be scheduled within 7 days of the 
participant’s last dose of study drug, 
to collect data listed in the Schedule 
of Procedures – Part 1 and Schedule 
of Procedures – Part 2.  Randomized 
Pparticipants who permanently 
discontinue treatment will immediately 
proceed into the 4-week Follow-up 
Period…  
missing data was added in this 
section as an additional 
resource.   
 
70 
Protocol Section 4.2.5, 
Reasons for 
Treatment/Study 
Discontinuation 
Participants may discontinue or may 
be discontinued from study drug or 
from the study for any of the following 
reasons…  
… 
Upon occurrence of an SAE or 
intolerable AE, the Investigator will 
confer with the medical monitor and 
sponsor…  The entire study may be 
stopped at any time at the discretion 
of the sponsor. 
 
Participants who permanently 
discontinue study treatment before the 
end of the study, should be 
encouraged to continue in the study 
through the last study visit. 
Participants They may discontinue or 
may be discontinued from study drug 
or from the study for any of the 
following reasons…  
… 
Upon occurrence of an SAE or 
intolerable AE, the Investigator will 
confer with the medical monitor and 
sponsor…  The entire study may be 
stopped at any time at the discretion 
of the sponsor. 
Additional text added to 
distinguish treatment 
discontinuation from study 
discontinuation (i.e., 
participants who discontinue 
treatment should be 
encouraged to continue in the 
study through study 
completion).  
 
Text on study termination 
deleted as a new protocol 
section (4.2.6) on study 
termination has been added. 


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71 
Protocol Section 4.2.6, 
Methods to Prevent Loss 
to Follow-up 
4.2.6 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, 
they should be identified as “lost to 
follow-up” in the eCRF. 
4.2.6 4.2.7 Methods to Prevent Loss 
to Follow-up 
 
The Investigator must make every 
attempt to contact participants who fail 
to return for scheduled visits to 
prevent participants from being “lost to 
follow-up” and follow-up with 
participants who have withdrawn from 
the study at any time and for any 
reason. Appendix 6 (Section 13.6) 
specifies the steps expected to be 
taken to prevent loss to follow-up.  All 
attempts to follow-up with participants 
in accordance with Section 13.6, must 
be documented in the source 
document. 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). 
Only after all measures to mitigate 
loss to follow-up have been exhausted 
should participants.If the participant 
cannot be reached, they should be 
identified as “lost to follow-up” in the 
eCRF. 
Protocol Section numbering 
updated to reflect inclusion of a 
new section 4.2.6. 
 
Updated the procedures related 
to contacting participants that 
are lost to follow-up. 
71 
(New) Protocol Section 
4.2.6, Study Termination 
 
4.2.6 Study Termination 
 
Text added to clarify reasons 
why the study may be 
terminated. 


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The study may be stopped at a study 
site at any time by the site 
investigator or the sponsor.  The 
sponsor may stop the study for any 
reason with appropriate notification, 
including inability to enroll a sufficient 
number of participants to meet study 
goals, an untoward safety signal as 
recommended by the IDMC and 
sponsor, or discontinuation of 
development of lixivaptan for 
ADPKD.  The study may also be 
stopped by a regulatory authority. 
72 
Protocol Section  4.2.8, 
Withdrawal of Consent 
…The Investigator should then follow 
the procedures outlined in Appendix 
5 (Section 13.5) to determine if the 
participant can continue participation 
in the trial if modifications to his/her 
treatment and/or schedule of 
procedures can be accommodated, 
including the potential to continue in 
the study at a lower dose level. 
Participants who withdraw their 
permission for all of the follow-up 
procedures listed above are 
considered to have completely 
withdrawn their consent to participate 
in the study. 
…The Investigator should then follow 
the procedures outlined in Appendix 
5 (Section 13.5) to determine if the 
participant can continue participation 
in the trial if modifications to his/her 
treatment and/or schedule of 
procedures can be accommodated, 
including the potential to continue in 
the study at a lower dose level. The 
scientific value of collecting data and 
information even after study drug is 
discontinued should be discussed 
with a participant who is at risk of 
withdrawing consent. Participants 
who withdraw their permission for all 
of the follow-up procedures listed 
above are considered to have 
completely withdrawn their consent to 
participate in the study. 
Text added to emphasize the 
scientific importance of 
continuing to collect complete 
data on all participants, even 
for those who discontinue study 
treatment. 
74 
Protocol Section 5.1.4, 
Study Drug Packaging, 
Labeling, and Storage 
In such cases, 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 home 
In such cases, 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 home 
Added the option to allow 
qualified site staff conducting 
remote visits to directly 
dispense study drug at the 
remote visit. 


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healthcare clinician (HHC)/ arrives. 
healthcare clinician (HHC)/qualified 
site personnel arrives. Alternatively, 
where permissible and approved by 
the sponsor or sponsor designee, 
qualified study staff conducting 
remote visits may dispense study drug 
directly to participants at the time of 
the remote visit. 
76 
Protocol Section 5.4, 
Treatment Compliance  
The dates of all study drug dosing, 
including interruptions, missed doses 
or overdose, must be recorded in the 
eCRF. If the participant is not ≥ 80% 
compliant with the prescribed study 
drug 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 study 
drug doses to be administered. 
However, if the Investigator, medical 
monitor…   
The dates of all study drug dosing, 
including interruptions, missed doses 
or overdose, must be recorded in the 
eCRF source document and study 
drug accountability forms. Compliance 
is defined as a minimum of 80% 
dosing compliance during any study 
interval.  If the participant is not ≥ 80% 
compliant with the prescribed study 
drug doses during the study overall, 
then the period of non-compliance 
should will be noted as a significant 
protocol deviation and the sponsor 
should be notified. The participant 
should be re-educated regarding the 
correct study drug doses to be 
administered whenever compliance is 
< 80%. However, if the Investigator, 
medical monitor… 
Clarified minimum compliance 
expected to guide protocol 
deviation reporting. 


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78 
Protocol Section 5.5.1.2, 
Prohibited Therapy 
 
 
diuretics (must be discontinued 
during Screening when anti-
hypertensive medications are 
being adjusted) except for a 
short course (up to 4 weeks at a 
time) of loop diuretic therapy to 
manage a temporary fluid 
retention condition; 
 
 
strong or moderate CYP3A4 or 
CYP2C8 inhibitors, including 
aprepitant, 
boceprevir…isoniazid, 
itraconazole, josamycin, 
ketoconazole, nefazodone, 
PaxlovidTM (nirmatrelvir co-
packaged with ritonavir), 
posaconazole, 
quinupristin/dalfopristin, 
remdesivir, ritonavir and 
ritonavir-containing products, 
telaprevir, teriflunomide, 
tofisopam, troleandomycin, 
verapamil, and voriconazole; 
 
 
KetoCitra™ or any beta-
hydroxybutyrate (BHB) 
containing supplements; 
 
 
medications, supplements, and 
herbal preparations that may 
interfere with the accurate 
measurement of serum 
creatinine including cimetidine, 
trimethoprim, pyrimethamine, 
phenacemide, and aspirin 
(aspirin dose above 150 mg per 
The list of prohibited therapy 
has been updated to reflect  
additional medications that may 
confound safety or efficacy 
assessments in this study. 


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day); 
 
 
vasopressin or drugs with 
vasopressin activity 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. 
81 
Protocol, Section 6.1.1 
Visit 1a 
serology: HbsAg and Anti-HCV  
serology: HbsAg and Anti-HCV (Note: 
A positive anti-HCV test requires a 
negative HCV RNA titer reflex test 
prior to enrollment.  Participants 
should undergo reflex testing at an 
Unscheduled Visit prior to Visit 2). 
 
81, 107 
Protocol Section 6.1.1, 
Visit 1a 
 
 
Protocol Section 7.3.2 
Physical Examinations 
and Medical History 
 Collect and review medical history 
information.. 
 
 
Medical history and demographic 
data will be recorded at the 
timepoints specified in the Schedule 
of Procedures – Part 1 and Schedule 
of Procedures – Part 2. 
 
Collect and review medical history 
information, including smoking 
and alcohol history. 
 
Medical history, smoking and alcohol 
history, and demographic data will be 
recorded at the timepoints specified in 
the Visit 1a as specified in the 
Schedule of Procedures – Part 1 and 
Schedule of Procedures – Part 2. 
Added collection of smoking 
and alcohol history at Visit 1a 
as part of the medical history. 
 
84, 85, 88, 
89, 91, 95, 
96, 97, 98, 
Protocol Section 6.1.3, 
Visit 2 
Protocol Section 6.2, 
Placebo Run-in Period 
and Visit 3 
6.3.1, Visit 4 to 8 
 
 Remind the participant to increase 
fluid intake to prevent dehydration 
 
Added instructions to remind 
the participant at each 
dispensing visit, to increase 
fluid intake to prevent 
dehydration. 


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(Lixivaptan Titration 
Period) 
Protocol Section 6.3.2, 
Visit 9/Last Titration 
Period 
Protocol Section 6.4.1, 
Visits 10 to 21 
Protocol Section Protocol 
6.5.2, Visit 25 
Protocol Section 6.6.1, 
Visits 26 to 28 
Protocol Section 6.6.2, 
Visit 29, Last Re-titration 
Visit 
Protocol Section 6.7.1, 
Visits 30 to 41  
95 
Protocol Section 6.6, 
Lixivaptan Re-titration 
Period – Part 2 
During the 2-to-4-week Lixivaptan Re-
titration Period, participants will be re-
titrated to the dose of lixivaptan last 
taken during the Double-blind, 
Randomized Treatment Period in Part 
1.  All participants will initiate re-
titration at a lixivaptan dose of 50 mg 
BID (at Visit 25).  Visits 26 to 29 will 
occur weekly ± 2 days as needed to 
achieve the last dose level. 
 
During the 2-to-4-week Lixivaptan 
Re-titration Period, all participants in 
Part 2 will be re-titrated to the dose 
level of lixivaptan last taken during 
the Double-blind, Randomized 
Treatment Period in Part 1 (i.e., the 
last actual dose level if they had 
received lixivaptan during the 
Double-blind, Randomized 
Treatment Period, or if they received 
placebo during the Double-blind, 
Randomized Treatment Period, the 
last inferred dose level (the dose 
level equal to the active dose level 
had the participant been randomized 
to the active arm)) in accordance 
with Table 2.  This will be performed 
by the IRT and the site, participant, 
and sponsor maintains a blinded 
status. For example, if no adjustment 
is made to the inferred dose during 
the Double-Blind, Randomized 
Text has been revised to clarify 
re-titration during Part 2 of the 
study, with emphasis on re-
titration for participants 
randomized to placebo in Part 1 
of the study. 


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Treatment Period, the last inferred 
dose for a participant randomized to 
placebo will be equal to the maximal 
tolerated lixivaptan dose established 
during the Titration Period in Part 1.   
103 
Protocol Section 7.1.1, 
eGFR Assessments 
The eGFR values will be calculated 
according to the CKD-EPI formula 
from the serum creatinine 
concentrations taken during the 
Screening Period and at the visits 
specified in the Schedule of 
Procedures Part-1 and  Schedule of 
Procedures- Part 2 of the study.  The 
eGFRs will be reported to 
Investigators up to and including Visit 
9 however, to maintain blinding, 
eGFR values will not be reported to 
the Investigators after randomization 
(Visit 9). Although serum creatinine 
results will be provided to the 
Investigators as part of the 
chemistries to allow safety evaluation 
at the visits specified in the Schedule 
of Procedures Part 1, eGFR values 
derived from the serum creatinine 
results post-randomization (Visit 9) 
will NOT be shared with the 
participant, the Investigator, the 
clinical sites, the sponsor, or the 
contract research organization (CRO) 
because of the potential for 
unblinding.  During the Screening 
Period, serum creatinine 
assessments…  Every attempt 
should be made to draw blood 
samples for eGFR determination 
around the same clock time during 
Visits 1a/1b, 2, and 3 and Visits 23, 
The eGFR values will be calculated 
according to the 2021 CKD-EPI 
formula (CKD-EPIcr_R) (Appendix 1 
(Section 13.1)) from the serum 
creatinine concentrations taken during 
the Screening Period and at the visits 
specified in the of the Schedule of 
Procedures Part-1 and Schedule of 
Procedures- Part 2 of the study. The 
eGFRs will be reported to 
Investigators up to and including Visit 
9 however, to maintain blinding, eGFR 
values will not be reported to the 
Investigators after randomization (Visit 
9). Although serum creatinine results 
will be provided to the Investigators as 
part of the chemistries to allow safety 
evaluation at the visits specified in the 
Schedule of Procedures – Part 1, 
eGFR values derived from the serum 
creatinine results post-randomization 
(Visit 9) will NOT be shared with the 
participant, the Investigator, the 
clinical sites, the sponsor, or the 
contract research organization (CRO) 
because of the potential for 
unblinding. 
During the Screening Period, serum 
creatinine assessments…  Every 
attempt should be made to draw blood 
samples for eGFR determination 
around the same clock time during 
Visits 1a/1b, 2, and 3 and Visits 23, 
The eGFR calculations from 
the central lab will no longer be 
suppressed post Visit 9 to 
enhance safety monitoring. 
 
Additionally, eGFR results 
calculated from the newly 
added exploratory endpoint 
utilizing serum creatinine and 
serum cystatin C (CKD-EPIcr-
cys_R) will not be shared with 
study sites to reduce the 
potential for decision errors, as 
eligibility and all treatment 
decisions will be made based 
on the eGFR calculated from 
CKD-EPIcr_R equation. 
 
 
 


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24, and 25, and again at Visits 43, 
44, and 45 for a given participant.  
 
24, and 25, and again at Visits 43, 44, 
and 45 for a given participant.  
As an exploratory endpoint, eGFR will 
also be assessed by the measurement 
of serum creatinine and serum 
cystatin C using a novel CKD-EPI 
equation (CKD-EPIcr-cys_R) 
(Appendix 1 (Section 13.1)). Along 
with serum creatinine concentrations, 
serum cystatin C will be obtained at 
Visits 1a, 2 and 3 or Visits 1b, 2 and 3 
and during Follow-up Period 1 (Visits 
23, 24, and 25) and during Follow-up 
Period II (Visits 43, 44 and 45). The 
mean of the 3 eGFR measurements 
calculated from the CKD-EPcr-cys 
equation during each period will be 
used for the baseline and follow-up 
period for analyses of the exploratory 
eGFR endpoint. To reduce potential 
decision errors, eGFR calculated from 
the CKD-EPIcr-cys_R equation will not 
be shared with sites as all eligibility 
and treatment decisions will be based 
on eGFR calculated from the CKD-
EPIcr_R equation. 
109 
Table 8, Clinical 
Laboratory Parameters 
Sodium 
 
 
 
 
 
 
Sodium* 
     
     
* Serum sodium will be assessed at 
all time-points specified in the 
Schedule of Procedures either as part 
of chemistry or liver chemistry testing.  
… Serum cystatin C 
 
 
Footnote added to table of 
clinical laboratory parameters to 
clarify sampling for serum 
sodium. 
 
 
 
 
Serum cystatin C added to 
clinical laboratory parameters 
collected.to support exploratory 


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endpoints. 
 
 
 
112 
Protocol Section 
7.3.7.1.2, Liver Test 
Abnormalities during the 
Lixivaptan Titration 
Period 
Serum aminotransferase or total 
bilirubin levels that are 1 × ULN to 2 
× ULN during the Lixivaptan Titration 
Period will require holding the dose 
constant and a discussion with the 
medical monitor.   
Serum aminotransferase or total 
bilirubin levels that are >1.2 × ULN to 
2 × ULN during the Lixivaptan 
Titration Period will require holding the 
dose constant and a discussion with 
the medical monitor.   
To align with inclusion criteria, 
liver enzyme thresholds for 
holding lixivaptan dose constant 
during Placebo Run-in or 
Lixivaptan Titration periods 
have been increased.   
121 
Protocol Section 8.2, 
Blinded Sample Size Re-
estimation 
After 20% of the randomized 
participants (i.e., 240 participants) 
complete Part 1 of the study (Visit 25) 
or before screening for the study has 
ended, a BSSR will be performed by 
a blinded, independent statistician… 
If the BSSR estimates that the 
standard deviation of the primary 
efficacy estimand is less than or 
equal to 6.20 mL per minute per 1.73 
m2, then the sample size will remain 
at 1200 randomized participants… 
After at least 20% of the randomized 
participants (i.e., 270 240 participants) 
complete Part 1 of the study (Visit 25) 
or before screening for the study has 
ended, a BSSR will be performed by a 
blinded, independent statistician. 
Based on this interim data set, the 
variance corresponding to the primary 
efficacy estimand will be estimated 
and the total sample size re-
estimated.  If the BSSR estimates that 
the standard deviation of the primary 
efficacy estimand is less than or equal 
to 6.20 mL per minute per 1.73 m2, 
then the sample size will remain at 
1200 1350 randomized participants… 
Increased the number of 
participants that need to 
complete Part 1 of the study 
before the BSSR can be 
conducted to reflect the 
increase in sample size. 
123 
Protocol Section 8.5, 
Secondary Efficacy 
Analyses 
If the primary efficacy analysis is 
statistically significant at the 1% level 
of significance, then the secondary 
efficacy endpoints of (1) annualized 
rate of change (slope) in eGFR 
based on all on-treatment eGFR 
determinations during the Double-
blind, Randomized Treatment Period 
calculated from the CKD-EPI 
equation for serum creatinine; and (2) 
annualized rate of change in TKV as 
If the primary efficacy analysis is 
statistically significant at the 1% level 
of significance, then the secondary 
efficacy endpoints of (1) annualized 
rate of change (slope) in eGFR based 
on all on-treatment eGFR 
determinations during the Double-
blind, Randomized Treatment Period 
calculated from the CKD-EPIcr_R 
equation for serum creatinine; and (2) 
annualized rate of change in TKV as 
Updated the equation used in 
the assessment of the 
secondary efficacy analysis 
from the CKD-EPI to the CKD-
EPIcr_R and also clarified the 
analysis of TKV.  


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measured by MRI.   
measured by MRI will be analyzed.   
126 
(New) Protocol Section 
8.10.3, Annualized 
Change in eGFR 
Assessed by Serum 
Creatinine and Cystatin-C 
(CKD-EPIcr-cys_R) 
 
8.10.3 Annualized Change in eGFR 
Assessed by Serum Creatinine and 
Cystatin-C (CKD-EPIcr-cys_R) 
 
This analysis is based on the change 
from the baseline eGFR to the post-
treatment follow-up eGFR calculated 
from the CKD-EPIcr-cys_R equation, 
annualized by each participant’s 
treatment duration. Baseline eGFR is 
defined as the mean of the 3 eGFR 
determinations obtained during the 
Screening and Placebo Run-in 
Periods. The post-treatment follow-up 
eGFR is defined as the mean of 3 
eGFR assessments obtained during 
the Follow-up Period I or the 
equivalent off-therapy eGFR 
determinations if a participant 
discontinues study drug earlier. 
 This annualized change from 
baseline to post-treatment follow-up in 
mean eGFR will be analyzed by 
means of an analysis of covariance 
model with fixed effects for treatment 
group and the randomization 
stratification factors and the baseline 
eGFR as a covariate.. 
Analysis added to correspond 
with new exploratory objective 
and endpoint. 
143 
Protocol Section 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: 
As of protocol Version 2, This this 
study will replace measurement of 
eGFR as calculated by uses the 2009 
CKD-EPI creatinine equation1 with the 
2021 CKD-EPI equation refit without 
race variable (CKD-EPIcr_R) (Levey 
et al, 2009 Delgado et al, 2021), 
which is recommended by the KDIGO 
The calculation of eGFR has 
changed from the 2009 CKD-
EPI creatinine equation to the 
2021 CKD-EPI equation refit 
without the race variable (CKD-
EPIcr_R). The 2009 CKD-EPI 
creatinine equation was moved 
to footnote 1. 


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Abbreviations/Units 
eGFR (estimated glomerular filtration 
rate) = mL/min/1.73 m2 
SCr (standardized serum creatinine) 
= mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 
(males) 
min = indicates the minimum of SCr 
/κ or 1 
max = indicates the maximum of SCr 
/κ or 1 
age = years 
Clinical Practice Guidelines for 
Management of Chronic Kidney 
Disease National Kidney Foundation 
American Society of Nephrology Task 
Force. 
 
The CKD-EPIcr_R equation is: 
 
 
Abbreviations/Units 
eGFR (estimated glomerular filtration 
rate) = mL/min/1.73 m2 
Scr (standardized serum creatinine) = 
mg/dL 
= 0.7 (females) or 0.9 (males) 
α = -0.241 (females) or -0.302 (males) 
min = indicates the minimum of Scr / 
or 1 
max = indicates the maximum of Scr / 
or 1 
age = years 
 
 
Serum Creatinine and Cystatin C 
(CKD-EPIcr-cys_R): 
In this study eGFR will also be 
assessed from a novel serum 
creatinine and serum cystatin C 
equation refit without the race variable 
(CKD-EPIcr-cys_R) (Delgado et al, 
2021). To reduce potential decision 
errors, eGFR calculated from this 
equation will not be shared with sites 
as all eligibility and treatment 
decisions will be based on eGFR 
 
Formula was added for the 
calculation of eGFR based on 
serum creatinine and serum 
cystatin C (CKD-EPIcr-cys_R) 
to correspond with the new 
exploratory objectives and 
endpoints. 
Note added to clarify that eGFR 
based on this equation will not 
be shared with sites as eligibility 
and all treatment decisions will 
be made based on the CKD-
EPIcr_R equation. 


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calculated from the CKDEPIcr_R 
equation. 
 
The CKD-EPIcr-cys_R equation is: 
 
 
 
 
Abbreviations/Units 
eGFR (estimated glomerular filtration 
rate) = mL/min/1.73 m2 
Scr (serum creatinine) = mg/dL 
Scys (serum cystatin C) = mg/L 
= 0.7 (females) or 0.9 (males) 
α = -0.219 (females) or -0.144 (males) 
min = indicates the minimum of Scr/k 
or 1 OR Scys/0.8 or 1 
max = indicates the maximum of Scr/k 
or 1 OR Scys/0.8 or 1 
age = years 
146 
Protocol Section 13.2 
Appendix 2: Liver 
Dysfunction Checklist 
The following items will be included in 
a checklist to be completed by the 
HHC for remote visits (Part 1- 
Symptoms section only) and by the 
site for clinic visits (Part 1- Symptoms 
and Part 2- Signs) when directed by 
the protocol.  For remote visits where 
there are findings on the Part 1-
Symptoms section of the checklist, 
telehealth will be utilized (e.g., 
telemedicine virtual visit, telephone or 
video call (without recording)) to 
determine if a clinic visit is needed to 
complete the Part 2-Signs section.   
 
… 
 
The following items will be included in 
a checklist to be completed by the 
HHC for remote visits (Part 1- 
Symptoms section only) and by the 
site for clinic visits (Part 1- Symptoms 
and Part 2- Signs) when directed by 
the protocol. For remote visits where 
there are findings on the Part 1-
Symptoms section of the checklist, 
telehealth will be utilized (e.g., 
telemedicine virtual visit, telephone or 
video call (without recording)) to 
determine if a clinic visit is needed to 
complete the Part 2-Signs section.   
 
 
… 
Revised instructions for 
completion of Liver Dysfunction 
checklist for clarity and 
consistency with the protocol. 


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Any symptoms, signs, or an 
associated diagnosis deemed 
clinically significant based on 
information entered in Part 1-
Symptoms or Part 2-Signs during 
either a remote visit or a clinic visit 
will be entered in the eCRF by the 
site as adverse events. 
 
 
The Investigator is responsible for 
adverse event reporting of Any 
symptoms, signs, or an associated 
diagnosis deemed clinically significant 
based on information entered in Part 
1-Symptoms or Part 2-Signs this 
checklistduring either a remote visit or 
a clinic visit will be entered in the 
eCRF by the site as adverse events. 
150 
Protocol Section 13.5 
Appendix 5: Minimization 
of Missing Data: Study 
and Study Treatment 
Modification 
4) Ask the participant, “If we 
discontinue your study drug 
permanently, would you continue with 
all visits and sample collections?” If 
the answer is “Yes”, discontinue study 
drug, perform an ET visit (Visit 22/ET 
if in Part 1 or Visit 42/ET if in Part 2), 
complete the Follow-up Period 
assessments, and continue with all 
other monthly assessments to the end 
of the trial to reduce missing data.  If 
the answer is “No” go to Step 5. 
 
4) Ask the participant, “If we 
discontinue your study drug 
permanently, would you continue 
with all visits and sample 
collections?” The Investigator should 
discuss the scientific value of 
continued data collection even in the 
absence of study treatment.  If the 
answer is “Yes”, the participant is 
willing to continue with all visits and 
sample collections, discontinue study 
drug, perform an ET visit (Visit 22/ET 
if in Part 1 or Visit 42/ET if in Part 2), 
complete the Follow-up Period 
assessments, and continue with all 
other monthly assessments to the 
end of the trial to reduce missing 
data.  If the answer is “No” go to Step 
5. 
Text added to clarify that there 
should be a discussion with the 
participant of the merits of  
continued study participation, 
despite not continuing on study 
treatment. 
151 
(New) Protocol Section 
13.6; Appendix 6: 
Procedures to Prevent 
Loss to Follow-up 
 
13.6 Appendix 6: Procedures to 
Prevent Loss to Follow-up 
 
The Investigator must make every 
effort to contact participants who fail 
to return for scheduled visits to 
prevent participants from being “lost 
to follow-up”. The following 
Additional instructions to limit 
missing data have been added. 


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procedures should be followed at a 
minimum, with additional measures 
taken if unsuccessful. 
1) Contact all numbers for the 
participant and their listed contacts 
(to be collected in source document 
at the participant’s entry into the 
trial). This includes making calls after 
normal business hours or on 
holidays and weekends. Notify the 
CRA and/or medical monitor 
promptly after participant fails to 
return for a scheduled visit. 
 
2) Contact the participant’s primary 
care physician, referring specialist, 
pharmacist or other health-care 
professional (using the contacts 
provided by the participant at entry to 
the trial). 
 
3) Send a text, e-mail and postal mail 
with certified (return-receipt 
requested) letters to all the 
participant’s addresses and all 
contacts (as provided by the 
participant at entry to the trial). 
 
4) In-home visit at last address 
given. 
 
5) Review available medical 
records/notes for details of 
hospitalizations, clinic visits or 
other procedures which may indicate 
the status of participants (as allowed 
through release of medical record 
forms to be completed by participant 
at trial entry). 


Summary of Changes 
Clinical Study Protocol Version 2.0; Dated 01 February 2022 
Palladio Biosciences 
 
PA‐ADPKD‐301 
 
22‐FEB‐2022 
Confidential Information 
Page 58 of 58 
 
Page 
Section 
Version 1.0, Dated 30JUN2021 
Version 2.0, Dated 01FEB2022 
Rationale 
 
6) Conduct an internet search for 
additional contact information (e.g., 
reverse directory for phone numbers 
or new address information; social 
media outlets (e.g., Facebook, 
LinkedIn or other social media for 
status updates). 
 
7) Check local, regional and national 
public records to locate the 
participant or search for mortality 
status as allowed by law.  Once all 
these actions have been exhausted 
(and documented), then the CRA or 
medical monitor should be contacted 
for additional guidance. 
 

SAP_001.pdf: 
Study Title: A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with 
Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, 
Placebo-controlled, Randomized Phase and 1-year Open-Label Phase: The ACTION Study 
 
ClinicalTrials.gov ID: NCT04064346 
 
 
 
Statistical Analysis Plan Version 1.0, dated 24-Aug-2022 
 


 
 
 Page 1 of 67 
 
   Statistical Analysis Plan 
Sponsor 
Palladio Biosciences 
Protocol Title: 
A Phase 3 Study of the Efficacy and Safety of Lixivaptan in 
Participants with Autosomal Dominant Polycystic Kidney Disease 
Consisting of a 1-year Double-blind, Placebo-controlled, 
Randomized Phase and 1-year Open-Label Phase: The ACTION 
Study 
Protocol Number: 
PA-ADPKD-301 
Premier Research PCN: 
PALL215088 
Document Version: 
Version 1.0 
Document Date:  
24-AUG-2022 
 
 


 
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Approvals 
Role 
Signatures 
Biostatistician 
 
Eli Sendra 
Senior 
Biostatistician 
Print Name: Eli Sendra 
Sign Name: 
 
 
 
 
 
Palladio 
Biosciences 
Representative 
 
Genzhou Liu, PhD 
Head of Biometrics 
and Data 
Management 
Print Name: Genzhou Liu, PhD 
Sign Name: 
 
 
 
 
 
Palladio 
Biosciences 
Representative 
 
Neil H. 
Shusterman, MD 
Chief Medical 
Officer 
Print Name: Neil H. Shusterman, MD 
Sign Name: 
 
 
 
 
 
 
 


 
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List of Abbreviations 
Abbreviation 
Definition 
ADPKD 
autosomal dominant polycystic kidney disease  
ADPKD-IS 
ADPKD Impact Scale 
ADPKD-PDS 
ADPKD Pain and Discomfort Scale 
ADPKD-UIS 
ADPKD Urinary Impact Scale 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ART 
Anti-retroviral therapy 
AST 
aspartate aminotransferase 
BHB 
beta-hydroxybutyrate 
BID 
twice daily 
BMI 
body mass index 
BSSR 
blinded sample size re-estimation 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-EPI 
chronic kidney disease epidemiology collaboration 


 
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Abbreviation 
Definition 
CKD-EPIcr_R 
Chronic Kidney Disease – Epidemiology Collaboration equation 
(eGFR) using serum creatinine revised without the race variable 
CKD-EPIcr-cys_R 
Chronic Kidney Disease – Epidemiology Collaboration equation 
(eGFR) using serum creatinine and serum cystatin C without the race 
variable 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CT 
computerized tomography 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
GCP 
good clinical practice 
HBsAg 
Positive test results for hepatitis B surface antigen 
HCV 
Positive test results for hepatitis C 
HERC 
hepatic events review committee 
HIF-PH 
hypoxia-inducible factor prolyl hydroxylase 
HIV 
human immunodeficiency virus 
HgbA1c 
glycosylated hemoglobin 


 
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Abbreviation 
Definition 
htLV 
height-adjusted liver volume 
htTKV 
height-adjusted total kidney volume 
ICF 
informed consent form 
IEC 
independent ethics committee 
IDMC 
independent data monitoring committee 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
KDIGO 
Kidney Disease Improving Global Outcomes 
LOE 
lack of efficacy 
LTSS 
lixivaptan treated safety set 
LV 
liver volume 
MAR 
missing at random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
mITT 
modified intent-to-treat 


 
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Abbreviation 
Definition 
MMRM 
mixed model for repeated measurements 
MNAR 
missing not at random 
MRI 
magnetic resource imaging 
NCS 
non-clinically significant 
P2EAS 
part 2 efficacy analysis set 
P2SS 
part 2 safety set 
PCS 
potentially clinically significant 
PEAS 
primary efficacy analysis set 
PK 
pharmacokinetics 
PPAS 
per-protocol efficacy analysis set 
PRO 
patient reported outcomes 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SEAS 
secondary efficacy analysis set 
SD 
standard deviation 
SDAC 
Statistical Data Analysis Center 
SGLT2 
sodium-glucose cotransporter 2 
SOC 
system organ class 


 
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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
TEAESI 
treatment-emergent adverse event of special interest 
TKV 
total kidney volume 
ULN 
upper limit of normal 
WHODD 
World Health Organization Drug Dictionary 


 
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Table of Contents 
Approvals ...................................................................................................................................2 
List of Abbreviations...................................................................................................................3 
Table of Contents ........................................................................................................................8 
List of Tables ............................................................................................................................ 12 
List of Figures ........................................................................................................................... 13 
1. 
Introduction ................................................................................................................... 14 
2. 
Study Objectives............................................................................................................ 14 
2.1. 
Study Objectives of the Double-blind Phase (Part 1/Year 1)..................................... 14 
2.1.1. Primary Objective .................................................................................................... 14 
2.1.2. Key Safety Objective ............................................................................................... 14 
2.1.3. Secondary Efficacy Objectives................................................................................. 14 
2.1.4. Secondary Safety Objective ..................................................................................... 14 
2.1.5. Health Outcomes Related Objectives ....................................................................... 14 
2.1.6. Pharmacokinetics Objective ..................................................................................... 15 
2.1.7. Exploratory Objectives ............................................................................................ 15 
2.2. 
Study Objectives of the Open-label Phase (Part 2/Year 2) ........................................ 15 
2.2.1. Key Objective .......................................................................................................... 15 
2.2.2. Key Safety Objective ............................................................................................... 15 
2.2.3. Secondary Objectives............................................................................................... 15 
2.2.4. Secondary Safety Objective ..................................................................................... 15 
2.2.5. Health Outcomes Related Objectives ....................................................................... 16 
2.2.6. Pharmacokinetics Objective ..................................................................................... 16 
2.2.7. Exploratory Objectives ............................................................................................ 16 
3. 
Study Design ................................................................................................................. 16 
3.1. 
Overall Design ......................................................................................................... 16 
3.2. 
Study Population...................................................................................................... 17 
3.2.1. Inclusion Criteria ..................................................................................................... 17 
3.2.2. Exclusion Criteria .................................................................................................... 19 
3.3. 
Placebo Run-in/Lixivaptan Titration ........................................................................ 20 
3.4. 
Randomization ......................................................................................................... 21 
3.5. 
Blinding ................................................................................................................... 21 
3.6. 
Dose Administration ................................................................................................ 22 
3.7. 
Sample Size ............................................................................................................. 23 
3.8. 
Schedule of Events .................................................................................................. 23 


 
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4. 
Study Endpoints ............................................................................................................ 24 
4.1. 
Study Endpoints of the Double-blind Phase (Part 1/Year 1) ..................................... 24 
4.1.1. Efficacy Endpoints................................................................................................... 24 
4.1.2. Health Outcome Endpoints ...................................................................................... 25 
4.1.3. Pharmacokinetic Endpoints ...................................................................................... 27 
4.1.4. Safety Endpoints ...................................................................................................... 27 
4.2. 
Study Endpoints of the Open-label Phase (Part 2/Year 2) ......................................... 27 
4.2.1. Key Endpoints ......................................................................................................... 27 
4.2.2. Other Endpoints ....................................................................................................... 28 
4.2.3. Pharmacokinetic Endpoints ...................................................................................... 29 
5. 
Analysis Populations ..................................................................................................... 29 
6. 
General Issues for Statistical Analysis ........................................................................... 30 
6.1. 
Statistical Definitions and Algorithms ...................................................................... 30 
6.1.1. Baseline ................................................................................................................... 30 
6.1.2. Treatment Group and Cohort ................................................................................... 30 
6.1.3. Multiple Comparisons .............................................................................................. 31 
6.1.4. Handling of Dropouts or Missing Data ..................................................................... 31 
6.1.5. Analysis Visit .......................................................................................................... 34 
6.1.6. Pooling of Sites ........................................................................................................ 34 
6.1.7. Data Adjustments/Handling/Conventions ................................................................. 34 
7. 
Study Participants and Demographics ............................................................................ 35 
7.1. 
Disposition of Participants and Withdrawals ............................................................ 35 
7.2. 
Protocol Deviations.................................................................................................. 36 
7.3. 
Demographics and Other Baseline Characteristics ................................................... 38 
7.4. 
Exposure and Compliance........................................................................................ 38 
8. 
Efficacy Analysis .......................................................................................................... 39 
8.1. 
Definition of Completer and Non-completer ............................................................ 39 
8.2. 
Primary Efficacy Analysis (Part 1) ........................................................................... 40 
8.2.1. Sensitivity Analyses of the Primary Efficacy Endpoint ............................................ 41 
8.3. 
Secondary Efficacy Analysis (Part 1) ....................................................................... 43 
8.3.1. Annualized Rate of Change (Slope) in eGFR ........................................................... 44 
8.3.2. Annualized Percent Change from Baseline in htTKV ............................................... 45 
8.4. 
Subgroup Efficacy Analysis (Part 1) ........................................................................ 47 
8.5. 
Health Outcomes Analyses (Part 1) .......................................................................... 47 
8.6. 
Exploratory Efficacy Analyses (Part 1) .................................................................... 48 
8.6.1. Annualized Change in eGFR (2021 CKD_EPIcr-cys_R) .......................................... 48 


 
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8.6.2. Annualized Percent Change in Height-adjusted Liver Volume (htLV) ..................... 48 
8.6.3. Urine Osmolality ..................................................................................................... 49 
8.7. 
Key Comparison Endpoint Analysis (Part 2) ............................................................ 49 
8.8. 
Sensitivity Analysis of the Key Comparison Analysis (Part 2) ................................. 49 
8.9. 
Other Comparison Analyses (Part 2) ........................................................................ 50 
8.9.1. Annualized Rate of Change (Slope) in eGFR ........................................................... 50 
8.9.2. Annualized Percent Change from Baseline in htTKV ............................................... 50 
8.10. Health Outcome Analyses (Part 2) ........................................................................... 51 
8.11. Exploratory Comparison Analyses (Part 2) .............................................................. 51 
8.11.1. Annualized Percent Change in htLV ........................................................................ 51 
8.11.2. Urine Osmolality ..................................................................................................... 51 
8.11.3. Annualized Change from Baseline in eGFR (2021 CKD-EPIcr-cys_R) .................... 51 
8.12. Additional Analyses (Part 2) .................................................................................... 51 
9. 
Safety and Tolerability Analysis .................................................................................... 51 
9.1. 
Key Liver Safety Analysis ....................................................................................... 52 
9.2. 
Adverse Events ........................................................................................................ 52 
9.2.1. Adverse Events Leading to Study Drug Discontinuation .......................................... 54 
9.2.2. Deaths and Serious Adverse Events ......................................................................... 54 
9.2.3. Other Significant Adverse Events ............................................................................ 54 
9.3. 
Clinical Laboratory Evaluations ............................................................................... 54 
9.3.1. Special Liver Events ................................................................................................ 57 
9.4. 
Vital Signs ............................................................................................................... 57 
9.5. 
Electrocardiograms .................................................................................................. 58 
9.6. 
Lixivaptan Treatment Safety Analysis...................................................................... 58 
9.7. 
Body Height, Weight and BMI ................................................................................ 59 
9.8. 
Concomitant Medication .......................................................................................... 59 
9.9. 
Pharmacokinetic Analysis ........................................................................................ 59 
10. 
Derived Variables .......................................................................................................... 59 
11. 
Interim Analysis and Data Monitoring ........................................................................... 61 
11.1. Independent Data Monitoring Committee (IDMC) ................................................... 61 
11.2. Hepatic Events Review Committee (HERC) ............................................................ 61 
12. 
Statistical Analysis and Reporting ................................................................................. 61 
13. 
Tables, Listings, and Figures ......................................................................................... 62 
14. 
Mock Tables, Listings, and Figures ............................................................................... 63 
15. 
Changes from Protocol .................................................................................................. 63 
16. 
Revision History ............................................................................................................ 65 


 
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17. 
References ..................................................................................................................... 65 
Appendix:  Method to Derive the Weight for the Weighted ANCOVA Analysis for the Primary 
Efficacy Endpoint .......................................................................................................... 66 
 
 
 


 
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List of Tables 
Table 1: Dosing Levels during the Titration Period ................................................................... 21 
Table 2: Domains and their Scoring of Three Patient Reported Health Outcomes ...................... 25 
Table 3: Potentially Clinically Important Criteria (PCS): Laboratory ......................................... 56 
Table 4: Potentially Clinically Important Criteria (PCS): Vital Signs......................................... 57 
 
 
 


 
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List of Figures 
Figure 1: Part 1 Study Schematic............................................................................................... 16 
Figure 2: Part 2 Study Schematic............................................................................................... 17 
 
 
 


 
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1. 
Introduction 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analysis of efficacy and safety data for Palladio Biosciences protocol number PA-ADPKD-301 
(A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with Autosomal 
Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, 
Randomized Phase and 1-year Open-Label Phase: The ACTION Study), version 3.0, dated 14-
Feb-2022.  
NOTE: Please see Section 12 for an explanation of the impact of early termination of this study 
on the actual output produced. 
2. 
Study Objectives 
2.1. 
Study Objectives of the Double-blind Phase (Part 1/Year 1) 
2.1.1. Primary Objective 
To demonstrate the efficacy of lixivaptan compared to placebo in the slowing of deterioration in 
kidney function in participants with ADPKD as demonstrated by the annualized change from 
baseline in estimated glomerular filtration rate (eGFR) determined from the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) creatinine equation without the race term 
(CKD-EPIcr_R).  
2.1.2. Key Safety Objective 
To compare the incidences of liver chemistry test elevations in participants randomized to 
lixivaptan with participants randomized to placebo.  
2.1.3. Secondary Efficacy Objectives 
• To compare the rate of change (slope) in on-treatment eGFR in participants treated with 
lixivaptan to participants treated with placebo;  
• To assess the effect of lixivaptan on height-adjusted total kidney volume (TKV) as 
measured by magnetic resonance imaging (MRI) compared to placebo.  
2.1.4. Secondary Safety Objective 
To assess the non-hepatic safety and tolerability of lixivaptan.  
2.1.5. Health Outcomes Related Objectives 
• To evaluate medical resource utilization (e.g., medication use/changes; unplanned office 
visit; urgent care and emergency department usage; and hospitalizations) resulting from 
clinical events in participants randomized to lixivaptan compared with those on placebo 


 
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and assess which events are driving any observed differences in medical resource 
utilization between lixivaptan and placebo;  
• To evaluate the change from baseline in domain scores of the ADPKD Impact Scale 
(ADPKD-IS), ADPKD Pain and Discomfort Scale (ADPKD-PDS), and ADPKD Urinary 
Impact Scale (ADPKD-UIS) in participants treated with lixivaptan compared with 
participants treated with placebo.  
2.1.6. Pharmacokinetics Objective 
To characterize the PK profile of lixivaptan utilizing PopPK based on sparse plasma sampling.  
2.1.7. Exploratory Objectives 
• To assess the effect of lixivaptan on height-adjusted liver volume (htLV) as measured by 
MRI compared to placebo;  
• To evaluate the change from baseline in urine osmolality in participants treated with 
lixivaptan compared with participants treated with placebo; 
• To evaluate the effect of lixivaptan on kidney function as assessed by eGFR using a 
novel serum creatinine and serum cystatin C-based CKD-EPI equation refit without the 
race variable (CKD-EPIcr-cys_R) compared with placebo. 
2.2. 
Study Objectives of the Open-label Phase (Part 2/Year 2) 
2.2.1. Key Objective 
To demonstrate the continued efficacy of lixivaptan in the slowing of deterioration in kidney 
function in participants randomized to lixivaptan in the double-blind phase (Part 1) as measured 
by the annualized change from baseline (Part 2) in eGFR as determined by the CKD-EPIcr_R 
equation at the end of the open-label phase (Part 2).  
2.2.2. Key Safety Objective 
To assess the incidence of liver chemistry test abnormalities during the open-label phase.  
2.2.3. Secondary Objectives 
• To assess the rate of change (slope) in on-treatment eGFR in Part 2 in participants treated 
with lixivaptan in Part 1 and Part 2;  
• To assess the effect of lixivaptan on height-adjusted TKV (htTKV) as measured by MRI 
in Part 2 in participants treated with lixivaptan in Part 1 and Part 2.  
2.2.4. Secondary Safety Objective 
To assess the non-hepatic safety and tolerability of lixivaptan.  


 
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2.2.5. Health Outcomes Related Objectives 
• To evaluate medical resource utilization (e.g., medication use/changes; unplanned office 
visits; urgent care and emergency department usage; and hospitalizations) resulting from 
clinical events in participants on lixivaptan;  
• To evaluate the change in domain scores of the ADPKD-IS, ADPKD-PDS, and ADPKD-
UIS.  
2.2.6. Pharmacokinetics Objective 
To further characterize the PK profile of lixivaptan utilizing PopPK based on sparse plasma 
sampling.  
2.2.7. Exploratory Objectives 
• To assess the effect of lixivaptan on htLV as measured by MRI following 52 weeks of 
open-label treatment;  
• To evaluate the change in urine osmolality; 
• To evaluate the effect of lixivaptan on kidney function as assessed by eGFR using the 
CKD-EPIcr-cys_R equation following 52 weeks of open-label treatment.  
3. 
Study Design 
3.1. 
Overall Design 
Figure 1: Part 1 Study Schematic 
 
 
 


 
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Figure 2: Part 2 Study Schematic 
 
3.2. 
Study Population 
A total of 1350 participants with ADPKD who meet all inclusion criteria and none of the 
exclusion criteria (see below) and tolerate the study medications are planned to be randomized in 
the study at approximately 250 sites globally. 
3.2.1. Inclusion Criteria 
The following are requirements for entry into the study: 
1. Male or female, between 18 and 60 years of age (inclusive) at the time of Screening 
(Visit 1a).  
2. Diagnosis of ADPKD by modified Pei criteria:  
• For participants with family history of ADPKD, by ultrasound:  
o 18-39 years: ≥3 cysts, unilateral or bilateral;  
o 40-59 years: ≥2 cysts in each kidney;  
o 60 years: ≥4 cysts in each kidney; or  
• For participants with family history of ADPKD, by computerized tomography (CT) 
or MRI:  
o 18-40 years: ≥10 cysts in both kidneys; or  
• For participants without family history of ADPKD 
o a minimum of 10 cysts per kidney by any radiologic method and exclusion of 
other cystic kidney diseases (multiple simple kidney cysts, renal tubular 
acidosis, cystic dysplasia of the kidney, multicystic kidney, multilocular cysts 
of the kidney, medullary cystic kidney and acquired cystic disease of the 
kidney); or  
o genetic diagnosis of ADPKD.  
3. At risk for rapid progression of ADPKD as based on the Mayo Clinic ADPKD Image 
Classification of 1C, 1D, or 1E based on age and height-adjusted TKV as determined by 
kidney MRI obtained during Screening, where class (class 1 [typical] versus class 2 
[atypical]) and TKV are determined by a central imaging vendor. 


 
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4. eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m2 based on the mean of 2 eGFR 
determinations (Visits 1a and 2 or Visits 1b and 2, if Visit 1b is required) calculated by 
the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR 
creatinine equation refit without the race variable (CKD-EPIcr_R) from serum creatinine 
values obtained during Screening.  
5. Appropriate control of hypertension for a minimum of 3 weeks including the use of an 
angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not 
considered appropriate for the participant) as suggested by the 2021 Kidney Disease 
Improving Global Outcomes (KDIGO) “Clinical Practice Guideline for the Management 
of Blood Pressure in Chronic Kidney Disease,” without the use of a diuretic.  
6. Body mass index (BMI) between 18 and 40 kg/m2 (inclusive) at the time of Screening. 
7.  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, agree to practice acceptable 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 trial and for 30 days after the last dose 
of study drug. Birth control methods that can be used during the study include the 
following:  
• hormonal contraceptives: combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation (i.e., oral, 
intravaginal, transdermal); progestogen-only hormonal contraception (i.e., 
oral, injectable, implantable). Note: in women with severe polycystic liver 
disease, contraceptives containing estrogen (and hormone replacement 
therapy) may be involved in the development and growth of liver cysts and 
polycystic liver disease progression; the supplemental risk of initiating or 
continuing estrogen treatment, as well as potential alternative contraceptives 
for WOCBP will be discussed with the potential participant  
• 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)  


 
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• diaphragm, cervical cap, or contraceptive sponge with spermicide (with or 
without male condom).  
8. Male participants must agree to use an acceptable form of birth control 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 study drug.  
9. Have read, understood, and provided written informed consent after the nature of the 
study has been fully explained and must be willing to comply with protocol requirements 
and study-related procedures.  
3.2.2. Exclusion Criteria 
1. Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria 
by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant 
kidney disease, kidney cancer, transplanted kidney, single kidney, kidney surgery within 
the past 6 months (including cyst drainage or fenestration) or acute kidney injury within 6 
months prior to Screening.  
2. Clinically significant 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. History of infection with human immunodeficiency virus (HIV) unless the participant is 
clinically stable and doing well on a non-CYP interacting anti-retroviral therapy (ART) 
regimen and the participant has not required more than 2 changes in their ART regimen 
since treatment inception.  
5. History of clinically significant drug or alcohol abuse in the 2 years prior to Screening 
Visit 1a.  
6. Contraindications to or interference with MRI assessments (e.g., ferromagnetic metal 
prostheses, aneurysm clips, severe claustrophobia, or large abdominal/back tattoos). 
Investigator should seek MRI safety guidance from the local MRI facility.  
7. Any malignancy within 5 years prior to Screening except for basal cell carcinoma 
successfully treated with local therapy or malignancies that are considered by the 
Investigator not to affect participant survival (after discussion with the medical monitor).  
8. Medical history or findings that preclude safe participation in the trial or participants who 
are likely to be non-compliant with trial procedures in the opinion of the Investigator or 
medical monitor.  
9. Clinically significant liver disease or impairment or alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or total bilirubin values >1.2 x ULN during Screening. 
Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 


 
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1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 
when results for Visit 2 are available.  
10. Requirement for ongoing diuretic use.  
11. Participants who are currently taking, or are expected to be taking, strong or moderate 
CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, 
Seville oranges, or St. John’s wort. If applicable, there should be a 14-day washout of 
these treatments prior to Visit 2.  
12. Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, 
dapagliflozin, empagliflozin, etc.) within the 2 months prior to Screening Visit 1a or 
expected need for initiation of treatment with a SGLT2 inhibitor during the study.  
13. Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the 
2 months prior to Screening Visit 1a or expected need for initiation of treatment with a 
HIF-PH inhibitor during the study.  
14. Simvastatin at a total daily dose >10 mg or amlodipine at a total daily dose >5 mg.  
15. Prior use of tolvaptan or lixivaptan within the 2 months prior to Screening Visit 1a.  
16. Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, 
etc.), metformin (except for diabetes), nicotinamide, bardoxolone, demeclocycline, 
mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.) or KetoCitra™ or any beta-
hydroxybutyrate (BHB) containing supplements within the 2 months prior to Screening 
Visit 1a.  
17. Participants who have taken any investigational drug or used an investigational device 
within 30 days, or 5 half-lives, whichever is longer, prior to Screening Visit 1a or plan to 
participate in an interventional trial during the study.  
18. Hypovolemia on physical examination at Screening.  
19. Abnormal serum sodium concentration at Screening.  
20. Positive test results for hepatitis B surface antigen (HBsAg).  
21. Positive test results for hepatitis C (HCV) antibody (Anti-HCV), with the exception of 
participants for whom the reflex HCV RNA titer test is negative.  
22. Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.  
3.3. 
Placebo Run-in/Lixivaptan Titration 
Participants who meet the inclusion criteria and none of the exclusion criteria will be enrolled in 
the study and enter the Placebo Run-in Period. During the Placebo Run-in Period, participants 
will receive four capsules of single-blind placebo twice daily (BID) approximately 10 hours 
apart over one week of dosing. Throughout the study, participants will take 4 capsules BID to 
mask transitions from one study period to the next. 
Participants who can tolerate the placebo will enter the Lixivaptan Titration Period. During the 
Lixivaptan Titration Period, single-blind lixivaptan will be started at Level 1 (50 mg BID) and 


 
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will be increased weekly through Levels 2 (100 mg BID), 3 (150mg BID), and 4 (200 mg BID) 
according to the dosing schedule in Table 1. At the 2 highest dose levels (Level 3 [150 mg BID] 
and Level 4 [200 mg BID]), there will be an opportunity to reduce the evening (PM) dose to 
Level 3a (150 mg AM/100 mg PM) or Level 4a (200 mg AM/150 mg PM) if aquaretic effects 
are problematic in certain participants. 
Table 1: Dosing Levels during the Titration Period 
Dose Level 
AM Dose 
PM Dose 
1* 
50 mg 
50 mg 
2 
100 mg 
100 mg 
3 
150 mg 
150 mg 
3a** 
150 mg 
100 mg 
4 
200 mg 
200 mg 
4a** 
200 mg 
150 mg 
*Dose Level 1 is for initiation of treatment.  
**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).  
 
Once the maximum tolerated dose is achieved during the Lixivaptan Titration Period, 
participants will generally stay on that dose for 1 additional week to confirm tolerability. As the 
maximum duration of the Lixivaptan Titration Period is 6 weeks, participants who require a dose 
reduction at Week 6 (Visit 9), as a result of emerging tolerability issues, will proceed to the 
double-blind period on the newly assigned (reduced) dose level without extension of the titration 
period. Participants who are unable to tolerate the minimum dose for entry into the Double-
Blind, Randomized Treatment Period (100 mg BID/ Level 2) will be discontinued from the 
study. 
3.4. 
Randomization 
Once the maximum tolerated dose during the Lixivaptan Titration Period is at least 100 mg BID, 
the participant will be randomized in 2:1 lixivaptan to placebo ratio to either receive lixivaptan 
or placebo treatment during the Double-blind, Randomized Treatment Period stratified into 1 of 
6 strata by the following stratification factors (determined at time of Screening): 
1. 
CKD stage (CKD 2 vs. CKD 3/4) 
2. 
Mayo Clinic ADPKD Image Classification (1C, ID, or IE) 
3.5. 
Blinding 
This is a double-blind study. Blinding was achieved by means of identical appearance for the 
capsules for lixivaptan and placebo.  The placebo capsule does NOT contain the active 
ingredient (lixivaptan) but contains the same inactive ingredients as in the investigational 


 
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product. Throughout the study, participants will take 4 capsules BID to mask transitions from 
one study period to the next. 
Treatment allocation after randomization will be blinded to all participants, investigators, site 
personnel, and sponsor employees and representatives except the Independent Data Monitoring 
Committee (IDMC) and its supporting individuals (e.g., study unblinded biostatistician) and 
Statistical Data Analysis Center (SDAC). The trial will be unblinded following the locking of the 
database in Part 1. In addition, all participants will be blinded to study drug (placebo or 
lixivaptan) during the Placebo Run-in Period and Lixivaptan Titration Period in Part 1. 
To maintain study blinding, data that can potentially be used to identify the treatment allocation 
will NOT be shared with the participant, investigator, clinical sites, sponsor, and CRO until the 
locking of the database in Part 1 of the study. The set of such data are MRI volumetric 
calculations and other derived data (e.g., htTKV), urine osmolality data, and PK data after 
randomization.  
3.6. 
Dose Administration 
Participants who tolerate their optimized dose in the Lixivaptan Titration Period will then enter 
the Double-blind, Randomized Treatment Period during which time they will take the lixivaptan 
dose level achieved at the end of the Lixivaptan Titration Period if participants were randomized 
into the lixivaptan group or receive matching placebo capsules if participants were randomized 
into the placebo group. During the Double-blind, Randomized Treatment Period, the dose may 
be adjusted downward at the Investigator’s discretion if needed to manage non-hepatic side 
effects. For these participants, the dose level should be increased back to the dose at the start of 
the Double-Blind, Randomized Treatment Period, once symptoms resolve. The Investigator may 
temporarily interrupt the study drug, if necessary, to manage acute intercurrent illness, 
tolerability issues, planned or unplanned surgical procedures or life situations, e.g., airplane 
travel, etc. In an effort to minimize missing data, wherever practicable, participants who 
experience a study drug interruption of 7 or more days will be scheduled to have 3 separate 
serum creatinine samples obtained (minimally 24 hrs. apart between 8 and 28 days after their last 
dose) for determination of eGFR. Participants who require a prolonged interruption (i.e., >4 
weeks in duration) due to illness, including COVID-19, or other reasons may be able to restart 
the study drug when medically stable. Re-establishment is required in the event of a prolonged 
interruption. If study drug is interrupted for longer than 8 weeks, then study drug treatment will 
be permanently discontinued. Note: In the event of tolerability issues at any time during the 
study, dosing may be decreased or temporarily stopped. If dosing is resumed during the Double-
Blind, Randomized Treatment Period at a dose level less than that achieved at Visit 9, attempts 
will be made every 4 to 8 weeks to re-establish the previously achieved dose level from Visit 9, 
if medically appropriate.  
For the participants who completed Part 1 and continued to Part 2, the lixivaptan re-titration is 
required. During the Lixivaptan Re-titration Period, dosing will start at Level 1 (50 mg BID) for 
all participants in Part 2 and will be increased weekly until the dose level taken at the end of the 
Double-blind, Randomized Treatment Period is achieved, or, if they had received placebo during 
the Double-blind, Randomized Treatment Period, to the last inferred dose level (the dose level 


 
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equal to the active dose level had the participant been randomized to the active arm). Re-titration 
will be performed by the IRT, and the site, participant, and sponsor maintain a blinded status to 
the prior treatment assignment in Part 1. The dose level obtained at end of the Lixivaptan Re-
Titration Period and equivalent to the dose level taken at the end of Double-blind, Randomized 
Treatment Period, will be continued for the remainder of Part 2. In the event of tolerability issues 
at any time during the study including either during the Lixivaptan Re-titration Period or during 
the Maintenance Treatment Period, dosing may be decreased or temporarily stopped. Attempts 
will be made every 4 to 8 weeks to re-establish the previously achieved dose level at the end of 
the Double-blind, Randomized Treatment Period of Part 1, if medically appropriate. If 
tolerability continues to be problematic, the participant may continue at the lower dose. If study 
drug is interrupted for longer than 8 weeks, then study drug treatment will be permanently 
discontinued. 
3.7. 
Sample Size 
Part 1: 
Based on the results of the REPRISE trial with tolvaptan (Torres et al, 2017), it is assumed that 
the standard deviation for the primary efficacy endpoint, change from baseline to post-treatment 
follow-up in mean eGFR, is 6.20 mL per minute per 1.73 m2. Assuming a between-treatment 
group difference of -1.40 mL per minute per 1.73 m2 and a randomization ratio of 2:1 for 
lixivaptan to placebo, a sample size estimate of 1314 participants (438 placebo-treated 
participants and 876 lixivaptan-treated participants) is required to achieve 90% power at a 
significance level of 0.01. This estimate has been adjusted up to 1350 participants (450 placebo 
participants and 900 lixivaptan participants). It is estimated that approximately 2250 participants 
will need to be screened in order to randomize 1350 participants. 
Part 2: 
This is a convenience sample based on the number of participants who elect to continue into Part 
2. It is estimated that approximately 1350 participants will be randomized in Part 1. All 
participants except those who discontinue due to an adverse event or withdraw consent will 
continue into Part 2. Approximately 90% (1215) of Part 1 participants are anticipated to continue 
into Part 2. 
3.8. 
Schedule of Events 
Please see the protocol for a detailed schedule of events. 


 
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4. 
Study Endpoints 
4.1. 
Study Endpoints of the Double-blind Phase (Part 1/Year 1) 
4.1.1. Efficacy Endpoints 
4.1.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the annualized change in eGFR calculated from 
the CKD-EPI equation (2021 CKD-EPIcr_R) for serum creatinine from baseline to the post-
treatment follow-up, annualized by participant’s elapsed duration as defined below. Baseline 
eGFR is defined as the mean of the 3 eGFR determinations obtained during the Screening and 
Placebo Run-in Periods i.e., the mean eGFR of Visit 1a or 1b, Visit 2, and Visit 3. The post-
treatment follow-up eGFR is defined as the mean of 3 eGFR assessments obtained during the 
Follow-up Period I after Week 52 for on-treatment completers, or, for participants who 
discontinue study drug treatment prior to Week 52 [Visit 22], during the Follow-up Period 8 to 
28 days following study drug treatment discontinuation. On-treatment completers are defined in 
Section 8.1.  The participant’s elapsed duration is defined as the number of years (number of 
days divided by 365.25) from the median of the collection dates of the baseline eGFR 
assessments to the median of the collection dates of the 3 eGFR assessments obtained during the 
post-treatment, follow-up period immediately following study drug discontinuation.  
4.1.1.2. 
Secondary Efficacy Endpoints 
The secondary endpoints are:  
• The annualized rate of change (slope) in eGFR, estimated from all on-treatment eGFRs, 
calculated from the CKD-EPI equation (2021 CKD-EPIcr_R) for serum creatinine, 
during the Double-Blind, Randomized Treatment Period in Part 1. An on-treatment eGFR 
is defined as any eGFR obtained while participants are on treatment (taking the study 
drug), i.e., any eGFR obtained within 24 hours after the latest dose.  
• The annualized percent change in height-adjusted TKV (htTKV, mL/m) from baseline to 
post-treatment follow up during Follow-up Period I after Week 52 for on-treatment 
completers, or, for participants who discontinue study drug treatment prior to Week 52 
[Visit 22], during the Follow-up Period 28 days following study drug treatment 
discontinuation. The htTKV is defined as the TKV value (mL) determined by MRI 
divided by the participant’s baseline height (meters) measured at Screening. Baseline 
htTKV is the one obtained at Screening (Visit 1a). 
4.1.1.3. 
Exploratory Efficacy Endpoints 
• The annualized percent change in height-adjusted LV (htLV, mL/m) from baseline to 
post-treatment follow up during Follow-up Period I after Week 52 for on-treatment 
completers, or, for participants who discontinue study drug treatment prior to Week 52 
[Visit 22], during the Follow-up Period 28 days following study drug treatment 
discontinuation. The htLV is defined as the LV value (mL) determined by MRI divided 


 
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by the baseline participant’s height (meters) observed at Screening. Baseline htLV is the 
one obtained at Screening (Visit 1a). 
• Mean change from baseline in morning spot urine osmolality at Visits 15, 22, and 25; 
Baseline is defined as urine osmolality obtained at Screening (Visit 2). 
• The annualized change in eGFR calculated from the 2021 CKD-EPIcr-cys_R equation 
from baseline to the post-treatment follow-up. The definitions of baseline eGFR, post-
treatment follow-up eGFR, elapsed duration, and annualization are the same as the 
primary efficacy endpoint except for using the different eGFR equations. 
4.1.2. Health Outcome Endpoints 
4.1.2.1. 
Medical Resource Utilization Endpoints 
A detailed description of the analysis for the medical resource utilization and health economics 
assessments will be specified in a prospective health outcomes analysis plan. 
4.1.2.2. 
Patient Reported Health Outcomes 
Endpoints for Patient Reported Health Outcomes consist of three patient questionnaires: 
ADPKD-IS, ADPKD-PDS, and ADPKD-UIS. Number of questions, domains and scoring for 
each questionnaire are listed in Table 2. Baseline score in each domain is defined as the observed 
score for that domain at Screening (Visit 2). If more than 50% of the items of a domain are 
missing, that domain score is missing; otherwise, the domain score is the mean of scores for all 
the non-missing items for that domain. 
Table 2: Domains and their Scoring of Three Patient Reported Health Outcomes 
HRQoL PRO 
Description 
Scoring 
ADPKD-Impact 
Scale (ADPKD-IS) 
• 18-item participant 
administered questionnaire 
• Scale of 1-5 with a two 
week recall period; 1 = not 
difficult at all/not bothered 
at all to 5 = extremely 
difficult/extremely bothered 
• 3 conceptual domains: 
physical, emotion and 
fatigue 
• Physical domain score = 
Items (1 + 2 + 3 + 4 + 5 + 
15 + 16) /7 
• Emotional domain score = 
Items (6 + 11 + 12 + 13)/4 
• Fatigue domain score = 
Items (10 + 17 + 18)/3 
• Items 7, 8, 9, and 14 are not 
included in the scoring 
 
 ADPKD-Pain and 
Discomfort Scale 
(ADPKD-PDS) 
• 20-item participant 
administered questionnaire 
• Scale of 1-5 with a one 
week recall period; 1 (none 
• Dull pain severity score = 
Items (1 + 2 + 3)/3 
• Sharp pain severity score = 
Items (4 + 5+ 6)/3 


 
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or not at all) to 5 (extreme, 
constantly, or completely) 
• Severity dimension consists 
of 4 severity scales: dull 
pain severity, sharp pain 
severity, discomfort 
severity, overall pain 
severity 
• Interference dimension 
consists of 2 scales: dull 
pain interference, 
discomfort interference 
• Discomfort severity score = 
Items (7 + 8 + 9)/3 
• Overall pain severity score 
= (dull pain severity score + 
sharp pain severity score + 
discomfort severity score)/3 
• Dull pain interference score 
= Items (10 + 11 + 12 + 13 
+ 14)/5 
• Discomfort interference 
score = Items (16 + 17 + 18 
+ 19 + 20)/5 
• Sharp pain interference 
score = Item 15 
ADPKD-Urinary 
Impact Scale 
(ADPKD-UIS) 
• 11-item participant 
administered questionnaire 
• Scale of 1-5 with a one 
week recall period; 1 (not 
difficult/bothered) to 5 (very 
difficult/bothered) 
• 3 domains: frequency, 
urgency, and nocturia 
• Frequency domain score = 
Items (1 + 3 + 6 + 8)/4 
• Urgency domain score = 
Items (2 + 4 + 7 + 9)/4 
• Nocturia domain score = 
Items (5 + 10 + 11)/3 
Endpoints for Patient Reported Health Outcomes at Visits 12, 15, 18, 22, and 25 are as follows: 
ADPKD-IS:  
• Change from baseline in physical domain score 
• Change from baseline in emotional domain score 
• Change from baseline in fatigue domain score 
ADPKD-PDS:  
• Change from baseline in dull pain severity score 
• Change from baseline in sharp pain severity score 
• Change from baseline in discomfort severity score 
• Change from baseline in overall pain severity score 
• Change from baseline in dull pain interference score 
• Change from baseline in discomfort interference score 
• Change from baseline in sharp pain interference score 


 
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ADPKD-UIS:  
• Change from baseline in frequency domain score 
• Change from baseline in urgency domain score 
• Change from baseline in nocturia domain score 
In addition, the above endpoints will be calculated at the evaluation visits during Lixivaptan 
Titration Period. Those will be analyzed separately. 
4.1.3. Pharmacokinetic Endpoints 
The calculation of parameters for population PK analysis of plasma lixivaptan concentrations 
will be described in a separate PK analysis plan. 
4.1.4. Safety Endpoints 
4.1.4.1. 
Key Safety Endpoint 
The key liver safety endpoint is the incidence of participants with serum ALT levels >3 x ULN 
during the Double-Blind, Randomized Treatment Period in Part 1. 
4.1.4.2. 
Secondary Safety Endpoints 
The safety and tolerability of lixivaptan assessed through evaluation of:  
• Treatment-emergent adverse events (TEAEs); a TEAE is defined as any adverse event 
that either occurred after the first dose of the study drug (i.e., placebo during the Placebo 
Run-in Period) or occurred prior to the first dose of the study drug but worsened after the 
first dose of the study drug. 
• Clinical laboratory findings (clinical chemistry including additional analyses of liver 
chemistry, hematology, and urinalysis);  
• Vital signs;  
• 12-lead electrocardiograms (ECG).  
4.2. 
Study Endpoints of the Open-label Phase (Part 2/Year 2) 
4.2.1. Key Endpoints 
4.2.1.1. 
Key Comparison Endpoint 
The primary endpoint of Part 2 is the annualized change in eGFR calculated from the CKD-EPI 
equation (2021 CKD-EPIcr_R) for serum creatinine from baseline to the post-treatment follow-
up in Part 2, annualized by participant’s treatment elapsed duration in Part 2 as defined below. 
Baseline eGFR in Part 2 is defined as the mean of the 3 eGFR determinations obtained at 3 post-
treatment follow-up visits (Visits 23, 24, and 25) after Week 52 in Part 1. The post-treatment 
follow-up eGFR of Part 2 is defined as the mean of 3 eGFR assessments obtained during the 


 
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Follow-up Period II after Week 104 for on-treatment completers or, for participants who 
discontinue study drug treatment prior to Week 104 [Visit 42], during the Follow-up Period 8 to 
28 days following study drug treatment discontinuation in Part 2. The participant’s treatment 
elapsed duration in Part 2 is defined as the number of years (number of days divided by 365.25) 
from the median of the collection dates of the baseline eGFR assessments to the median of the 
collection dates of the 3 eGFR assessments obtained during the post-treatment follow-up. 
4.2.1.2. 
Key Safety Endpoint 
The key liver safety endpoint is incidence of serum ALT levels > 3 x ULN in participants 
exposed to lixivaptan in Part 2.  
4.2.2. Other Endpoints 
4.2.2.1. 
Other Comparison Endpoints 
The additional secondary endpoints are: 
• The annualized rate of change (slope) in eGFR, estimated from all on-treatment eGFRs, 
calculated from the CKD-EPI equation (2021 CKD-EPIcr_R) for serum creatinine during 
the Maintenance Treatment Period in Part 2. An on-treatment eGFR is defined as any 
eGFR obtained while participants are on treatment (taking lixivaptan) in Part 2.  
• The annualized percent change in htTKV from baseline (post-treatment follow-up after 
Week 52 in Part 1) to post-treatment follow-up during Follow-up Period II after Week 
104 for on-treatment completers, or, for participants who discontinue study drug 
treatment prior to Week 104 [Visit 42], during the Follow-up Period 28 days following 
study drug treatment discontinuation in Part 2.  
4.2.2.2. 
Secondary Safety Endpoints 
The safety and tolerability of lixivaptan assessed through evaluation of: 
• Treatment-emergent adverse events (TEAEs);  
• Clinical laboratory findings (clinical chemistry including additional analyses of liver 
chemistry tests), hematology, and urinalysis);  
• Vital signs;  
• 12-lead electrocardiograms (ECG).  
4.2.2.3. 
Medical Resource Utilization Endpoints 
A detailed description of the analysis for the medical resource utilization and health economics 
assessments will be specified in a prospective health outcomes analysis plan. 


 
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4.2.2.4. 
Endpoints for Patient Reported Health Outcomes 
See Section 4.1.2.2 for the definitions for domains, how to calculate domain scores, and the 
definitions of endpoints for each patient report health outcome questionnaire. Baseline in Part 2 
is defined as the observed domain score in the post-treatment follow-up visit (Visit 25) after 
Week 52 in Part 1.  
4.2.3. Pharmacokinetic Endpoints 
The calculation of parameters for population PK analysis of plasma lixivaptan concentrations 
will be described in a separate PK analysis plan. 
4.2.3.1. 
Exploratory Endpoints 
• The annualized percent change in htLV determined by MRI from baseline (post-
treatment follow-up visit [Visit 25] after Week 52 in Part 1) to post-treatment follow-up 
during Follow-up Period II after Week 104 for on-treatment completers, or, for 
participants who discontinue study drug treatment prior to Week 104 [Visit 42], during 
the Follow-up Period 28 days following study drug treatment discontinuation in Part 2;  
• Mean change from baseline in morning spot urine osmolality in Part 2; Baseline is 
defined as urine osmolality obtained at 28 days post-treatment follow-up visit (Visit 25) 
after Week 52 in Part 1. 
• The annualized change in eGFR calculated from the 2021 CKD-EPIcr-cys_R equation 
from baseline to the post-treatment follow-up. The definitions of baseline eGFR, post-
treatment follow-up eGFR and annualization are the same as the key comparison 
endpoint in Part 2 (Section 4.2.1.1) except for using the different eGFR equations. 
5. 
Analysis Populations 
The following analysis populations are planned for this study:  
Part 1: 
• Placebo Run-in Safety Set: The Placebo Run-in Safety Set includes all participants who 
received at least one dose of placebo during Placebo Run-In Period in Part 1. 
• Lixivaptan Titration Safety Set: The Lixivaptan Titration Safety Set includes all 
participants who received at least one dose of lixivaptan during Lixivaptan Titration 
Period in Part 1.  
• Randomized Safety Set: The Randomized Safety Set includes all participants who 
received at least one dose of study drug after randomization. 
• Intent-to-Treat Analysis Set (ITT): The ITT includes all participants who were 
randomized in Part 1. 


 
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• Modified Intent-to-Treat Analysis Set (mITT): The mITT includes all participants in 
the ITT who received at least one dose of study drug in Part 1. Note that the mITT 
Analysis Set consists of the same set of the participants in the Randomized Safety Set. 
• Primary Efficacy Analysis Set (PEAS): The PEAS includes all participants in the mITT 
Analysis Set who have both baseline and at least one assessment of eGFR after the 
treatment is complete or discontinued in Part 1. 
• Secondary Efficacy Analysis Set (SEAS): The SEAS includes all participants in the 
mITT Analysis Set who have both baseline and at least one on-treatment assessment of 
eGFR. 
• Per-protocol Efficacy Analysis Set (PPAS): The PPAS includes all participants in the 
PEAS who do not have any protocol deviations that are deemed to potentially impact 
efficacy. 
Assignment of participants to populations will be confirmed at a blinded data review meeting to 
be held before the study database is locked for Part 1. 
Part 2: 
• Part 2 Safety Set (P2SS): The Part 2 Safety Set includes all participants who receive at 
least one dose of lixivaptan in Part 2. 
• Part 2 Efficacy Analysis Set (P2EAS): The Part 2 Efficacy Analysis Set includes all 
participants in the Part 2 Safety Set who have at least one assessment of off-treatment 
eGFR in Part 2. 
Parts 1 & 2 (Combined): 
• Lixivaptan Treated Safety Set (LTSS): The Lixivaptan Treated Safety Set is defined as 
all participants who received at least one dose of lixivaptan treatment after randomization 
during the entire study. This analysis population will be used to summarize safety data 
during the study for all randomized, lixivaptan-treated participants. 
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded before the first dose of lixivaptan during Lixivaptan Titration 
Period will be used as the baseline observation for all calculations of change from baseline 
unless otherwise specified.  
6.1.2. Treatment Group and Cohort 
For Part 1 summaries after randomization, the analysis results will be presented by two treatment 
groups: lixivaptan and Placebo. 
Since all participants in Part 2 are treated with lixivaptan, the summaries for Part 2 will be 


 
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presented in the following treatment cohorts and overall (treatment cohorts combined): 
• Part1/Part2 – Placebo/Lixivaptan: all participants in Part 2 who were randomized into 
Placebo treatment group in Part 1 
• Part1/Part2 – Lixivaptan/Lixivaptan: all participants in Part 2 who were randomized into 
lixivaptan treatment group in Part 1 
6.1.3. Multiple Comparisons 
To control the family-wise type I error at the pre-specified level (≤ 0.01), the primary and 
secondary endpoints in Part 1 will be tested in hierarchical order: 
• Treatment difference for the primary endpoint must be statistically significant (p-value ≤ 
0.01) 
• Treatment difference for annualized rate of change (slope) in on-treatment eGFRs is 
tested only if treatment difference for the primary endpoint is statistically significant (p-
value ≤ 0.01) 
• Treatment difference for annualized percent change from baseline in htTKV is tested 
only if treatment difference for annualized rate of change (slope) in on-treatment eGFRs 
is statistically significant (p-value ≤ 0.01) 
Because the testing is sequential, the type I error rate of ≤ 0.01 is maintained. Failure at any stage 
in the sequence implies automatic failure at all subsequent stages. All p-values for each 
comparison without adjustments will be provided in the summary tables for informational 
purposes.  
No adjustments will be made for multiple comparisons for other endpoints.  
6.1.4. Handling of Dropouts or Missing Data 
Assessments are planned, by protocol, to be collected from all randomized participants except 
those who 1) withdraw consent AND 2) do not consent to any collection of data. Every effort 
will be made to keep randomized participants in the study and offer them options for continued 
treatment and, at a minimum, continued study participation to the degree possible; strategies of 
these efforts are described in the study protocol Section 4.2.4, Section 4.2.7, and Appendix 5 
(Section 13.5) in order to minimize missing data. While all possible efforts will be made to 
ensure that participants stay in the study and all data is collected as scheduled, the occurrence of 
missing data cannot be completely eliminated. 
The handling of missing data is dependent upon the efficacy analyses (see Section 8 Efficacy 
Analysis for detail).  The missing data for efficacy analyses are generally imputed by the 
following methods: 
• Missing at random (MAR) – mixed-effects model for repeated measures (MMRM): a 
modeling approach (missing data are not imputed prior to the analysis) 


 
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• Missing at random (MAR) – multiple imputation (MI)  
• Missing not at random (MNAR) – multiple imputation (MI) with assumptions of missing 
not at random. Treatment impact on efficacy endpoints for missing data varies 
independently on the two treatment arms bi-dimensionally. Pattern-mixture approach is 
applied to investigate the MNAR pattern based on dropout reasons. Specifically, MNAR 
in the following patterns of dropout reasons will be investigated as MNAR: 
o Lack of efficacy (LOE) 
o LOE and adverse events (AE) 
o All dropouts 
6.1.4.1. 
Multiple Imputation Methods 
MI is a simulation-based approach where missing values are replaced using an appropriate 
stochastic model given the observed data and covariates, creating multiple completed data sets. 
These completed datasets (observed data and imputed data) are then analyzed using pre-specified 
analysis methods, and the different parameter estimates across the datasets are then combined to 
produce unique point estimates, standard errors, confidence intervals, and p-value taking into 
account the uncertainty of the imputation process.  
The following 2 MI analysis models, one based on the standard MAR imputation approach and 
the other based on the MNAR imputation approach, will be used to examine robustness of the 
primary analysis results.  
6.1.4.1.1 
Standard MAR Imputation 
The MAR imputation model will impute missing values using a regression-based multiple 
imputation model (Little et al, 1996). A by-treatment multiple regression model will be fit that 
includes the observed outcome at that visit as the dependent variable. The independent variables 
will generally include baseline value, sex, age, randomization stratification factors, and treatment 
duration of study drug unless otherwise specified. Using these regression models, a missing 
value for a participant will be imputed as a draw from the predictive distribution. This process 
will be repeated 50 times, resulting in 50 complete analysis data sets. The analysis has the 
following steps: 
• Using Monte Carlo Markov Chain (MCMC) methodology from SAS PROC MI by 
treatment group to impute the missing data to obtain 50 complete analysis data sets 
• Using the pre-specified analysis to analyze each set of the completed data along with the 
imputed data 
• Obtaining the overall results using PROC MIANALYZE  
6.1.4.1.2 
MNAR Imputation 
The MNAR imputation of missing data and data analysis are implemented as following: 


 
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• Using a standard MAR-based multiple imputation approach (See Section 6.1.4.1.1) to 
impute missing data to obtain 50 complete analysis data sets 
• The imputed data for missing reason matching the MNAR pattern will be adjusted by the 
following: 
o If the participant is randomized in the lixivaptan group, the imputed value will be 
reduced by k (e.g., 50%) times the treatment difference (obtained using the MAR 
approach) 
o If the participant is randomized in the placebo group, the imputed value will be 
increased by l (e.g., 100%) times the treatment difference (obtained using the 
MAR approach)  
o k and l are independently determined   
• Using the pre-specified analysis to analyze each set of the completed data along with the 
imputed data 
• Obtaining the overall results using PROC MIANALYZE 
6.1.4.1.3 
Tipping Point Analysis 
As a sensitivity analysis to the multiple imputation analysis as described above in Section 
6.1.4.1.2, a tipping point analysis will be performed in order to determine the robustness of the 
primary efficacy analysis. 
A tipping point is the inflection point at which the inference under the MNAR assumption 
changes substantially (i.e., the specific k and l in MNAR imputation to reverse the statistical 
significance). 
Since the missing data with the MNAR pattern are imputed bi-dimensionally, the tipping point 
curve will be determined for each of MNAR patterns by the following: 
• Let l = 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 
175%, 200%, 250%, 300%, 350%, 400%, 450%, and 500%.  
Note that: 
o l = 0% (imputed missing in placebo as MAR) 
o l = 100% (imputed missing in placebo as lixivaptan) 
• For each l, search a tipping point k by implementing k=0%, 10%, 20%, 30%, 40%, 50%, 
60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 
450%, and 500%. Report the analysis results at the tipping point when a tipping point is 
found; otherwise, report the analysis results for k=500% when a tipping point is not 
reached.  
Note that: 
o k = 0% (imputed missing in lixivaptan as MAR) 
o k = 100% (imputed missing in lixivaptan as placebo) 


 
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• The tipping point curve consists of all the paired points of k and l when the tipping point 
is found. 
6.1.5. Analysis Visit 
Data summarized by study visit will be based on the nominal visit as reported on the eCRF.  
Data collected at unscheduled visits will only be included in by-visit summaries if the data is 
missing at a visit and the date of an unscheduled visit is within the visit window by protocol. All 
data will be included in participant listings. 
Visit 22 is referred to as the Week 52 visit in Part 1. 
Visit 42 is referred to as the Week 104 visit in Part 2. 
Early Termination (ET) visit is defined as the last visit either during the Double-blind, 
Randomized Treatment Period in Part 1 or during the Maintenance Treatment Period in Part 2 
for participants who early terminated from study or early discontinued from study drug during 
that period in Part 1 or Part 2. 
Visit 22/ET is defined as either Visit 22 or the ET visit in Part 1. Similarly, Visit 42/ET is 
defined as either Visit 42 or the ET visit in Part 2.  
6.1.6. Pooling of Sites 
Analyses will be based on data pooled across investigative sites. 
6.1.7. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
All P values will be displayed to four decimal places and rounded using standard scientific notation 
(e.g., 0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as < 0.0001. 
Adverse events in the clinical database will be coded using the MedDRA version 24.0. 
A treatment related AE is any AE with a relationship to the study drug of possibly related, probably 
related, definitely related or missing relationship to the study drug. 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date before the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 


 
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month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the the date 
is not the same as the date of first dose. 
7. 
Study Participants and Demographics 
Summaries for disposition of participants and demographic and baseline characteristics will be 
presented by treatment group (treatment cohort and overall in Part 2). 
7.1. 
Disposition of Participants and Withdrawals 
Disposition of participants in Part 1 will include, but not limited to, the following:  
• The number of participants who 
o Screened  
 Failed screening 
 Reasons failed screening 
o Placebo Run-in/Placebo Run-in Safety Set 
 Not completed 
 Reasons not completed 
o Lixivaptan Titration/Lixivaptan Titration Safety Set 
 Not completed 
 Reasons not completed 
• The number and percentage (percentage is calculated based on all the randomized 
participants) of participants who 
o Randomized/ITT 
 Treated/mITT/Randomized Safety Set 
 Completers/PEAS 
- On-treatment completers 


 
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- Off-treatment completers 
 At least one on-treatment eGFR assessment/SEAS 
 Discontinued from study drug early and reasons 
 Not completed in Part 1 and reasons 
 In PPAS 
Disposition of participants in Part 2 will include, but not limited to, the following:  
• The number and percentage (percentage is calculated based on all the continuing 
participants in Part 2) of participants who 
o Continued in Part 2 
 Treated/P2SS 
 At least 1 off-treatment eGFR/P2EAS 
 Discontinued from study drug early and reasons 
 Not completed in Part 2 and reasons 
Note that Lixivaptan Treated Safety Set for Parts 1 and 2 combined consists of the participants 
who are randomized and treated (Randomized Safety Set) in lixivaptan treatment group in Part 1 
and the participants who are treated (P2SS) in Part 1/Part 2 - Placebo/Lixivaptan cohort in Part 2. 
7.2. 
Protocol Deviations 
Protocol deviations will be tracked, recorded, and reviewed prior to database lock, following the 
Protocol Deviation Guidance Plan for this study. 
Protocol deviations will be classified as “Important” or “Not Important”.  
Important protocol deviations include: 
• Enrollment of a participant that did not meet inclusion criteria of the study/Enrollment of 
a participant that met exclusion criteria of the study.  
• Missed safety assessments during Screening that are required for the thorough vetting of 
study inclusion/exclusion criteria are considered important deviations. They will be 
documented through failure of the respective Inclusion or Exclusion Criterion.  
• Informed Consent Form (ICF) not obtained, or obtained after initiation of respective 
study procedures, important deviation from GCP consenting procedure, such as wrong 
version used, missing signature(s) and/ or date(s), ICF signed prior to IRB/IEC approval, 
other important deviation from GCP consenting process  
• Prohibited Medications - Use of a prohibited concomitant medication  
• Dosing Adherence – defined as taking less than 80% of the protocol-specified amount of 
study drug across the study 


 
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• Randomization error  
• Mis-stratification of a participant within IRT system  
• Drug dispensation without IRT assignment, incorrect drug kit administration, dose 
mistakes over inappropriate titration/re-titration  
• Used the study drug with incorrect storage (temperature excursions, improper transport, 
security, etc.) which compromises Investigational Product safety or chemical activity 
• MRI examination of kidneys during the screening, in Follow Up Period I, in Follow Up 
Period II not done/done with deviation from imaging technique described in Imaging 
manual  
• Serum creatinine blood sample from Screening, Placebo Run-In, Follow-up Period I (or 
for participants who discontinue treatment prior to Visit 22, from the Follow-up Period 
following study drug treatment discontinuation) and Follow-up Period II not collected/ 
not sent to Central Lab for evaluation/ non evaluable, laboratory manual requirements not 
followed, serum creatinine result missing for any other reason, age/ sex/ race data 
missing or incomplete  
• Liver Chemistry laboratory sample not collected/ not performed as required per protocol  
• Repeat Liver Chemistry tests not performed within 48 hours of knowledge that 
aminotransferase levels >3 x ULN or total bilirubin >2 x ULN  
The following deviation codes will be used to categorize/summarize the important protocol 
deviation above: 
• Inclusion Criteria  
• Exclusion Criteria  
• Study Drug  
• Assessment – Safety  
• Assessment – Efficacy  
• Lab Endpoint Data  
• Visit Window  
• Informed Consent  
• Prohibited Medication  
• Other 
Study participants will be excluded from the PPAS if they meet any of the following criteria: 
• Participant who did not meet all inclusion and exclusion criteria 
• Placebo randomized participant who received lixivaptan treatment 


 
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• Lixivaptan randomized subject who received placebo treatment only throughout study 
• Any participant who received protocol prohibited medications that could affect efficacy 
• Participant with overall study treatment compliance of less than 80% 
The protocol deviations that impact the analysis populations will be recorded once identified and 
periodically reviewed by the study team. The final decision regarding inclusion and exclusion of 
participants from the analysis populations will be determined during a (blinded) data review 
meeting before any unblinding occurs or database freeze/lock, with input from the Clinical, 
Biostatistics, Data Management and Clinical Operations team members and approval from the 
Sponsor. 
Additionally, inclusion and exclusion criteria not met and reasons for screen failures will be 
listed. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, sex, race, ethnicity, height, weight, and BMI will be presented by 
treatment group.  
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, median, minimum, and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    
These analyses will be conducted for the Randomized Safety Set and PEAS (Part 1) and P2SS 
and P2EAS (Part 2). 
The number and percent of participants with a family history of ADPKD, the counts and 
percentages of each method used to diagnose ADPKD, the counts and percentages of each Mayo 
Clinic ADPKD Classification, the counts and percentages of each CKD stage, and the time since 
diagnosis will be presented by treatment group for Part 1. The number and percent of participants 
prior treated with tolvaptan and associated safety information will be summarized by treatment 
group for Part 1. The number and percent of participants reporting various medical histories, 
grouped by MedDRA system organ class and preferred term (coded using MedDRA v.24), will 
be tabulated by treatment group. This analysis will be conducted for the Randomized Safety Set 
and PEAS (Part 1) and P2SS and P2EAS (Part 2). 
In addition, the above summary will be presented for all the participants who entered in the 
Lixivaptan Titration Period (Lixivaptan Treated Safety Set). 
7.4. 
Exposure and Compliance 
Exposure and compliance will be presented for Randomized Safety Set during the Double-Blind, 
Randomized Treatment Period (Part 1) and P2SS during the Maintenance Treatment Period (Part 
2). 
The duration of exposure will be presented in days and calculated as the date of last dose in 
treatment period minus the date of first dose in treatment period, plus one. Duration of exposure 


 
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and total dose taken (mg) will be summarized using descriptive statistics by treatment group 
(treatment cohort in Part 2).  
Compliance to study drug is calculated by dividing the total capsules taken by the total capsules 
the participants were scheduled to take during the treatment period: 
Treatment Compliance (%) = 
𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑆𝑆𝑆𝑆ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 x 100 
Dosing compliance will be summarized using descriptive statistics by treatment group (treatment 
cohort in Part 2). The number and percentages of participants who are < 80% compliant and 
≥ 80% compliant overall in the study will be summarized. 
8. 
Efficacy Analysis 
8.1. 
Definition of Completer and Non-completer 
Part 1 completer and non-completer will be defined as the following: 
• 
On-treatment completer: all the randomized participants who take double-blind study 
drug in accordance with the protocol through Visit 22 (Week 52), and complete some or 
all of their required trial visits/assessments through Visit 22 and have at least one follow-
up serum creatinine assessment during off-treatment Follow-up Period I. 
• 
Off-treatment completer: all the randomized participants who permanently discontinue 
double-blind study drug (or never begin double-blind treatment) and complete some or all 
of their required study visits/assessments through Visit 22 and have at least one follow-up 
serum creatinine assessment during Follow-up Period I. 
• 
Non-completer: all the randomized participants who take the study drug (or never take 
the study drug) but do not complete the Visit 22/ET visit or complete Visit 22/ET visit 
and do not have at least 1 follow up serum creatinine assessment during Follow-up Period 
I. 
Part 2 completer and non-completer will be defined as the following: 
• 
On-treatment completer: all the randomized participants who enter Part 2 of the study, 
take open-label study drug in accordance with the protocol through Visit 42 (Week 104), 
and complete some or all of their required study visits/assessments through Visit 42 and 
have at least one follow-up serum creatinine assessment during Follow-up Period II. 
• 
Off-treatment completer: all the randomized participants who enter Part 2 of the study, 
but permanently discontinue open-label study drug (or never begin open-label treatment) 
and complete some or all of their required study visits/assessments through Visit 42 and 
have at least one follow-up serum creatinine assessment during Follow-up Period II. 
• 
 Non-completer: all the randomized participants who enter Part 2 of the study, take the 
study drug (or never take the study drug) but do not complete the Visit 42/ET visit or 


 
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complete Visit 42/ET visit but do not have at least 1 follow up serum creatinine 
assessment during Follow-up Period II. 
8.2. 
Primary Efficacy Analysis (Part 1) 
The primary efficacy endpoint is the annualized change in eGFR (2021 CKD-EPIcr_R), with 
restriction as defined below, for serum creatinine from baseline (mean of 3 eGFR determinations 
obtained during Screening and Placebo Run-in Periods, i.e., Visits 1a (or 1b, if required), Visit 2, 
and Visit 3) to final assessment (mean of 3 eGFR determinations obtained during Follow-up 
Period I after Week 52 for on-treatment completers or, for participants who discontinue study 
drug treatment prior to Week 52 [Visit 22], 8 to 28 days following study drug treatment 
discontinuation).  
Restriction refers to all annualized changes in eGFR of participants that discontinued study drug 
treatment that are greater (or less) than the maximum (or minimum) of the annualized eGFR 
change based on off-treatment serum creatinine assessments of all on-treatment completers 
regardless of treatment groups. For such participants, the annualized change in eGFR will 
assume the maximum (or minimum) value of all on-treatment completers to reduce the impact of 
the outliers created by the annualized eGFR change in participants that early discontinued study 
drug treatment. 
The primary estimand for the primary efficacy endpoint is the between-treatment group 
difference in the change from baseline in off-treatment eGFR if all the participants in the PEAS 
had tolerated and adhered to their treatment for 52 weeks. Potential bias due to randomized 
participants prematurely discontinuing from double-blind treatment will be handled by 
annualizing the changes from baseline by multiplying each participant’s change from baseline by 
365.25 days divided by the duration from the median of the collection dates of the baseline 
eGFR assessments to the median of the collection dates of the 3 eGFR assessments made during 
the post-treatment, follow-up period immediately (8-28 days) following study drug 
discontinuation. 
An analysis of covariance (ANCOVA) model with fixed effects for treatment group (0=placebo, 
1=lixivaptan) and the randomization stratification factors (CKD stage [CKD2 versus CKD3/4] 
and Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]) and the baseline eGFR as a 
covariate. 
The following SAS code will be used for the primary efficacy analysis: 
PROC GLM ALPHA =0.01; 
CLASS TREATMENT CKD_STAGE MAYO_CLASS; 
MODEL ANNUALIZED_CHANGE = TREATMENT BASELINE CKD_STAGE MAYO_CLASS/SOLUTION 
SS3 CLPARM; 
LSMEANS TREATMENT/STDERR 
ESTIMATE “Treatment Effect: Lixivaptan - Placebo" TREATMENT -1 1; 
RUN; 
This analysis assumes that data are missing at random. The stratification by CKD stage at the 
time of randomization will be based on the baseline eGFR creatinine equation in effect at the 


 
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time of baseline visits. However, all efficacy analyses of change in eGFR will be based on the 
CKD-EPIcr_R equation.  
The primary efficacy analysis will be performed on the PEAS at the 1% level of significance 
(p<0.01). 
8.2.1. Sensitivity Analyses of the Primary Efficacy Endpoint  
8.2.1.1. 
Primary Sensitivity Analyses  
Sensitivity analyses on the primary efficacy endpoint will be performed using the same 
ANCOVA model as the primary efficacy analysis with fixed effects for treatment group and the 
randomization stratification factors (CKD stage [CKD2 versus CKD3/4] and Mayo Clinic 
ADPKD Image Classification [1C, 1D, or 1E]) and the baseline eGFR as a covariate. 
Two sensitivity analyses will be performed on the mITT: 
• The annualized change in eGFR (2021 CKD-EPIcr_R) without restriction from baseline 
to off treatment assessment after Week 52 (mean of 3 eGFR values obtained during off-
treatment follow-up visits after Week 52); missing data are handled by multiple 
imputation: 
o MAR (Section 6.1.4.1.1) 
• The annualized change in eGFR (2021 CKD-EPIcr_R) with restriction from baseline to 
final assessment (mean of 3 eGFR values obtained during Follow-up Period I after Week 
52 for on-treatment completers or, for participants who discontinue study drug treatment 
prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug 
treatment discontinuation); missing data are handled by multiple imputation: 
o MAR (Section 6.1.4.1.1) 
o MNAR and tipping point analysis (Sections 6.1.4.1.2 & 6.1.4.1.3)  
Two sensitivity analyses will be performed on the PEAS: 
• The annualized change in off-treatment eGFR (2021 CKD-EPIcr_R) without restriction 
from baseline to final assessment (mean of 3 eGFR values obtained during Follow-up 
Period I after Week 52 for on-treatment completers or, for participants who discontinue 
study drug treatment prior to Visit 22, during the Follow-up Period 8 to 28 days 
following study drug treatment discontinuation) 
• The annualized change in eGFR (2009 CKD-EPI) with restriction from baseline to final 
assessment (mean of 3 eGFR values obtained during Follow-up Period I after Week 52 
for on-treatment completers or, for participants who discontinue study drug treatment 
prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug 
treatment discontinuation) 
One sensitivity analysis will be performed on the on-treatment completers of the PEAS :  
• The annualized change in eGFR (2021 CKD-EPIcr_R) without restriction from baseline 
to final assessment (mean of 3 eGFR values obtained during Follow-up Period I after 
Week 52 for on-treatment completers or, for participants who discontinue study drug 


 
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treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study 
drug treatment discontinuation) 
One sensitivity analysis will be performed on the PPAS:  
• The annualized change in eGFR (2021 CKD-EPIcr_R) with restriction from baseline to 
final assessment (mean of 3 eGFR values obtained during Follow-up Period I after Week 
52 for on-treatment completers or, for participants who discontinue study drug treatment 
prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug 
treatment discontinuation) 
8.2.1.2. 
Secondary Sensitivity Analyses  
Sensitivity on the annualized change in eGFR (2021 CKD-EPIcr_R) with restriction from 
baseline to final assessment (mean of 3 eGFR values obtained during Follow-up Period I after 
Week 52 for on-treatment completers or, for participants who discontinue study drug treatment 
prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug treatment 
discontinuation) using a weighted ANCOVA will be performed on the PEAS. The weighted 
analysis is based on the reciprocal of the estimated variance of the “estimated slopes” for 
participants based on individual off-treatment eGFR values obtained during Follow-up Period I 
after Week 52 for on-treatment completers or, for participants who discontinue study drug 
treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug 
treatment discontinuation). The detailed algorithm to derive the weight is provided in an 
Appendix.  
The weighted ANCOVA model will include fixed effects for treatment group and the 
randomization stratification factors (CKD stage [CKD2 versus CKD3/4] and Mayo Clinic 
ADPKD Image Classification [1C, 1D, or 1E]) and the baseline eGFR as a covariate. 
8.2.1.3. 
Exploratory Sensitivity Analysis 
The annualized change from baseline in eGFR theoretically contains natural disease progression 
due to no treatment such as a period for placebo run-in or a period between the last treatment and 
serum creatinine assessment. To explore the hypothetical treatment effect, a sensitivity analysis 
will also be performed on the PEAS based on all the changes from baseline in off-treatment 
eGFRs (2021 CKD-EPIcr_R) that are assessed after 8 days off treatment after randomization in 
Part 1. The linear mixed effect model with effects of pre-randomization time, off-treatment time, 
on-treatment time, treatment-by-on-treatment time, randomization stratification factors (CKD 
stage [CKD2 versus CKD3/4] and Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]), 
and eGFR baseline will be used to fit the eGFR data. Intercept, pre-randomization time are both 
a fixed effect and a random effect. An unstructured variance-covariance matrix is used for 
modeling. 
PROC MIXED EMPIRICAL; 
CLASS TREATMENT CKD_STAGE MAYO_CLASS USUBJID; 
MODEL CHANGE = BASELINE PRIOR-TIME OFF-TIME ON-TIME ON-TIME*TREATMENT 
CKD_STAGE MAYO_CLASS; 


 
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RANDOM INTERCEPT PRIOR-TIME/TYPE=UN SUB= USUBJID; 
ESTIMATE "Annualized Change from Baseline in eGFR in Lixivaptan Group" BASELINE 1 ON-TIME 
1 ON-TIME*TREATMENT 0 1; 
ESTIMATE " Annualized Change from Baseline in eGFR in Placebo Group " BASELINE 1 ON-TIME 1 
ON-TIME*TREATMENT 1 0; 
ESTIMATE "Treatment Difference in Annualized Slope of On-Treatment eGFR" ON-
TIME*TREATMENT -1 1; 
RUN; 
where: 
• Treatment group (TREATMENT) is coded as 0=Placebo and 1=lixivaptan 
• Total time (years) for each off-treatment eGFR = elapsed time from baseline [median 
date of 3 baseline eGFRs obtained during Screening and Placebo Run-In Periods 
(Visits1a [1b, if required], Visit 2, and Visit 3) to time of off-treatment eGFR (≥ 8 days 
off treatment). Total time is divided into three portions: pre-randomization time (PRIOR-
TIME), on-treatment time (ON-TIME) and off-treatment time (OFF-TIME). 
• Pre-randomization time (years) = elapsed time (years) from baseline to date of 
randomization 
• On-treatment time (years) = time (years) on treatment after randomization, number of 
treated days with randomized treatment from randomization to date of eGFR 
assessment/365.25. 
• Off-treatment time (years) = Total time (years) for each off-treatment eGFR - Pre-
randomization time (years) - On-treatment time (years).  
8.3. 
Secondary Efficacy Analysis (Part 1) 
If the primary efficacy endpoint is statistically significant at the 1% level of significance, then 
the secondary efficacy endpoints will be tested at the 1% level of significance in sequential order 
on the SEAS: 
1. Annualized rate of change (slope) in eGFR based on all on-treatment eGFR (2021 CKD-
EPIcr_R) determinations during the Double-blind, Randomized Treatment Period  
2. Annualized percent change from baseline in htTKV as measured by MRI 
Because the testing is sequential, the type I error rate of ≤ 0.01 is maintained. Failure at any stage 
in the sequence implies automatic failure at all subsequent stages. If the primary efficacy 
endpoint is not significant at the 1% level of significance then all other p-values will be 
presented as exploratory only.  
If the primary efficacy endpoint is significant at the 1% level of significance, the first secondary 
efficacy endpoint will be tested. If the first secondary efficacy endpoint is significant at the 1% 
level of significance, the second efficacy endpoint will be tested. If the first secondary efficacy 
endpoint is not significant at the 1% level of significance, the second secondary efficacy 
endpoint is presented for exploratory purposes only. 


 
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8.3.1. Annualized Rate of Change (Slope) in eGFR  
The first secondary efficacy endpoint is annualized rate of change (slope) in eGFR (2021 CKD-
EPIcr_R) at on-treatment timepoints using the SEAS. This annualized rate of change (slope) in 
eGFR on treatment will be estimated by utilizing a mixed-effects model for repeated measures 
(MMRM) on the observed changes in eGFR from baseline (mean of the 3 eGFR values obtained 
during the Screening and Placebo Run-in Periods) to all visits with on-treatment eGFR values 
during the Double-Blind, Randomized Treatment Period visits, i.e., Visit 10 (Week 4) to Visit 22 
(Week 52), while on study drug treatment. Any eGFR values obtained 1 day after study drug 
treatment during the Double-Blind, Randomized Treatment Period are excluded from the 
analysis. The MMRM will include treatment group, visit, treatment group-by-visit, and 
randomization stratification factors (CKD stage [CKD2 versus CKD3/4] and Mayo Clinic 
ADPKD Image Classification [1C, 1D, or 1E]) as fixed effects, baseline eGFR as a covariate, 
and the baseline-by-visit interaction. An unstructured variance-covariance matrix is assumed for 
the repeated measures.  
Analysis of MMRM will be applied to the change from baseline in eGFR among the 13 on-
treatment visits: visit 10 (week 4), visit 11 (week 8),visit 12 (week 12), visit 13 (week 16), visit 
14 (week 20), visit 15 (week 24), visit 16 (week 28), visit 17 (week 32), visit 18 (week 36), visit 
19 (week 40), visit 20 (week 44), visit 21 (week 48) and visit 22 (week 52). The median of the 
13 visits is the 7th visit, i.e., Visit 16 (Week 28).  
To estimate the slope in eGFR on treatment, the contrast coefficients of the linear trend for visits 
will become -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6. Under assumptions that the annualized slope 
and acute hemodynamic effect are constant over time, this contrast can be used to estimate the 
slope (note that the acute hemodynamic effect is eliminated by the contrast). The resulted 
estimate corresponding to those coefficients will be slope (per week) multiplied by 728 (-6*4 -
5*8 -4*12 -3*16 -2*20 -1*24 +0*28 +1*32 +2*36 +3*40 +4*44 +5*48 +6*52=728) or 
annualized slope multiplied by 14 (728/52=14). 
Thus, the coefficients of the linear trend contrast of these 13 visits to estimate the annualized 
slope are -6/14, -5/14, -4/14, -3/14, -2/14, -1/14, 0/14, 1/14, 2/14, 3/14, 4/14, 5/14, 6/14. 
Example SAS code is shown below: 
PROC MIXED EMPIRICAL; 
CLASS TREATMENT VISIT CKD_STAGE MAYO_CLASS USUBJID; 
MODEL CHANGE = TREATMENT BASELINE VISIT VISIT*TREATMENT BASELINE*VISIT CKD_STAGE 
MAYO_CLASS /SOLUTION; 
REPEATED VISIT/TYPE=UN SUB= USUBJID; 
ESTIMATE “Lixivaptan Annualized Slope" VISIT -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 
                    VISIT*TREATMENT 0 0 0 0 0 0 0 0 0 0 0 0 0 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6/DIVISOR=14; 
ESTIMATE “Placebo Annualized Slope" VISIT -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 
                    VISIT*TREATMENT -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 0 0 0 0 0 0 0 0 0 0 0 0 0 /DIVISOR=14; 
ESTIMATE “Treatment Difference in Annualized Slope"  
VISIT*TREATMENT 6 5 4 3 2 1 0 -1 -2 -3 -4 -5 -6  -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6/DIVISOR=14; 
RUN; 


 
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A linear contrast of the treatment slope differences for visits will be used for this analysis. 
8.3.1.1. 
Sensitivity Analysis of Annualized Rate of Change (Slope) in eGFR  
Two sensitivity analyses will be performed on the annualized rate of change (slope) in eGFR 
(2021 CKD-EPIcr_R) using the PPAS and SEAS.  
The sensitivity analysis using the PPAS is the same as the primary analysis for the annualized 
rate of change (slope) in eGFR on treatment (Section 8.3.1) but using PPAS. 
The sensitivity analysis using the SEAS will use the change from baseline in eGFR values 
assessed at the end of lixivaptan titration, on-treatment eGFR values assessed during the Double-
blind, Randomized Treatment visits and off-treatment eGFR values assessed during the Follow-
up Period I visits. Note that on-treatment eGFR values obtained 1 days after the latest dose and 
off-treatment eGFR values obtained prior to 8 days after the last dose will be excluded in the 
analysis. An acute hemodynamic effect will be considered for eGFR at the end of lixivaptan 
titration for all the participants and for all eGFRs on treatment for the lixivaptan participants. All 
other eGFRs will not be considered for the hemodynamic effect. The acute hemodynamic effect 
indicator/flag (ACUHEMO) will be included in the model (1=Yes) or (0=No). 
The linear mixed effect model with effects of time (as a continuous variable in years), treatment, 
time-by-treatment interaction, acute hemodynamic effect, baseline (of the primary 
endpoint), and randomization stratification factors (CKD stage [CKD2 versus CKD3/4] and 
Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]) will be used to fit the GFR 
estimates, in which the intercept and time are both a fixed effect and a random effect. An 
unstructured variance-covariance matrix is assumed for the modeling.  
Example SAS code is shown below: 
PROC MIXED EMPIRICAL; 
CLASS TREATMENT ACUHEMO CKD_STAGE MAYO_CLASS USUBJID; 
MODEL CHG_eGFR = TREATMENT ACUHEMO BASELINE TIME TIME*TREATMENT CKD_STAGE 
MAYO_CLASS /SOLUTION; 
RANDOM INTERCEPT TIME/TYPE=UN SUB= USUBJID; 
ESTIMATE "Annualized Slope of On-Treatment eGFR" TIME*TREATMENT -1 1; 
RUN; 
The estimate of the treatment group by visit interaction will be used for this analysis. 
8.3.2. Annualized Percent Change from Baseline in htTKV 
The 2nd secondary efficacy endpoint is the annualized percent change in htTKV from baseline to 
28 days after the last dose of the study drug, i.e., Visit 25 during the Follow-up Period I after 
Week 52 for on-treatment completers or, for participants who discontinue study drug treatment 
prior to Week 52 [Visit 22], during the Follow-up Period 28 days following study drug treatment 
discontinuation. Baseline htTKV is the one obtained at Screening (Visit 1a). 


 
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Missing data will be handled by multiple imputation using an ANCOVA with factors of 
treatment, stratification factors and sex with age, time on treatment (date of last dose – date of 
first dose + 1), and baseline as covariates.  
In order to reduce the variability in the time of post-baseline MRI acquisition, elapsed time from 
baseline to post-baseline MRI will be treated as a continuous variable, expressed as years from 
date of baseline MRI acquisition to date of off-treatment MRI acquisition visit (date of MRI visit 
– date of Baseline MRI + 1,). In addition, in order to reduce heterogeneity in variance and 
achieve linearity over time, log10 transformation will be applied to the htTKV data.  
An ANCOVA will be used to analyze the change from baseline in log-transformed htTKV data 
on the PEAS to estimate annualized percent change in htTKV by time. The model will include 
fixed effects for the randomization stratification factors (CKD stage [CKD2 versus CKD3/4] and 
Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]) with baseline htTKV, and treatment 
group-by-time interaction as a covariate. 
Example SAS code is shown below (treatment group is coded as 0=placebo and 1=lixivaptan): 
PROC GLM ALPHA=0.01; 
CLASS TREATMENT CKD_STAGE MAYO_CLASS; 
MODEL CHG_LOGTKV = LOG_BASETKV TIME*TREATMENT CKD_STAGE MAYO_CLASS / 
SOLUTION SS3 CLPARM; 
ESTIMATE "Annualized Change from Baseline for Lixivaptan (Log-scale)" INTERCEPT 1 
LOG_BASETKV mean TIME*TREATMENT 0 1 CKD_STAGE 0.5 0.5 MAYO_CLASS 0.3333 0.3333 
0.3333; 
ESTIMATE "Annualized Change from Baseline for Placebo (Log-scale)" INTERCEPT 1 
LOG_BASETKV mean TIME*TREATMENT 1 0 CKD_STAGE 0.5 0.5 MAYO_CLASS 0.3333 0.3333 
0.3333; 
ESTIMATE "Treatment Difference in Annualized Change from Baseline (Log-scale)" 
TIME*TREATMENT -1 1; 
RUN; 
Where “mean” is the overall mean of log-transformed baseline htTKV values. 
A significance level of 0.01 (two-sided) will be used to declare statistical significance of 
treatment effect at the final analysis. Antilog (with a base of 10) of the treatment effect and 99% 
confidence intervals (99% CIs) derived from the model (in a log10 scale) provide a ratio of 
geometric means of the relative change (ratio) from baseline in htTKV (i.e., 100% plus 
annualized percent change). 
8.3.2.1. 
Sensitivity Analysis of Annualized Percent Change from Baseline in htTKV 
Two sensitivity analyses will be performed on the annualized percent change from baseline in 
htTKV using the PPAS and SEAS.  
The sensitivity analysis using the PPAS is the same as the primary analysis for the annualized 
percent change from baseline in htTKV (Section 8.3.2) but using PPAS. 
The sensitivity analysis will be performed for the annualized percent change from baseline to 
off-treatment follow-up Visit 25 after Week 52 in htTKV using the SEAS. Missing data will be 


 
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handled by multiple imputation using an ANCOVA with factors of treatment, stratification 
factors and sex with age, time on treatment (date of last dose – date of first dose + 1), and 
baseline as covariates. An ANCOVA model with fixed effects of treatment (0=placebo, 
1=lixivaptan) and randomization stratification factors, and baseline, (elapsed) time, treatment-by-
time as a covariate will be used to fit the log10-transformed htTKV data. 
8.4. 
Subgroup Efficacy Analysis (Part 1) 
Descriptive statistics will be presented for the primary and secondary efficacy analyses for the 
following subgroups: 
• Age (Tertiles) 
• Sex (Male, Female) 
• Race (White, non-White) 
• Region (US, non-US) 
• Baseline eGFR (≤median, >median) 
• CKD stage (CKD2, CKD3/4) 
• Mayo Clinic ADPKD Image Classification (1C, 1D, and 1E) 
• Baseline htTKV (≤median, >median) 
8.5. 
Health Outcomes Analyses (Part 1) 
The endpoints from ADPKD-Impact Scale (ADPKD-IS), ADPKD-Pain and Impact Scale 
(ADPKD-PDS), ADPKD-Urinary Impact Scale (ADPKD-UIS) Patient Reported Outcomes 
(PROs) will be evaluated separately by domain (see Section 4.1.2.2) for the PEAS. Missing data 
are not imputed prior to the analysis. 
An analysis utilizing a MMRM will be performed on the changes in each domain score from 
baseline (visit 2) to all Double-Blind, Randomized Treatment Period visits up to Follow up 
Period I (i.e., Visits 12, 15, 18, 22 and 25). The MMRM will include treatment group, visit, 
treatment group-by-visit, and randomization stratification factors (CKD stage [CKD2 versus 
CKD3/4] and Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]) as fixed effects, 
baseline as a covariate, and the baseline-by-visit interaction. An unstructured variance-
covariance matrix is assumed for the repeated measures. The treatment difference in change from 
baseline at each post-baseline visit will be produced from the analysis. 
Example SAS code is shown below: 
PROC MIXED EMPIRICAL ALPHA=0.01; 
CLASS TREATMENT VISIT CKD_STAGE MAYO_CLASS USUBJID; 
MODEL CHANGE = TREATMENT BASELINE VISIT VISIT*TREATMENT BASELINE*VISIT CKD_STAGE 
MAYO_CLASS /SOLUTION CL; 
REPEATED VISIT/TYPE=UN SUB= USUBJID; 
LSMEANS VISIT*TREATMENT/ALPHA=0.01 PDIFF CL; 
ESTIMATE  ‘Lixivaptan – Placebo Change from Baseline at Visit 12’  
                    TREATMENT -1 1 VISIT*TREATMENT -1 0 0 0 0 1 0 0 0 0; 


 
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ESTIMATE  ‘Lixivaptan – Placebo Change from Baseline at Visit 15’  
                    TREATMENT -1 1 VISIT*TREATMENT 0 -1 0 0 0 0 1 0 0 0; 
… 
RUN; 
In addition, descriptive summary (n, mean, standard deviation, median, minimum, and 
maximum) will be used to summarize the change from baseline in each domain score at the 
Lixivaptan Titration Period visits (Visits 4-9) for all the participants in the Lixivaptan Treated 
Safety Set. 
8.6. 
Exploratory Efficacy Analyses (Part 1) 
8.6.1. Annualized Change in eGFR (2021 CKD-EPIcr-cys_R)  
This analysis is based on the annualized change in eGFR (2021 CKD-EPIcr-cys_R) with 
restriction (defined in Section 8.2 Primary Efficacy Analysis except that in this analysis the 
eGFR values will be calculated from 2021 CKD-EPIcr-cys_R) on the PEAS. An ANCOVA 
model with fixed effects for treatment group (0=placebo, 1=lixivaptan) and the randomization 
stratification factors (CKD stage [CKD2 versus CKD3/4] and Mayo Clinic ADPKD Image 
Classification [1C, 1D, or 1E]) and the baseline eGFR as a covariate. 
SAS code from the primary efficacy endpoint analysis can be used (Section 8.2). 
This analysis assumes that data are missing at random.  
8.6.2. Annualized Percent Change in Height-adjusted Liver Volume (htLV) 
This analysis is based on the annualized percent change in htLV from baseline to 28 days after 
the last dose of the study drug, i.e., Visit 25 during the Follow-up Period I after Week 52 for on-
treatment completers or, for participants who discontinue study drug treatment prior to Week 52 
[Visit 22], during the Follow-up Period 28 days following study drug treatment discontinuation. 
Baseline htLV is the one obtained at Screening (Visit 1a). Missing data will not be imputed for 
this analysis. 
In order to reduce the variability in the time of post-baseline MRI acquisition, elapsed time from 
baseline to post-baseline MRI will be treated as a continuous variable, expressed as years from 
date of Baseline MRI acquisition to date of MRI acquisition visit (date of MRI visit – date of 
Baseline MRI + 1). In addition, in order to reduce heterogeneity in variance and achieve linearity 
over time, log10 transformation will be applied to the htLV data. 
An ANCOVA will be used to analyze the log-transformed htLV data on the PEAS to estimate 
annualized percent change in htLV by time. The model will include fixed effects for treatment 
group (0=placebo, 1=lixivaptan), the randomization stratification factors (CKD stage [CKD2 
versus CKD3/4] and Mayo Clinic ADPKD Image Classification [1C, 1D, or 1E]), baseline htLV, 
(elapsed) time, and treatment group-by-time interaction as a covariate. 


 
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Example SAS code in Section 8.3.2 for the htTKV analysis can be used to analyze the htLV 
when the log-transformed htTKV data are replaced by the log-transformed htLV data. 
A significance level of 0.01 (two-sided) will be used to declare statistical significance of 
treatment effect at the final analysis. Antilog (with a base of 10) of the treatment effect and 99% 
confidence intervals (99% CIs) derived from the model (in a log10 scale) provide a ratio of 
geometric means of the relative change (ratio) from baseline in htLV (i.e., 100% plus annualized 
percent change). 
8.6.3. Urine Osmolality  
Descriptive statistics for the change from baseline (Visit 2) in morning spot urine osmolality will 
be presented by treatment group for the PEAS. The number (%) of participants who show 
suppressed urine osmolality in each treatment group, defined by 2 levels of spot urine osmolality 
≤250 mOsm/kg and ≤300 mOsm/kg will be summarized descriptively at each time point. 
8.7. 
Key Comparison Endpoint Analysis (Part 2) 
All the eGFR assessments for this analysis are calculated from the 2021 CKD-EPI equation 
(2021 CKD-EPIcr_R). 
Descriptive statistics will be presented by treatment cohort for the key comparison analysis of 
annualized change in eGFR from baseline (mean of 3 eGFR values obtained at off-treatment 
visits after Week 52 during Follow-up Period I) to final assessment (mean of 3 eGFR values 
obtained during Follow-up Period II after Week 104 for on-treatment completers or, for 
participants who discontinue study drug treatment prior to Week 104 [Visit 42], 8 to 28 days 
following study drug treatment discontinuation) for the P2EAS.  
To assess durability and continuation of treatment effect observed in Part 1, the mean annualized 
change from baseline by treatment cohort for Part 2 will be presented along with Part 1 results 
for the participants in that treatment cohort. 
In addition, descriptive statistics for the annualized change from baseline in the eGFR to final 
assessment will be presented for all the participants in P2EAS (overall).  
8.8. 
Sensitivity Analysis of the Key Comparison Analysis (Part 2) 
All the eGFR assessments for this analysis are calculated from the 2021 CKD-EPI equation 
(2021 CKD-EPIcr_R). 
Descriptive statistics will be performed for all available annualized changes from baseline (the 
mean of the 3 off-treatment eGFR values obtained after Week 52 in Part 1) to the mean of the 3 
off-treatment eGFRs after Week 104 for the P2EAS. Descriptive statistics will be presented by 
treatment cohort and overall along with Part 1 results for the same participants in each treatment 
cohort. 


 
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8.9. 
Other Comparison Analyses (Part 2) 
8.9.1. Annualized Rate of Change (Slope) in eGFR 
All the eGFR assessments for this analysis are calculated from the 2021 CKD-EPI equation 
(2021 CKD-EPIcr_R). 
All the observed changes from baseline (mean of the 3 eGFR values obtained at off-treatment 
visits after Week 52 in Part 1) to all visits with on-treatment eGFR values during the 
Maintenance Treatment Period visits, i.e., Visit 30 (Week 56) up to Visit 42 (Week 104), while 
on study drug treatment in the P2EAS will be utilized for determining the annualized rate of 
change (slope) in eGFR. Any eGFR values obtained after 1 or more days off of study drug 
treatment during the Maintenance Treatment Period are excluded from the analysis.  
To determine the annualized rate of change (slope) in eGFR, the average of observed changes 
from baseline at each visit by treatment cohort and overall will be calculated. The annualized rate 
of change (slope) in the eGFR will be calculated by: 
The annualized rate of change (slope) in eGFR = (-6 x mean change at Visit 30 -5 x mean change 
at Visit 31 -4 x mean change at Visit 32 -3 x mean change at Visit 33 -2 x mean change at Visit 
34 -1 x mean change at Visit 35 -0 x mean change at Visit 36 +1 x mean change at Visit 37 +2 x 
mean change at Visit 38 +3 x mean change at Visit 39 + 4 x mean change at Visit 40 + 5 x mean 
change at Visit 41 + 6 x mean change at Visit 42)/14. 
The annualized rate of change (slope) from baseline in eGFR in Part 2 will be presented by 
treatment cohort and overall for participants in the P2EAS along with the annualized rate of 
change (slope) from baseline at Part 1 for the participants in each treatment cohort.  
8.9.2. Annualized Percent Change from Baseline in htTKV 
The annualized percent change from baseline in htTKV is estimated by the annualized change in 
log10-transformed htTKV, annualized by the elapsed time (years) between two dates of MRI 
taken, from baseline to 28 days after the last dose of the study drug,  i.e., Visit 45 during the 
Follow-up Period II after Week 104 for on-treatment completers or, for participants who 
discontinue study drug treatment prior to Week 104 [Visit 42], during the Follow-up Period 28 
days following study drug treatment discontinuation. Baseline htTKV is the one obtained at off 
treatment follow-up Visit 25 after Week 52 in Part 1.  The annualized change from baseline in 
log10 transformed htTKV will be summarized by treatment cohort for all participants in the 
P2EAS. Anti-log of the mean annualized change from baseline in log10 transformed htTKV will 
provide an estimate of the geometric mean of the related growth of htTKV to baseline htTKV 
(i.e., 100% plus annualized percent change). 
The annualized percent change from baseline in htTKV in Part 2 will be presented by treatment 
cohort and overall for participants in the P2EAS along with the annualized percent change from 
baseline at Part 1 for the participants in each treatment cohort.  


 
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The above comparison will also be performed by replacing the log10-transformed htTKV value 
at 28 days after the last dose of the study drug by the log10-transformed htTKV value at 28 days 
after Week 104. 
8.10. Health Outcome Analyses (Part 2) 
The descriptive statistics for change from baseline in each domain score of three patient reported 
health questionnaires are presented at each evaluated visit in Part 2 by treatment cohort and 
overall for all the participants in the P2EAS. Baseline score is defined as the domain score from 
Follow-up period I (Visit 25) after Week 52 in Part 1. In order to compare the results from Part 2 
to those in Part 1, the descriptive statistics for change from baseline in each domain score of 
three patient reported health questionnaires are presented at each corresponding visit at Part 1 by 
treatment cohort. 
8.11. Exploratory Comparison Analyses (Part 2) 
8.11.1. Annualized Percent Change in htLV 
The derivation of the annualized percent change from baseline in htLV in Part 2 and presentation 
of the analysis results will be the same as the analysis of htTKV described in Section 8.9.2 
except that the htTKV data will be replaced by the htLV data. 
8.11.2. Urine Osmolality  
Descriptive statistics for the change from baseline (Visit 2) in morning spot urine osmolality will 
be presented for the participants in the P2EAS by treatment cohort and overall at each scheduled 
time point. The number (%) of participants who show suppressed urine osmolality by treatment 
cohort and overall, defined by two levels of spot urine osmolality ≤250 mOsm/kg and ≤300 
mOsm/kg will be summarized descriptively at each time point. 
8.11.3. Annualized Change from Baseline in eGFR (2021 CKD-EPIcr-cys_R) 
The analysis of the annualized change in eGFR analysis will be the same as described in Section 
8.7, except that the eGFR values used will be determined using the 2021 CKD-EPIcr-cys_R 
equation for serum creatinine and cystatin C. 
8.12. Additional Analyses (Part 2) 
Additional exploratory analyses may be conducted to address any issues caused by potentially 
different treatment/exposure patterns between Part 1 and Part 2 for the participants in the 
P2EAS. 
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, changes in clinical laboratory values, changes in 


 
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vital signs, and electrocardiogram (ECG results). 
A Safety Analyses will be performed for the following:  
• Single-Blind Placebo Run-in Period for the Placebo Run-in Safety Set (Part 1)  
• Lixivaptan Titration Period for the Lixivaptan Treated Safety Set (Part 1)  
• Double-blind, Randomized Treatment and Follow-up I Periods for the Randomized 
Safety Set (Part 1) 
• Maintenance Treatment and Follow-up II Periods for the P2SS (Part 2)  
• Double-blind, Randomized Treatment and Follow-up I Periods and Maintenance 
Treatment and Follow-up II Periods for the LTSS (Part 1 and Part 2 combined) 
The tolerability will be summarized by: 
• Incidence of participants with the maximum dose level taken by the final tolerated dose 
level determined for the double-blind treatment period during Lixivaptan Titration Period 
• Count and percentage of participants up-titrated, down-titrated, remaining unchanged, or 
discontinued by the dose levels by visit (or time after titration initiation) during 
Lixivaptan Titration Period  
• Count and percentage of participants by dose level by Visit (or time after randomization) 
during the double-blind treatment period in Part 1 by treatment group 
• Count and percentage of participants by dose level by Visit (or time after initiation of 
maintenance period) during the maintenance period in Part 2 by treatment group 
9.1. 
Key Liver Safety Analysis 
The incidence of participants who develop serum ALT levels >3 x ULN will be summarized by 
treatment group for Part 1 and by treatment cohort for Part 2. For Part 1, Fisher’s exact test will 
be used to test if the incidence rate in the lixivaptan group is different from that in the placebo 
group. 
In addition, an eDISH plot will be presented for Part 1. 
9.2. 
Adverse Events 
An AE is defined as any untoward medical occurrence in a participant enrolled into this study 
regardless of its causal relationship to study drug.  
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study 
drug or any event already present that worsens in either intensity or frequency after exposure to 
study drug. 
A serious adverse event (SAE) is defined as any event that:  
• results in death,  
• is immediately life threatening,  


 
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• requires in-participant 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. 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary (v24.0 March 2021). 
The causality to treatment will be grouped into three categories for the summaries: not related 
(reported as either “not related” or “unlikely related”), possibly related (reported as “possible 
related”), and related (reported as either “probably related”, “definitely related”, or missing 
causality) 
For Part 1 and Part 2 the number and percent of participants reporting TEAEs, grouped by 
MedDRA system organ class and preferred term, will be tabulated by treatment group (treatment 
cohort for Part 2) and causality to treatment (total, not related, possibly related, or related). In the 
case of multiple occurrences of the same TEAE within the same participant, the most related one 
will be counted for the participant. This summary will be repeated for the common TEAEs defined 
as the incidence rate of ≥ 3% at the lixivaptan group in Part 1. 
The number and percent of participants reporting TEAEs, grouped by MedDRA system organ 
class and preferred term, will be tabulated by severity and treatment group (treatment cohort for 
Part 2) for all the TEAEs. In the case of multiple occurrences of the same TEAE within the same 
participant, the most severe one will be counted. 
Adverse event summaries, grouping by MedDRA system organ class and preferred term, will be 
repeated by severity and treatment group (treatment cohort for Part 2) for treatment related 
TEAEs including possibly related TEAEs. 
An overall summary of TEAEs will be presented by treatment group. The overall summary will 
include the total number and percent of participants reporting: 
• 
Any TEAEs 
• 
Any treatment-related TEAE 
• 
Any severe TEAE 
• 
Any severe treatment-related TEAE 
• 
Any serious TEAE 


 
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• 
Any serious treatment-related TEAE  
• 
Any TEAE of special interest (TEAESI) 
• 
Any TEAE leading to permanent study drug discontinuation 
• 
TEAEs resulting in death  
In the AE data listings, all AEs will be displayed to include whether the adverse events are 
SAEs, AESIs, date of AEs, relationship to study drug, severity, and action taken. AEs that are 
not treatment-emergent will be flagged. 
9.2.1. Adverse Events Leading to Study Drug Discontinuation 
For Parts 1 and 2, a summary of incidence rates (frequencies and percentages) of the participants 
with TEAEs leading to study drug discontinuation, by treatment group (treatment cohort for Part 
2), SOC, and preferred term will be prepared. No inferential statistical tests will be performed. 
A data listing of AEs leading to study drug discontinuation will also be provided, displaying 
details of the event(s) captured on the CRF. 
9.2.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented by treatment group (treatment cohort for Part 2). 
9.2.3. Other Significant Adverse Events 
Adverse events of special interest (AESI) will be as collected on the CRF as a special interest 
event involving liver. 
9.3. 
Clinical Laboratory Evaluations 
For Part 1, descriptive statistics (n, mean, standard deviation [SD], median, minimum, and 
maximum) for clinical laboratory data and changes from baseline at each post-baseline time 
point will be presented by treatment group (treatment cohort for Part 2).  
The baseline value is the last value observed prior to first administration of study drug and any 
information obtained after first administration of study drug is regarded as post-baseline 
information. The change-from-baseline variables will be calculated as the post-baseline value 
minus the value at baseline. Change from baseline on continuous data will be summarized using 
descriptive statistics at each post-baseline time point by treatment group. For categorical data, 
change from baseline will be summarized using frequency and proportion at each post-baseline 
timepoint by treatment group (treatment cohort for Part 2).  


 
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For all continuous clinical laboratory variables, a shift table comparing the baseline value 
(normal, low, and high) to the last observation on treatment will be presented by treatment group 
(treatment cohort for Part 2).  
For urinalysis, a shift table (using number of participants with results of negative, trace, or 
positive) comparing the baseline value to the maximum value will be presented by treatment 
group (treatment cohort for Part 2).  
For Part 2, descriptive statistics (n, mean, standard deviation [SD], median, minimum, and 
maximum) for clinical laboratory data and changes from baseline (last value observed during 
Follow-up Period I in Part 1) at each post-baseline time point will be presented for all 
participants for each scheduled time point.  
For all continuous clinical laboratory variables in Part 2, a shift table comparing the baseline (last 
value observed during Follow-up Period I in Part 1) value (normal, low, and high) to the last 
observation on treatment will be presented for all participants.  
For urinalysis in Part 2, a shift table comparing the baseline (last value observed during Follow-
up Period I in Part 1) value to the maximum value will be presented for all participants (using 
number of participants with results of negative, trace, or positive).  
Potentially clinically significant results of clinical laboratory evaluations identified using 
prospectively defined criteria (Table 3) will also be summarized descriptively by treatment group 
(treatment cohort for Part 2). 
 
 


 
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Table 3: Potentially Clinically Important Criteria (PCS): Laboratory 
Lab Test Category 
PCS 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 or < 80 g/L (absolute 
value) 
Hematocrit: Decrease from baseline of ≥ 10% (absolute change) or < 
24% (absolute value) 
Urinalysis 
Glucose: ≥2+ 
RBC/HPF: >10 
Protein: >2+ 
Ketones: > 2 + 
Leukocytes: >10 
For Part 1 and Part 2, individual data listings of clinical laboratory results will be presented for 
each participant. Values that meet laboratory PCS will be flagged in the clinical laboratory listings 
(see Table 3). 


 
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9.3.1. Special Liver Events 
For Part 1 and 2, summarizes using incidence (rates) for participants with special liver events 
will be presented for all participants by treatment group (treatment cohort for Part 2) for the 
following: 
• 
ALT > 5 x, 10 x, or 20 x ULN 
• 
AST > 3 x, 5 x, 10 x, or 20 x ULN 
• 
ALT or AST > 3 x, 5 x, 10 x, or 20 x ULN 
• 
Total Bilirubin > 2 x ULN 
• 
Alkaline phosphatase >1.5 x ULN 
• 
Hy’s Law (ALT > 3 x ULN and Total Bilirubin > 2 x ULN) 
• 
Elevation of aminotransferase in temporal association with nausea, vomiting, anorexia, 
abdominal pain, or fatigue 
• 
Possible liver-related deaths and liver-related treatment discontinuations 
A time to first event analysis will also be presented using Kaplan-Meier product-limit estimates 
by treatment group for ALT > 3 x, AST > 3 x, ALT or AST > 3 x, and Total Bilirubin > 2 x 
ULN. 
9.4. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline (last value observed prior to 
the first dose of study drug) will be calculated by treatment group (treatment cohort for Part 2) for 
systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and oral body 
temperature at each post-baseline timepoint.  
In addition, potentially clinically significant results of vital signs identified using prospectively 
defined criteria (Table 4) will also be summarized descriptively. 
Table 4: Potentially Clinically Important Criteria (PCS): 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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Individual data listings of vital sign results will be presented for each participant. Values that meet 
vital sign PCS will be flagged in the listings (see Table 4). 
9.5. 
Electrocardiograms 
For Part 1 and Part 2, observed values and changes from baseline (last value observed prior to 
the first dose of study drug) at each post-baseline timepoint for continuous ECG parameters 
including heart rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), and 
QTcF interval will be summarized by treatment group (treatment cohort for Part 2) using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  
Overall evaluation of ECG 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. QTcF will be summarized using frequency and percentage for the following 
categories: 
Participants with the highest QTcF post-baseline value: 
• < 450 msec 
• 450-480 msec 
• ≥ 480 msec 
Participants with the highest QTcF change value: 
• < 30 msec 
• 30-60 msec 
• > 60 msec 
Potentially clinically important criteria (Sponsor defined): 
• ≥ 450 msec 
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. 
ECG results will be listed by treatment group (treatment cohort for Part 2) for all participants. 
Additionally, a listing will be provided for Investigator-identified ECG abnormalities. 
9.6. 
 Lixivaptan Treatment Safety Analysis 
The lixivaptan treatment safety will summarize the following safety information occurred post 
the first dose of lixivaptan treatment after randomization during the study based on the LTSS by 
treatment cohort and overall: 
• 
Incidence of special liver events (ALT > 3 x, AST > 3 x, ALT or AST > 3 x, and Total 
Bilirubin > 2 x ULN) 
• 
Kaplan-Meier product-limit curve for special liver events 
• 
Summaries of TEAEs (see Section 9.2) 


 
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o Overall summary of TEAEs 
o TEAEs by preferred term and causality 
o TEAEs by preferred term and severity 
o Treatment-related TEAEs by preferred term and severity 
9.7. 
Body Height, Weight and BMI 
Body height measured at Screening in Part 1 will be used to calculate the BMI at each time point 
in Part 1 and Part 2. 
For Part 1, changes in body weight and BMI from baseline (last value observed prior to the first 
dose of study drug) to end of the Double-blind, Randomized Period and to end of Follow-up 
Period I (last value observed) will be summarized by treatment group using descriptive statistics 
(n, mean, SD, median, minimum, and maximum).  
For Part 2, changes in body weight and BMI from baseline (last value observed during Follow-
up Period I in Part 1) to end of Maintenance Treatment Period and to end of Follow-up Period II 
(last value observed) will be summarized for all participants using descriptive statistics (n, mean, 
SD, median, minimum, and maximum).  
For Part 1 and Part 2, the change from baseline is defined as the post-baseline value minus the 
baseline value. There will not be any imputation for missing values. Body height, weight and 
BMI data will be listed individually for all participants. 
9.8. 
Concomitant Medication 
For Part 1 and 2, prior and concomitant medications will be summarized descriptively by 
treatment group (treatment cohort for Part 2) using counts and percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started before first dose of study drug will be considered prior medications whether or not they 
were stopped before first dose of study drug. Any medications continuing or starting after study 
drug will be considered to be concomitant. If a medication starts before study drug and continues 
after study drug it will be considered both prior and concomitant. 
Medications will be coded using World Health Organization Drug Dictionary (WHODD) v. 
Global B3 March 2021. 
9.9. 
Pharmacokinetic Analysis 
The PK analysis is not included in this SAP.  
10. 
Derived Variables 
• Change from baseline = value at current time point – value at baseline.  


 
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• Annualized change in eGFR from baseline to post-treatment follow up = (Post-treatment 
follow-up eGFR – Baseline) / Duration (in years), where Duration (in years) = (median of 
post-treatment follow-up assessment dates – median of baseline eGFR assessment dates + 
1) /365.25 
• htTKV (mL/m) = TKV(mL)/participant’s height (m).  
• htLV = LV(mL)/participant’s height (m).  
• 2009 CKD-EPI equation:  
eGFR (mL/min/1.73 m2) = 141 × 𝑚𝑚𝑚𝑚𝑚𝑚ቀ
𝑆𝑆𝑆𝑆𝑆𝑆
𝑘𝑘,  1ቁ
𝛼𝛼
× 𝑚𝑚𝑚𝑚𝑚𝑚 ቀ
𝑆𝑆𝑆𝑆𝑆𝑆
𝑘𝑘,  1ቁ
−1.209
× 0.993𝑎𝑎𝑎𝑎𝑎𝑎×
1.018 [if female]× 1.159 [if black]  
where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 
for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max 
indicates the maximum of Scr or 1, age = years.  
• 2021 CKD-EPIcr_R equation: 
eGFR (mL/min/1.73 m2) = 142 × 𝑚𝑚𝑚𝑚𝑚𝑚ቀ
𝑆𝑆𝑆𝑆𝑆𝑆
𝑘𝑘,  1ቁ
𝛼𝛼
× 𝑚𝑚𝑚𝑚𝑚𝑚 ቀ
𝑆𝑆𝑆𝑆𝑆𝑆
𝑘𝑘,  1ቁ
−1.200
× 0.9938𝑎𝑎𝑎𝑎𝑎𝑎×
1.012 [if female] 
where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.241 
for females and -0.302 for males, min indicates the minimum of Scr/κ or 1, and max 
indicates the maximum of Scr/κ or 1, age = years. (Delgado et al, 2021) 
• 2021 CKD-EPIcr-cys_R equation: 
eGFR (mL/min/1.73 m2) = 135 × 𝑚𝑚𝑚𝑚𝑚𝑚ቀ
𝑆𝑆𝑆𝑆𝑆𝑆
𝑘𝑘,  1ቁ
𝛼𝛼
× 𝑚𝑚𝑚𝑚𝑚𝑚ቀ
𝑆𝑆𝑆𝑆𝑆𝑆
𝑘𝑘,  1ቁ
−0.544
×
𝑚𝑚𝑚𝑚𝑚𝑚ቀ
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
0.8 ,  1ቁ
−0.323
× 𝑚𝑚𝑚𝑚𝑚𝑚 ቀ
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
0.8 ,  1ቁ
−0.778
× 0.9961𝑎𝑎𝑎𝑎𝑎𝑎× 0.963 [if female] 
where Scr is serum creatinine (mg/dL), Scys is serum cystatin C (mg/L), 𝑘𝑘 = 0.7 (female) 
or 0.9 (male), 𝛼𝛼 = -0.219 (female) or -0.144 (male), min indicates the minimum of Scr/κ 
or 1 OR Scys/0.8 or 1, max indicates the maximum of Scr/κ or 1 OR Scys/0.8 or 1, age = 
years. (Delgado et al, 2021) 
• Age for the calculation of eGFR: Since date of birth is not collected in the study and to 
avoid the calculation error due to the whole number of age, relative age used for the 
calculation of eGFR is defined as follows: 
Age (years) = Age at Screening + (date of blood sample collection for serum creatinine – 
date of Inform Consent +1)/365.25, rounded to three decimals. 
For all efficacy analyses, the eGFR values will be calculated and rounded to 1 decimal 
based on equations and age defined above for analysis. However, the calculated eGFRs 
for efficacy analyses will not impact the determination of the randomization stratification 
factors. 


 
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11. 
Interim Analysis and Data Monitoring 
Data analyses are planned to be conducted for Part 1 after the completion of Part 1 and 
unblinding of study after completion of Part 1. No interim analysis is planned for the efficacy 
analysis. 
11.1. Independent Data Monitoring Committee (IDMC) 
In order to ensure the safety of participants, the sponsor will use an IDMC. An IDMC charter 
was written to describe the IDMC objectives, schedule for data reviews, and general 
responsibilities in respect to the study. The IDMC will meet on a regular basis as specified in the 
Charter. In addition to the pre-determined data review meetings, the IDMC may meet on an ad 
hoc basis in the face of an emerging safety issue. The Committee will have access to unblinded 
data and will make recommendations to the sponsor without revealing participant treatment 
assignment. No efficacy assessments will be performed by the IDMC, therefore, no adjustment 
of type I error is required for the final data analysis. 
11.2. Hepatic Events Review Committee (HERC) 
In order to adequately characterize the liver safety profile of lixivaptan, additional testing and 
data collection will be required for any participant who develops clinically significant liver 
chemistry test abnormalities and/or signs or symptoms of liver dysfunction during the study. The 
HERC will independently and in a treatment-blinded manner expertly judge attribution to study 
drug as detailed in the HERC Charter and will communicate in writing with the sponsor and the 
IDMC. The IDMC reviews data at a study-level and, as such, its recommendations will not be 
made known to the HERC so as not to bias the HERC when adjudicating participant cases. These 
two committees are independent and will have a one-way line of communication from HERC to 
IDMC. The results of the HERC review and adjudication will be incorporated into the reporting 
of the safety results of the trial.  
12. 
Statistical Analysis and Reporting 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will primarily use SAS (release 9.4 or higher). If the use of other 
software is warranted, the final statistical methodology report will detail what software, 
including version, was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of participants (n) with 
non-missing values, mean (geometric mean for log-transformed data), standard deviation (SD), 
median, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the particular category or each possible value. In general, the 
denominator for the percentage calculation will be based upon the total number of participants 


 
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with non-missing data in the study population for the treatment groups, unless otherwise 
specified.  
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
This study has been early terminated by the Sponsor. Due to only 5 participants being 
randomized into double-blinded, randomized treatment period in Part 1 and all being 
prematurely terminated in Part 1 of the study, no statistical analyses will be performed and only a 
limited set of summary tables will be generated along with the study data listings to facilitate the 
creation of a synoptic clinical study report. 
13. 
Tables, Listings, and Figures 
All listings, tables, and figures will have 
• A header showing the sponsor company name, protocol, and page number 
• A footer showing the file name and path, the source of the data (ADaM dataset or listing 
number) and date/time created. 
The layouts of tables, listings, and figures are presented in SAP Mock Tables, Listings and 
Figures. These layouts incorporate all the appropriate table titles, table numbers, and footnotes. 


 
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14. 
Mock Tables, Listings, and Figures 
The table, listing, and figure shells will be provided in a separate document. 
15. 
Changes from Protocol 
Any analyses that deviated from the study protocol are documented below. 


 
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Text in Protocol 
Change in SAP 
Justification 
None 
Placebo Run-in Safety 
Set, Lixivaptan Titration 
Safety Set, ITT, mITT, 
PPAS, Lixivaptan 
Treated Safety Set are 
added in Section 5 
Analysis Population 
Those analyses population will be 
needed to summarize the efficacy 
or safety data 
Analysis safety and 
efficacy sets for Part 
2 in Section 5 
Analysis Populations 
Re-define as two 
analysis sets: P2SS for 
safety and P2EAS 
efficacy, but summary 
in Part 2 will be 
presented by treatment 
cohort 
The revised analysis populations 
are more appropriate for safety and 
efficacy analyses in Part 2. 
LV for analysis 
htLV for analysis 
To reduce the variance of LV and 
normalize to participant’s height 
Annualized change 
from baseline in 
htTKV (htLV) 
Annualized percent 
change from baseline in 
htTKV (htLV) 
Anti-log of annualized change 
from baseline based on the log-
transformed htTKV (htLV) 
implies the annualized ratio of 
htTKV (htLV) at the evaluated 
timepoint to baseline htTKV 
(htLV). This ratio minus one as 
expressed as percentage will 
represent annualized percent 
change from baseline in htTKV 
(htLV), but not annualized change 
from baseline in htTKV (htLV).  
None 
 Lixivaptan treated 
safety summaries have 
been added in Section 
9.6 
To add overall safety after 
randomization during the entire 
study for all lixivaptan-treated 
participants during double-bind 
phase and/or open-label phase. 
Blind sample size re-
estimation (BSSR) 
BSSR is removed 
BSSR is not needed for the study 
due to the following: 
• Sample size increased due to 
the increased power from 85% 
to 90% 
• BSSR may not be feasible 
according to the currently 
projected enrollment 
 


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16.
Revision History
The non-editorial changes made to the statistical analysis plan (SAP) will be recorded in the 
table below. All changes require a new signature page be completed. 
Description of the Change/Reason 
for Change 
Document Version 
Number Before 
Change 
Date of 
Change 
Original 
N/A 
N/A 
17. 
References
ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2018. http://www.amstat.org/about/ethicalguidelines.cfm 
ICH (1998). ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9; 
1998. https://database.ich.org/sites/default/files/E9_Guideline.pdf 
Delgado, C., Baweja, M., Crews, D. C., Eneanya, N. D., Gadegbeku, C. A., Inker, L. A., Mendu, 
M. L., Miller, W. G., Moxey-Mims, M. M., Roberts, G. V., St Peter, W. L., Warfield, C., & 
Powe, N. R. 2021. A Unifying Approach for GFR Estimation: Recommendations of the NKF-
ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. J Am Soc 
Nephrol. 2021 Sep 23:ASN.2021070988. doi: 10.1681/ASN.2021070988. Epub ahead of print.
RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
https://rss.org.uk/about/policy-and-guidelines/code-of-conduct/. 
Little R., Rubin D. 1987. Statistical Analysis with Missing Data. New York: John Wiley. 
Little R., Yau L. 1996. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs, 
Biometrics. 52. 1324-1333. 
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, 
McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. 2017. Tolvaptan in later-stage autosomal 
dominant polycystic kidney disease. N Engl J Med. 377:1930-1942. 


 
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Appendix:  Method to Derive the Weight for the Weighted ANCOVA Analysis 
for the Primary Efficacy Endpoint 
The following method is proposed to derive the weight for the weighted ANCOVA analysis for 
the primary efficacy endpoint if the number of eGFR observations is kept at 3 in the pre-
treatment baseline period. In order to derive the weight used in the weighted analysis, the 
following model is considered: 
yi,0,k = αi + ei,0,k  
where k = 1, 2, Ki,0  
 
 
 
 
 
(1) 
yi,j,k = αi + δi,j + ei,j,k  
where k = 1, 2, Ki,j 
 
 
 
 
 
(2) 
where Ki,0 is the number of eGFR observations during the pre-treatment baseline period for 
subject i, and Ki,j is the number of eGFR observations during the post-treatment follow-up period 
for subject i, with visit j as the visit 22 (Week 52) for completers or mapped regular visits for 
early dropouts. αi is a random variable for the “real” eGFR baseline of subject i, and this variable 
will be cancelled out for change from baseline. δi,j is a random variable for change from pre-
treatment baseline for subject i to visit j. These δi,js are normally distributed, with means being 
δP,j for placebo subjects and δL,j for lixivaptan subjects, and variance σδ,j2. These δi,js are 
supposed to be independent from subject to subject, and each subject has only one post-baseline 
visit j in the primary analysis. In addition, αis are assumed iid normally distributed, ei,j,k are 
assumed iid N(0, σ2), and all these random variables are mutually independent. Their average 
over the Ki,0 observations at baseline and the Ki,j observations at post-treatment follow-up will be: 
ӯi,0 = αi + ēi,0,   
where ēi,0 ~ N(0, σ2/Ki,0) 
 
 
 
 
 (3) 
ӯi,j = αi + δi,j + ēi,j,  
where ēi,j ~ N(0, σ2/Ki,j) 
 
  
 
 
 (4) 
the distribution of their difference is: 
ӯi,j - ӯi,0 = δi,j + ēi,j - ēi,0 ~ N(.,σδ,j2 + σ2(1/Ki,0 +1/Ki,j)), 
 
 
 
 (5) 
where the mean of the normal distribution is δP,j for placebo subjects and δL,j for lixivaptan 
subjects. 
In order to estimate the variance components given in (5), a further assumption of all σδ,j2’s are 
equal, ie, σδ,j2 = σδ2 is made, since there may not be enough subjects withdraw to stabilized the 
estimate of σδ,j2 at some visits. In addition, it is assumed all subjects get 3 eGFR observations at 
baseline. This assumption is reasonable, since usually subjects follow protocol schedules more 
strictly at the beginning of the trial and could simplify the estimation of the variance 
components. Then, a formula of change from baseline can be written similar to (5) for the 
estimation of the variance components: 
yi,j,k - ӯi,0 = δi,j + ei,j,k - ēi,0 ~ N(.,σδ2 + σ2(1 + 1/3)),  
 
 
 
 
(6) 
A mixed model with fixed effect factors of treatment nested within visit, replication (for the 
repeated observations at the post-treatment follow-up in eGFR) will be applied to change from 
baseline (as the average of the 3 pre-treatment eGFR observations) in eGFR observed at each 
replication. In this mixed model, replications at the post-treatment follow-up are considered as 
the repeated measurements, with a compound symmetric variance matrix structure. In this 


 
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estimated variance-covariance matrix, the diagonal elements are the estimate of σδ2 + σ2(1 + 
1/3), and the off-diagonal elements are the estimate of σδ2 + σ2(1/3). Solving these two equations 
will get the estimates of σδ2 and σ2. With these variance component estimates, the variance given 
in formula (5) is estimated for each subject. Dividing the estimated variance given in (5) by the 
subject’s trial duration will provide an estimated variance for the subject’s annualized change in 
eGFR. The inverse of this estimated variance will be the weight of the subject used in the 
primary analysis. 
SAS code for the estimation of variance component 
PROC MIXED; 
CLASS USUBJID VISIT TREATMENT REPLICATION; 
MODEL CHANGE = TREATMENT(VISIT) REPLICATION; 
REPEATED REPLICATION/TYPE=CS SUB=USUBJID; 
RUN; 
 
In this estimation of variance components, it is assumed the post-treatment follow-up eGFR 
observations of early withdrew subjects are mapped into scheduled visits. Since the 4-week 
scheduled visits in this protocol, for a subject early withdrew the study drug, compared to the 
subject’s last scheduled on-treatment visit, if the first post-treatment follow-up eGFR is observed 
less or equal to 24 days (= 14 + 7 + 3) after the last scheduled on treatment visit, then the 
subject’s post-treatment follow-up eGFR observations will be mapped to the subject’s last 
scheduled on-treatment visit; otherwise, if the first posttreatment follow-up eGFR is observed 
less or equal to 52 days (= 28 + 14 + 7 + 3) after the last scheduled on treatment visit, then the 
subject’s post-treatment follow-up eGFR observations will be mapped to the visit after the 
subject’s last scheduled on-treatment visit; etc.