Conditions: Polycystic Kidney Disease, Adult ADPKD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver safety, and efficacy of lixivaptan in participants who previously experienced liver chemistry test abnormalities while treated with tolvaptan and were permanently discontinued from the drug for that reason. Up to 50 eligible participants will be enrolled and treated with lixivaptan for 52 weeks following titration to an optimal dose.

Detailed description:
This is a Phase 3, open-label, repeat-dose study designed to assess liver safety, non-liver safety, and efficacy of lixivaptan in participants who previously experienced liver chemistry test abnormalities while treated with tolvaptan and were permanently discontinued from the drug for that reason. Up to 50 participants will be enrolled and treated. Evaluations will include frequent testing of liver chemistry (every week during the Baseline and Titration Periods and every 4 weeks during the Maintenance Period), physical examinations, vital signs, safety labs (serum chemistry, hematology, urinalysis), estimated glomerular filtration rate (eGFR), urine specific gravity and osmolality determinations and trough serum concentration of lixivaptan. After meeting entry criteria during a 1- to 3-week Screening Period that can extend up to 8 weeks for medication adjustment, participants will enter a 3-week no study treatment Baseline Period to obtain baseline measurements followed by a 3- to 6-week Titration Period during which lixivaptan administered twice daily (BID) will be titrated to a dose that is tolerated and results in a reduced trough urine specific gravity, or to the maximum dose level. The minimum dose to enter the Maintenance Period is 100 mg BID. Treatment will continue for up to 52 weeks (12 months) after which study drug will be held, and final assessments obtained during the Follow-up Period of 4 weeks. The total study duration will be up to approximately 73 weeks (16.8 months).

Arms:
arm 1: Lixivaptan oral capsules, 100-200 mg twice daily

Interventions: intervention 1: Lixivaptan
Intervention descriptions: intervention 1: Oral vasopressin V2 receptor antagonist

Protocol document:
Prot_000.pdf: 
Study Title: An Open-Label Study of Lixivaptan in Subjects With Autosomal Dominant 
Polycystic Kidney Disease Who Previously Experienced Abnormal Liver Chemistry Test 
Results While Receiving Tolvaptan: The ALERT Study 
 
ClinicalTrials.gov ID: NCT04152837 
 
 
 
Clinical Study Protocol Version 4.0, dated 17-Nov-2021 
 
Clinical Study Protocol Version 4.0, dated 17-Nov-2021, Summary of Changes 
 
Clinical Study Protocol Version 3.0, dated 02-Sep-2020, Summary of Changes 
 
 
Note: the first approved version of the protocol was Version 2.0. 
 
 


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CLINICAL STUDY PROTOCOL 
An Open-label Study of Lixivaptan in Subjects with Autosomal Dominant 
Polycystic Kidney Disease Who Previously Experienced Abnormal Liver 
Chemistry Test Results While Receiving Tolvaptan: The ALERT Study  
Protocol Number: PA-ADPKD-303 
IND Number: 136,419 
Sponsor: 
Sponsor Contact: 
Medical Monitor: 
Version of Protocol:  
Date of Protocol:  
Palladio Biosciences, Inc. 
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
Neil Shusterman, MD FACP 
Chief Medical Officer 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive, Suite 120 
Horsham, PA 19044 
Email: nshusterman@palladiobio.com  
David Frid, MD 
ICON Clinical Research 
Direct: (215) 616-2504 (including urgent medical issues) 
Fax: +1 (215) 699-6288 
Email: David.Frid@iconplc.com  
In a study related health emergency, when the assigned 
Medical Monitor cannot be reached, please refer to Section 
7.3.8.3 for further contact information. 
4   
November 17, 2021 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Palladio Biosciences.  
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Palladio Biosciences.   


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Protocol Approval - Sponsor Signature 
Protocol Title 
An Open-label Study of Lixivaptan in Subjects with Autosomal 
Dominant Polycystic Kidney Disease Who Previously Experienced 
Abnormal Liver Chemistry Test Results While Receiving Tolvaptan: 
The ALERT Study  
Protocol Number: PA-ADPKD-303 
Protocol Number PA-ADPKD-303 
Protocol Version 
4 
Protocol Date 
November 17, 2021 
 
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  
 
 
 
__________________________________________ 
November 17, 2021___________ 
Signature   
 
 
 
 
 
 
Date 
 


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Declaration of Investigator 
I have read and understood all sections of the protocol titled “An Open-label Study of 
Lixivaptan in Subjects with Autosomal Dominant Polycystic Kidney Disease Who 
Previously Experienced Abnormal Liver Chemistry Test Results While Receiving Tolvaptan: 
The ALERT Study” 
 
Protocol Number: PA-ADPKD-303 
 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the protocol, the ICH harmonized tripartite guideline E6(R2) Good Clinical 
Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry, the Declaration of 
Helsinki, and all applicable government regulations.  I will not make changes to the protocol 
before consulting with Palladio Biosciences or implement protocol changes without 
Institutional Review Board (IRB)/Ethics Committee (EC) approval except to eliminate an 
immediate risk to subjects.  I agree to administer study treatment only to subjects 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.  Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Palladio Biosciences. 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF TABLES .....................................................................................................................8 
LIST OF FIGURES ...................................................................................................................9 
PROTOCOL SYNOPSIS .........................................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................25 
1 
INTRODUCTION ............................................................................................................27 
1.1 
Background .............................................................................................................27 
1.2 
Overview of ADPKD ..............................................................................................27 
1.3 
Overview of Available Therapies for ADPKD .......................................................28 
1.4 
Rationale for Lixivaptan Therapy for ADPKD .......................................................28 
1.5 
Summary of Nonclinical Studies ............................................................................30 
1.6 
Summary of Clinical Studies ..................................................................................31 
1.7 
Study Rationale .......................................................................................................31 
1.8 
Dose Rationale ........................................................................................................34 
2 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................35 
2.1 
Study Objectives .....................................................................................................35 
2.1.1 
Primary Objectives ..................................................................................35 
2.1.2 
Secondary Objectives ..............................................................................35 
2.1.3 
Exploratory Objectives ............................................................................35 
2.2 
Study Endpoints ......................................................................................................35 
2.2.1 
Primary Endpoint .....................................................................................35 
2.2.2 
Secondary Endpoints ...............................................................................35 
2.2.3 
Exploratory Endpoints .............................................................................36 
3 
INVESTIGATIONAL PLAN ...........................................................................................37 
3.1 
Study Design ...........................................................................................................37 
3.1.1 
Overview of Study Design .......................................................................37 
3.1.2 
Detailed Study Design .............................................................................37 
3.2 
Rationale for Study Design .....................................................................................39 
4 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA .........................................41 
4.1 
Selection of Study Population .................................................................................41 


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4.1.1 
Inclusion Criteria .....................................................................................41 
4.1.2 
Exclusion Criteria ....................................................................................43 
4.2 
Completion and Withdrawal of Subjects from the Study .......................................44 
4.2.1 
Definition of Completed Subjects ...........................................................44 
4.2.2 
Screening and Baseline Failures ..............................................................44 
4.2.3 
Subject Withdrawal Criteria.....................................................................44 
4.2.4 
Reasons for Withdrawal ...........................................................................45 
4.2.5 
Methods to Prevent Lost to Follow-up ....................................................46 
4.2.6 
Replacements ...........................................................................................46 
4.2.7 
Withdrawals Due to Abnormal Liver Chemistry Test Results .................46 
5 
STUDY DRUG AND CONCOMITANT MEDICATION ...............................................47 
5.1 
Study Drug ..............................................................................................................47 
5.1.1 
Identity of the Investigational Product.....................................................47 
5.1.2 
Route of Administration ..........................................................................47 
5.1.3 
Study Drug Packaging, Labeling, and Storage ........................................47 
5.1.4 
Accountability ..........................................................................................48 
5.2 
Dose Administered ..................................................................................................48 
5.3 
Method of Assigning Subjects to Identification Numbers ......................................49 
5.4 
Blinding ..................................................................................................................50 
5.5 
Randomization and Treatment Assignment ............................................................50 
5.6 
Treatment Compliance ............................................................................................50 
5.7 
Prior and Concomitant Therapy ..............................................................................50 
5.7.1.1 
Permitted Therapy ....................................................................................51 
5.7.1.2 
Prohibited Therapy ..................................................................................52 
5.8 
Diet, Fluid, Activity, and Lifestyle Considerations .................................................52 
6 
TIMING OF STUDY PROCEDURES ............................................................................54 
6.1 
Screening Period .....................................................................................................54 
6.1.1 
Visit 1 .......................................................................................................54 
6.1.2 
Visit 2 .......................................................................................................55 
6.2 
Baseline Period .......................................................................................................56 
6.2.1 
Visit 3 .......................................................................................................56 
6.2.2 
Visit 4 .......................................................................................................56 
6.2.3 
Visit 5 .......................................................................................................57 
6.3 
Titration Period .......................................................................................................58 
6.3.1 
Visits 6 to 10 ............................................................................................58 


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6.3.2 
Visit 11/Last Titration Visit ......................................................................61 
6.4 
Maintenance Period ................................................................................................62 
6.4.1 
Visits 12 to 23 ..........................................................................................62 
6.4.2 
Visit 24/Early Termination .......................................................................63 
6.5 
Follow-up Period ....................................................................................................64 
6.5.1 
Visit 25 .....................................................................................................64 
6.5.2 
Visit 26 .....................................................................................................64 
6.5.3 
Visit 27 (End of Study Visit) ....................................................................65 
6.5.4 
Early Termination Procedures ..................................................................65 
7 
DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES ...........................66 
7.1 
Efficacy Assessments ..............................................................................................66 
7.1.1 
eGFR ........................................................................................................66 
7.2 
Pharmacodynamic Assessments .............................................................................66 
7.2.1 
Specific Gravity and Urine Osmolality ...................................................66 
7.3 
Safety and Tolerability Assessments .......................................................................67 
7.3.1 
Body Height, Weight, and BMI ...............................................................67 
7.3.2 
Demographics and Medical History ........................................................67 
7.3.3 
Physical Examinations .............................................................................67 
7.3.4 
Vital Sign Measurements .........................................................................68 
7.3.5 
12-Lead ECGs .........................................................................................68 
7.3.6 
Clinical Laboratory Tests .........................................................................69 
7.3.6.1 
Sample Collections ..................................................................................70 
7.3.7 
Assessment of Liver Symptoms, Signs, or Test Abnormalities ...............70 
7.3.7.1 
Requirements for Additional Liver Chemistry Testing ............................70 
7.3.7.2 
Changes in Study Drug Dosing if Liver Chemistry Test Abnormalities 
Occur During the Titration or Maintenance Periods ................................71 
7.3.7.3 
Special Reporting of Liver Events ...........................................................72 
7.3.8 
Adverse Events ........................................................................................73 
7.3.8.1 
Definitions of Adverse Events .................................................................73 
7.3.8.2 
Eliciting and Documenting Adverse Events and Serious Adverse Events
 .................................................................................................................73 
7.3.8.3 
Reporting Adverse Events, Serious Adverse Events, and Adverse Events 
of Special Interest ....................................................................................74 
7.3.8.4 
Assessment of Severity ............................................................................75 
7.3.8.5 
Assessment of Causality ..........................................................................75 
7.3.8.6 
Follow-Up of Subjects Reporting Adverse Events ..................................76 
7.3.8.7 
Overdose Management ............................................................................76 


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7.3.8.8 
Pregnancy ................................................................................................76 
7.3.9 
Clinical Laboratory and Other Safety Assessments .................................77 
7.3.10 
Hepatic Events Review Committee (HERC) ...........................................77 
7.4 
Pharmacokinetic Assessments ................................................................................77 
7.4.1 
Pharmacokinetic Blood Sampling ...........................................................77 
8 
STATISTICAL AND ANALYTICAL PLAN ...................................................................79 
8.1 
Sample Size .............................................................................................................79 
8.2 
Populations for Analysis .........................................................................................79 
8.3 
Analysis of Demographic and Baseline Characteristics .........................................79 
8.4 
Safety Analyses .......................................................................................................79 
8.4.1 
Primary Hepatic Safety Endpoint ............................................................79 
8.4.2 
Secondary Hepatic Safety Endpoints .......................................................79 
8.4.3 
Additional Hepatic Safety Endpoints ......................................................80 
8.4.4 
Adverse Events ........................................................................................80 
8.4.5 
Clinical Laboratory Tests .........................................................................80 
8.4.6 
ECGs ........................................................................................................81 
8.4.7 
Vital Signs ................................................................................................81 
8.5 
Efficacy Analysis ....................................................................................................81 
8.6 
Exploratory Analyses ..............................................................................................81 
8.6.1 
Relationship of Liver Chemistry Test Abnormalities to Drug Levels .....81 
8.6.2 
Assessment of Genetic Variants ...............................................................82 
8.6.3 
Pharmacodynamic Assessments ..............................................................82 
8.7 
Statistical Analysis Methodology ...........................................................................82 
8.8 
Data Quality Assurance...........................................................................................82 
8.8.1 
Data Management ....................................................................................82 
9 
ETHICS ............................................................................................................................84 
9.1 
Institutional Review Board (IRB)/Ethics Committee (EC) ....................................84 
9.2 
Ethical Conduct of the Study ..................................................................................84 
9.3 
Subject Information and Consent ...........................................................................84 
10  INVESTIGATOR’S OBLIGATIONS AND STUDY PERSONNEL ..............................85 
10.1  Confidentiality ........................................................................................................85 
10.2  Financial Disclosure and Obligations .....................................................................85 
10.3  Investigator Documentation ....................................................................................85 
10.4  Study Conduct .........................................................................................................86 


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10.5  Adherence to Protocol ............................................................................................86 
10.6  Adverse Events and Study Report Requirements ...................................................86 
10.7  Investigator’s Final Report .....................................................................................86 
10.8  Records Retention ...................................................................................................86 
10.9  Publications .............................................................................................................87 
11  STUDY MANAGEMENT ...............................................................................................88 
11.1  Monitoring ..............................................................................................................88 
11.1.1 
Monitoring of the Study ...........................................................................88 
11.1.2 
Inspection of Records and Quality Assurance .........................................88 
11.2  Management of Protocol Amendments and Deviations..........................................88 
11.2.1 
Modification of the Protocol ....................................................................88 
11.2.2 
Protocol Deviations .................................................................................88 
11.3  Study Termination ...................................................................................................89 
11.4  Final Report ............................................................................................................89 
12  REFERENCE LIST ..........................................................................................................90 
13  APPENDICES ..................................................................................................................93 
13.1  Appendix 1: Chronic Kidney Disease Classification Criteria ................................93 
13.2  Appendix 2: DILI Network Causality Criteria, modified .......................................93 
13.3  Appendix 3: Additional Potential Hepatic Testing if Liver Chemistry 
Abnormalities Occur .......................................................................................94 
13.4  Appendix 4: Liver Dysfunction Checklist ..............................................................95 
 
LIST OF TABLES 
Table 1 Schedule of Procedures .............................................................................................. 23 
Table 2 DILIsym simulations of lixivaptan and tolvaptan ...................................................... 32 
Table 3.  Investigational Product ............................................................................................ 47 
Table 4  Dosing Levels during the Lixivaptan Titration Period .............................................. 48 
Table 5. Dosing Diagram in the Lixivaptan Titration Period .................................................. 49 
Table 6  Clinical Laboratory Parameters ................................................................................ 70 
Table 7  Additional Liver Chemistry Testing and Other Testing ............................................ 71 
Table 8  Guideline for Assessment of Adverse Event Causality ............................................. 76 


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LIST OF FIGURES 
Figure 1.  
Study Schematic.............................................................................................. 22 
Figure 2. 
Time course of ALT levels in relationship to dosing of tolvaptan in a patient 
with painful ADPKD....................................................................................... 33 
Figure 3.  
Time course of ALT levels in relationship to dosing of lixivaptan in a patient 
with painful ADPKD....................................................................................... 34 
Figure 4. 
Titration Flowchart ......................................................................................... 60 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol 
Number: 
PA-ADPKD-303 
Protocol Title: 
An Open-label Study of Lixivaptan in Subjects with Autosomal 
Dominant Polycystic Kidney Disease Who Previously Experienced 
Abnormal Liver Chemistry Test Results While Receiving Tolvaptan: 
The ALERT Study  
Protocol Number: PA-ADPKD-303 
Sponsor: 
Palladio Biosciences, Inc. 
5 Walnut Grove Drive 
Suite 120 
Horsham, PA 19044 
Study Phase: 
Phase 3 
Study Sites: 
Up to approximately 25 global sites 
Indication: 
Autosomal Dominant Polycystic Kidney Disease (ADPKD) 
Rationale: 
 
 
 
 
 
 
ADPKD is the most frequent, inherited cause of end-stage renal 
failure. Animal models have shown that vasopressin activity is 
necessary for the disease to manifest and progress.  Studies of the 
vasopressin V2 receptor antagonist tolvaptan have shown that it can 
slow the progression of renal function deterioration in patients with 
ADPKD.  However, serious drug induced liver injury (DILI) occurs in 
a certain percentage of patients treated with tolvaptan, requiring 
diligent testing of liver chemistry in all patients and discontinuation of 
the drug when the test results are elevated in order to prevent serious 
outcomes.  The vasopressin V2 receptor antagonist, lixivaptan, has 
also been shown to ameliorate polycystic disease manifestations in 
animal models of disease.  Evidence from Quantitative Systems 
Toxicology modeling and initial clinical results suggest that lixivaptan 
does not have the same potential for liver injury.  Thus, lixivaptan may 
represent a safer alternative to tolvaptan with similar efficacy.  This 
Phase 3 study will assess the safety and efficacy of lixivaptan in 
subjects with ADPKD who experienced abnormal liver chemistry test 
results on tolvaptan resulting in permanent discontinuation of 
tolvaptan. 
Objectives: 
 
 
 
The primary objective of this study is: 
 To assess the hepatic safety of lixivaptan in subjects with 
ADPKD who experienced abnormal liver chemistry test results 
on tolvaptan that resulted in permanent discontinuation of 
tolvaptan. 
The secondary objectives of this study are: 
 To characterize the non-hepatic safety and tolerability of 
lixivaptan in subjects with ADPKD who previously 


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experienced abnormal liver chemistry test results while treated 
with tolvaptan. 
 To assess renal function (efficacy) in ADPKD subjects while 
on lixivaptan using change in estimated glomerular filtration 
rate (eGFR). 
The exploratory objectives of this study are: 
 To explore any possible relationships between liver chemistry 
abnormalities and trough levels of lixivaptan collected during 
the study. 
 To assess potential genetic risk factors for hepatic 
abnormalities (if and when feasible). 
Subject 
Population: 
At Visits 1 and 2, subjects must meet all of the Inclusion criteria and 
none of the Exclusion criteria.  An eligibility review and discussion 
between the Investigator and the medical monitor will be conducted 
before each subject is enrolled (prior to Visit 3) at each site. 
Inclusion criteria: 
1. Male or female, between 18 and 65 years of age (inclusive) at 
the time of Screening.  
2. Female subjects must: 
a. not be pregnant, lactating, or breastfeeding.   
b. be either postmenopausal (defined as amenorrhea for 
≥12 months), surgically sterile (defined as having 
undergone hysterectomy and/or bilateral 
oophorectomy), or if of child-bearing potential 
(WOCBP) must agree to practice appropriate methods 
of birth control or remain abstinent (only if this is the 
usual and preferred lifestyle of the participant) during 
the study and for 30 days after the last dose of study 
drug. Acceptable forms of contraception include any of 
the following: 
 hormonal contraceptives (i.e., oral, intravaginal, 
transdermal, injectable, implantable) 
 double barrier methods of non-hormonal 
contraception are permitted in this study:  
o male or female condom with spermicide 
(cream, spray, gel, suppository, 
contraceptive sponge, or polymer film) 
o diaphragm, cervical cap, or 


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contraceptive sponge with spermicide 
(with or without a condom) 
 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 
 bilateral tubal ligation 
 Essure® procedure (tubal occlusion). 
3. Male subjects and their female partners of childbearing 
potential must also use the contraceptive methods listed above 
or remain abstinent (only if this is the usual and preferred 
lifestyle of the participant) during the study and for 30 days 
after the last dose of study drug. 
4. Diagnosis of ADPKD confirmed by previous treatment with 
tolvaptan specifically for that indication and supported by 
evidence from any imaging modality or genetic analysis. 
5. Screening eGFR ≥ 20 ml/min/1.73 m2. 
6. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) 
at the time of Screening. 
7. Documented history of: 
a. Based on upper limit of normal (ULN): at least 2 
elevated alanine aminotransferase (ALT) levels, 1 ALT 
level >2 times (x) the ULN and 1 ALT level >3 x ULN 
while the subject was receiving tolvaptan, or within 4 
weeks after tolvaptan discontinuation, with no other 
explanation for the ALT elevations.  The 2 elevated 
ALT measurements could be recorded during the same 
instance of liver injury or during distinct instances;  
OR 
b. Based on the subject’s stable baseline as determined by 
the Investigator: at least 2 elevated ALT levels, 1 ALT 
level >2 x the subject’s stable baseline level and 1 ALT 
level >3 x the subject’s stable baseline level while the 
subject was receiving tolvaptan, or within 4 weeks after 
tolvaptan discontinuation, with no other explanation for 
the ALT elevations; provided that at least one ALT 
elevation was >2 x ULN.  The 2 elevated ALT 
measurements could be recorded during the same 
instance of liver injury or during distinct instances; 


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OR 
c. A pattern of ALT elevations deemed by the Investigator 
to be consistent with tolvaptan liver injury with no 
other explanation for the ALT elevations and the 
agreement of the medical monitor and sponsor. 
8. Permanent discontinuation of prior tolvaptan treatment 
because of the abnormal liver chemistry test results. 
9. The subject may or may not have been re-challenged with 
tolvaptan.  If re-challenge with tolvaptan was performed, the 
ALT level should have increased to >2 x ULN upon re-
challenge or the ALT level was increasing but tolvaptan was 
stopped for patient safety reasons before it reached > 2 x ULN 
after having previously normalized. 
10. Appropriate control of hypertension including an angiotensin 
converting enzyme inhibitor or angiotensin receptor blocker 
(unless not considered appropriate for the subject) without the 
use of a diuretic in concert with KDIGO “Clinical Practice 
Guideline for the Management of Blood Pressure in Chronic 
Kidney Disease”. 
11. 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. 
Exclusion criteria: 
1. Known sensitivity, allergy, or idiosyncratic reaction to any 
compound present in lixivaptan and related compounds. 
2. Hypovolemia on physical examination at Screening. 
3. Abnormal serum sodium concentration at Screening. 
4. Subjects who have taken any investigational drug or used an 
investigational device within 30 days, or 5 half-lives, 
whichever is longer, prior to Screening  
5. Subjects who are taking, have taken within the 2 weeks prior 
to Screening, 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. 
6. Simvastatin at total daily doses >10 mg or amlodipine at total 
daily doses >5 mg. 
7. Prior use of tolvaptan within the 3 months prior to Screening 
OR until a previously elevated ALT level has returned to ≤1 x 
ULN for at least 3 months.  
8. Prior use of lixivaptan or participation in a clinical study with 
lixivaptan within the 3 months of Screening. 
9. Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, 


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pasireotide, octreotide, etc.), metformin (allowed for diabetes 
mellitus), nicotinamide, bardoxolone, venglustat, 
demeclocycline, or mTOR kinase inhibitors (e.g., everolimus, 
sirolimus, etc.) to treat ADPKD within the 3 months prior to 
Screening. 
10. Requirement for chronic diuretic use. 
11. History of advanced diabetes (e.g., glycosylated hemoglobin 
[HgbA1c] >7.5%, and/or glycosuria by dipstick, significant 
proteinuria [>300 mcg albumin/mg creatinine], retinopathy), 
other significant renal disease, transplanted kidney, recent 
kidney surgery within the 6 months prior to Screening 
(including cyst drainage or fenestration) or acute kidney injury 
within 6 months prior to Screening. 
12. Clinically significant incontinence, overactive bladder, or 
urinary retention (e.g., benign prostatic hyperplasia). 
13. 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 subject. 
14. Clinically significant liver disease or impairment or active 
chronic hepatitis at Screening. 
15. Positive test results for hepatitis B surface antigen (HBsAg) or 
hepatitis C (HCV) antibody.  
16. History of infection with human immunodeficiency virus 
(HIV) unless the subject is stable and doing well on a non-
CYP interacting anti-retroviral therapy (ART) regimen and 
who has not required more than 2 changes in their ART 
regimen. 
17. Serum ALT or aspartate aminotransferase (AST) values >1.5 x 
ULN during Screening/Baseline. 
18. Total bilirubin values >1.0 x ULN during Screening/Baseline. 
19. History of drug or alcohol abuse in the 2 years prior to 
Screening.  
20. Any malignancy within 5 years prior to Screening except for 
basal cell carcinoma successfully treated with local therapy. 
21. Medical history or findings that preclude safe participation in 
the study or who are likely to be non-compliant with study 
procedures in the opinion of the Investigator or medical 
monitor. 
Study Design: 
This is a Phase 3, open-label, repeat-dose study designed to assess 
hepatic safety, non-hepatic safety, and efficacy of lixivaptan in 
subjects who previously experienced abnormal liver chemistry test 
results while treated with tolvaptan and were permanently 
discontinued from the drug for that reason.  Up to 50 subjects will be 


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enrolled and treated.  Evaluations will include frequent testing of liver 
chemistry tests (ALT, AST, total and direct bilirubin, and alkaline 
phosphatase values every week during the Baseline and Titration 
Periods and every 4 weeks during the Maintenance Period), physical 
examinations, vital signs, safety labs (serum chemistry, hematology, 
urinalysis), eGFR, urine specific gravity and osmolality 
determinations and trough serum concentration of lixivaptan.  After 
meeting entry criteria during a 1-3-week Screening Period that can 
extend up to 8 weeks for subjects who need to be discontinued from 
diuretic therapy and/or have their anti-hypertensive medication 
adjusted, subjects will enter a 3-week no study drug Baseline Period to 
obtain baseline measurements followed by a 3-6 week Titration Period 
during which lixivaptan administered twice daily will be titrated to a 
dose that is tolerated and results in a reduced trough urine specific 
gravity (or until the maximum dose level is reached).  The minimum 
dose to enter the Maintenance Period is 100 mg BID. Treatment will 
continue for up to 52 weeks (12 months) after which study drug will 
be stopped, and final assessments obtained during the Follow-up 
Period of 4 weeks. The total study duration will be up to 
approximately 73 weeks (16.8 months).  Note that the study may be 
interrupted at any time if safety issues compromise the safety of the 
subjects.   
Study Period 
Description and 
Estimated 
Duration: 
 
 
 
 
 
 
 
 
 
The study schematic is depicted in Figure 1.  Certain visits may be 
conducted remotely with a home healthcare clinician (HHC), but 
Visits 1, 5, 17, 24, and 27 are to be conducted in the clinic (with only 
extraordinary exceptions at the discretion of the medical monitor and 
sponsor). Some of the remote visits will include a telemedicine 
component with the Investigator.  Details are provided in Table 1. 
Screening Period (Visits 1, 2): To obtain informed consent and 
determine subject eligibility, screening assessments will be performed 
during Visit 1. Subjects whose anti-hypertensive medications in the 
absence of diuretics are known and documented to have been stable 
(unchanged) for at least 3 weeks prior to Visit 1 may proceed to Visit 
2 in 1 week to confirm eligibility. Subjects for whom the stability of 
anti-hypertensive medications in the absence of diuretics is unknown 
or not documented must be observed for 3 weeks during the Screening 
Period to ensure stable dosing of anti-hypertensive medications and 
then will be scheduled for Visit 2.  For those subjects who need to be 
discontinued from diuretic therapy and/or have their anti-hypertensive 
therapy optimized, the Screening Period may be extended up to a total 
of 8 weeks prior to Visit 2.  Subjects who meet all the inclusion 
criteria and none of the exclusion criteria and achieve stability of 
background anti-hypertensive medications in the absence of diuretics 
will either return to the clinic or be scheduled for a remote visit with a 
HHC for Visit 2 end-of-screening assessments, including body weight, 


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vital signs, and serum chemistry testing (if diuretics were discontinued 
or anti-hypertensive medications were adjusted) and final eligibility 
determination (utilizing telemedicine if a remote visit).  Subjects 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 and sponsor.  Immediately following successful completion of 
Visit 2, subjects will enter the Baseline Period. 
 
Baseline Period (Visits 3 – 5): Following completion of all screening 
assessments and establishment of background medication stability, 
subjects will enter the 3-week no-study-drug Baseline Period during 
which time liver chemistry tests and serum creatinine (for eGFR 
calculation) will be assessed weekly to obtain baseline measurements 
and assess individual variability. Visits 3 and 4 may be conducted 
remotely by a HHC. After successful completion of Visit 5 
assessments in the clinic, subjects will be dispensed study drug and 
begin treatment. This completes the Baseline Period and subjects will 
enter the Titration Period.  
 
Titration Period (Visits 6 – 11): During a period of 3-6 weeks, the 
lixivaptan dose will be increased weekly according to the titration 
schedule to achieve a level that results in both a tolerable dose and 
reduced first morning (trough) spot urine specific gravity or until the 
maximum dose level (Level 4 [200 mg BID]) is reached.  Dosing will 
be started at Level 1 (50 mg BID), but the minimum dose to enter the 
Maintenance Period is Level 2 (100 mg BID).  In general, dose 
tolerability will be confirmed over an additional week of dosing 
before the subject advances to the Maintenance Period.  At the 2 
highest dose levels where aquaretic effects may be problematic in 
certain subjects, there will be an opportunity to reduce the evening 
(PM) dose (Level 3a [150 mg AM/100 mg PM] and Level 4a [200 mg 
AM/150 mg PM]).  Liver chemistry tests will be assessed weekly 
throughout the Titration Period. Urine osmolality and specific gravity 
will be assessed at all titration visits that occur except Visit 11.  All 
titration visits may be conducted remotely by a HHC with 
telemedicine. 
 
Maintenance Period (Visits 12-24): Following successful completion 
of the Titration Period, subjects will continue to receive lixivaptan in 
the Maintenance Period at the dose level achieved at the end of the 
Titration Period for up to 52 weeks (12 months).  In consultation with 
the medical monitor and sponsor, the Investigator has the option of 
reducing the dose to address potential hepatic and non-hepatic adverse 
events.  Assessments, including liver chemistry tests, will be 
performed every 4 weeks during this period.  Visits 12, 13, 14, 15, 16, 


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18, 19, 20, 21, 22, and 23 may be conducted remotely by a HHC.  If 
conducted remotely, Visits 14 and 20 will include telemedicine. All 
other remote maintenance visits may include a telemedicine 
component if deemed necessary by the Investigator. 
 
Follow-up Period (Visits 25-27): After the last dose of lixivaptan is 
given, subjects will enter the Follow-up Period which will last 4 
weeks.  Serum creatinine, to determine final eGFR, will be obtained 
over three (3) visits starting the 8th day after the final dose of study 
drug and continuing through the 28th day of the Follow-up Period.  
Visits 25 and 26 may be conducted remotely by a HHC (using 
telemedicine if necessary). Other routine final safety assessments will 
be performed at the last visit on Day 28 following the final dose of 
study drug.   
The total study duration will be up to 73 weeks (16.8 months).  Note 
that the study may be interrupted at any time if safety issues 
potentially compromise the safety of the subjects.   
The Hepatic Events Review Committee (HERC), consisting of 3-4 
expert hepatologists, will review safety data in subjects who develop 
liver abnormalities of concern during the study.  This committee will 
independently determine the probable causality for liver chemistry test 
abnormalities of concern and the relatedness to lixivaptan. 
Study Drug, 
Dosage, and 
Route of 
Administration: 
The sponsor (Palladio Biosciences, Inc.) will provide adequate 
supplies of lixivaptan 50 mg capsules for use during the study. All 
doses will be self-administered orally at home.  During the Titration 
Period, dosing will start at Level 1 (50 mg BID) and will be increased 
periodically through Levels 2, 3, and 4 according to the dosing 
schedule shown in the table below.  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 
aquaresis is limiting the subject’s tolerability at either the 150 mg BID 
or 200 mg BID dose levels, respectively.  Titration will stop when a 
tolerable dose level at or above the minimum (Level 2) is reached that 
achieves the goal of lowering trough (first AM) urine specific gravity 
to ≤1.005 or the highest dose (Level 4 or 4a) is achieved (regardless of 
urine specific gravity).  Subjects tolerating the drug at Levels 2, 3, or 
3a, but not achieving the urine specific gravity goal may be allowed to 
continue in the study after consultation with the medical monitor and 
sponsor.  Throughout the study, subjects will take the allotted capsules 
BID approximately 10 hours apart.  
Dosing Levels during the Titration Period 
Dose Level 
AM Dose 
PM Dose 
1* 
50 mg (1 capsule) 
50 mg (1 capsule) 


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2 
100 mg (2 capsules) 
100 mg (2 capsules) 
3 
150 mg (3 capsules) 
150 mg (3 capsules) 
3a** 
150 mg (3 capsules) 
100 mg (2 capsules) 
4 
200 mg (4 capsules 
200 mg (4 capsules) 
4a*** 
200 mg (4 capsules) 
150 mg (3 capsules) 
*Dose Level 1 is for initiation of treatment 
**Subjects 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) 
***Subjects 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 and reduced urine specific gravity (or tolerability 
and maximum dose) are achieved, subjects will stay on that dose for 1 
additional week to confirm tolerability (except when the dose is 
reduced to Level 3a or Level 4a after 2 weeks of dosing at Level 3 or 
Level 4, respectively, when a single final week at the lower dose level 
is sufficient; see Dosing Diagram below).   
The usual dosing scenarios that can be advanced to the Maintenance 
Period are shown in the Dosing Diagram below. With concurrence of 
the medical monitor and the sponsor, some subjects may be allowed to 
enter maintenance at a lower dose if tolerability is an issue after trying 
a higher dose (regardless of specific gravity result at the lower dose). 
Dosing Diagram 
Dose 
Level 
Week 1 
Week 
2 
Week 
3 
Week 4 
Week 5 
Week 6 
Level 2 
50mg 
BID 
100mg 
BID 
100mg 
BID 
 
 
 
Level 3 
50mg 
BID 
100mg 
BID 
150mg 
BID 
150mg 
BID 
 
 
Level 3a 
50mg 
BID 
100mg 
BID 
150mg 
BID 
150/100 
mg (AM/ 
PM) 
150/100 
mg (AM/ 
PM) 
 
Level 3a 
(if 2nd 
week of 
Level 3 
is not 
tolerated) 
50mg 
BID 
100mg 
BID 
150mg 
BID 
150 mg 
BID 
150/ 
100mg 
(AM/ 
PM) 
 
Level 4 
50mg 
BID 
100mg 
BID 
150mg 
BID 
200mg 
BID 
200mg 
BID 
 
Level 4a 
50mg 
BID 
100mg 
BID 
150mg 
BID 
200mg 
BID 
200/ 
150mg 
(AM/ 
PM) 
200/ 
150mg 
(AM/ 
PM) 
Level 4a 
(if 2nd 
week of 
50mg 
BID 
100mg 
BID 
150mg 
BID 
200mg 
BID 
200mg 
BID 
200/ 
150mg 
 (AM/ 


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Level 4 
is not 
tolerated) 
PM) 
Subjects who tolerate their optimized dose will then enter the 
Maintenance Period during which they will continue at the lixivaptan 
dose level achieved at the end of the Titration Period.  During the 
Maintenance Period, in consultation with the medical monitor and 
sponsor, the dose may be adjusted downward at the Investigator’s 
discretion if needed to manage hepatic or non-hepatic side effects and 
may also be increased back to the dose achieved at the end of the 
Titration Period.  The Investigator may temporarily hold the drug for 
up to 7 days, if necessary, to manage acute intercurrent illness, 
tolerability issues, planned or unplanned surgical procedures or life 
situations, e.g., airplane travel, etc. Additionally, subjects who have a 
longer interruption due to illness, including COVID-19, or other 
reasons may be able to re-start study drug when medically stable after 
discussion with the medical monitor and sponsor. 
Study 
Assessments: 
Safety: Liver chemistry tests (ALT, AST, total bilirubin, direct 
bilirubin, alkaline phosphatase), clinical laboratory (hematology, non-
hepatic clinical chemistry, and urinalysis), 12-lead ECGs, vital signs, 
physical examination, adverse events (AEs), and serious adverse 
events (SAEs). 
Efficacy: eGFR 
Pharmacokinetic: Trough measurements of lixivaptan   
Additional Investigations:  DNA sample to assess genetic variants 
associated with hepatic abnormalities (if and when feasible). This is 
obtained under a biobanking informed consent at Visit 5 (or later). 
Criteria for 
Evaluation: 
Primary Endpoint  
Safety: 
Proportion of subjects who develop ALT levels >3 x ULN during the 
Titration or Maintenance Periods that were assessed by the 
independent HERC to be at least probably related to lixivaptan and 
resulted in discontinuation of the study drug.  
Secondary Endpoints 
Safety: 
Proportion of subjects who develop ALT levels >5 x ULN during the 
Titration or Maintenance Periods that were assessed by the 
independent HERC to be at least probably related to lixivaptan and 
resulted in discontinuation of the study drug. 
Proportion of subjects who develop ALT levels >3 x ULN during the 
Titration or Maintenance Periods that were assessed by the 
independent HERC to be at least probably related to lixivaptan and 
resulted in dose reduction of the study drug. 


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The safety and tolerability of lixivaptan assessed through evaluation 
of AEs, clinical laboratory findings (clinical chemistry including 
additional analyses of liver chemistry tests, hematology, and 
urinalysis), vital signs, and 12-lead ECG. 
Efficacy: 
Change in eGFR from baseline (mean of 3 eGFR determinations 
obtained during the Baseline Period) to final assessment (eGFR 
determination obtained during the Follow-up Period).  
Statistical 
Methods: 
Sample Size: 
Up to 50 subjects will be enrolled and treated based on the design of a 
similar study with a different drug. 
Populations for Analysis: 
The Enrolled Population is defined as all subjects who meet 
inclusion/exclusion criteria during Screening Period and complete 
Visit 3. All general summaries, except safety and efficacy analyses are 
based on the Enrolled Population, unless specified otherwise. 
The Safety Population is a subset of the Enrolled Population defined 
as those subjects who received at least 1 dose of lixivaptan.  This 
population will be utilized for all safety analyses. 
The Efficacy Population is a subset of the Safety Population defined 
as those subjects who have at least 1 eGFR determination during the 
Baseline Period and have at least 1 eGFR determination during the 
Follow-up Period.  This population will be used for all efficacy 
analyses. 
The Pharmacokinetic (PK) Population is a subset of the Safety 
Population defined as those subjects who had at least 1 on-therapy 
evaluable PK measurement. 
The Pharmacodynamic (PD) Population is a subset of the Enrolled 
Population defined as those subjects who have at least 1 set of urine 
specific gravity and urine osmolality measurements from the same 
specimen. 
Analysis of Primary and Secondary Safety Endpoint: 
Descriptive statistics (n and percentage) and 95% confidence intervals 
will be used to present the proportion of subjects who develop ALT 
levels >3 x ULN that were assessed by the independent HERC to be at 
least highly likely related to lixivaptan and resulted in discontinuation 
of the study drug during the Titration or Maintenance Periods. 
Similarly, descriptive statistics and 95% confidence intervals will be 
utilized to present the 2 secondary endpoints: the proportion of 
subjects who develop ALT levels >5 x ULN during the Titration or 
Maintenance Periods that were assessed by the independent HERC to 
be related to lixivaptan and resulted in discontinuation of the study 
drug and the proportion of subjects who develop ALT levels >3 x 


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ULN during the Titration or Maintenance Periods that were assessed 
by the independent HERC to be related to lixivaptan and resulted in 
lixivaptan dose reduction. 
Analysis of Additional Hepatic Safety Endpoints: 
Proportion of subjects who develop during the Titration and 
Maintenance Periods: 
 >3 x, 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 
 ALT or AST levels >2 x their baseline 
 Any elevation of total bilirubin to >2 x ULN 
 Any elevation of alkaline phosphatase (ALP) >2 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. 
Analysis of Additional Non-hepatic Safety Endpoints: 
The following safety variables will be summarized using appropriate 
descriptive statistics: 
Treatment-emergent adverse events, clinical laboratory data, 12-lead 
ECGs, and vital signs.  Potentially clinically significant results in 
certain clinical laboratory tests, 12-lead ECGs, and vital signs 
identified using prospectively defined criteria will also be summarized 
descriptively. 
Efficacy Analysis: 
Baseline eGFR is defined as the mean of the 3 eGFR assessments 
obtained during the Baseline Period.  The endpoint eGFR is defined as 
the mean of 3 eGFR assessments obtained during the Follow-up 
Period.  Descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum) will be presented for the change from 
baseline in eGFR at endpoint. 
 
 


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Figure 1.  Study Schematic 
 
 
 
Screening 
Period 
 Baseline 
Period 
   1-8 weeks       3 weeks        3-6 weeks 
  
             
         
              52 weeks 
       
                   
  4 weeks 
Titration Period 
Maintenance                   Period 
Follow-
up Period 
V1                        V2   V3         V5 V6                  V11 V12                                                                                                                                                           V24  V25      V27 


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Table 1 Schedule of Procedures 
Assessment 
Screening 
 (1-8 weeks) 
 
Baseline 
(Weekly ± 3 
days) 
(3 weeks) 
Titration Period 
(Weekly ± 3 days) 
(Up to 6 weeks) 
 
Maintenance Period 
(every 28 days ± 3 days) 
for 52 weeks 
Follow-up 
Period 
 (4 weeks after 
last doseb) 
Visit Number 
V1  
V2a
 
V3, 4, 5 
V6 
V7 
V8 
V9 
V10 
V11 
V12-V23 
V24 
V25, 26, 27 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/Prior meds 
X 
X 
 
 
 
 
 
 
 
 
 
 
Review eligibility 
(Inclusion/Exclusion) 
X 
X 
V5 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
V5 
 
 
 
 
 
 
V17 
X 
V27 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
V27 
Physical examinationd 
X 
 
 
 
 
 
 
 
 
V17 
X 
V27 
Body weight/heighte 
X 
X 
V5 
X 
X 
X 
X 
X 
X 
 
X 
 
Pregnancy test (WOCBP)f 
X 
 
V5 
 
 
 
 
 
X 
V14,17,20 
X 
V27 
Chemistry/Serology samplesg 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Chemistry Panel 
X 
(X) 
V5 
 
 
 
 
 
X 
V14,17,20 
X 
V27 
Liver Chemistry Panel 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
V27 
Serum Creatinine 
 
 
V3, 4 
 
 
 
 
 
 
 
 
V25, 26 
HBsAg, Anti-HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
 
V5 
 
 
 
 
 
X 
V17 
X 
V27 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
V27 
Urine specific gravity/ 
osmolalityi 
 
 
V5 
X 
X 
X 
X 
X 
 
 
X 
V27 
Trough PK samplej 
 
 
V5 
 
 
 
 
 
X 
(X) 
(X) 
 
DNA samplek 
 
 
V5 
 
 
 
 
 
 
 
 
 
Dosing review/Tolerability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug dispensation 
 
 
V5 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug reconciliation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
IRT entry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsl 
<--------------------------------------------------------------------------------------------------------------------------------------------------------------> 
Assess for liver dysfunction 
 
<--------------------------------------------------------------------------------------------> 
V25 
Concomitant medications 
<-------------------------------------------------------------------------------------------------------------------------------------------------------------> 


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NOTES:  
 
V24 also serves as the Early Termination (ET) visit.  
 
Remote visits (if available) may occur at V2 (with telemedicine), V3, V4, V6 – V11 (each with telemedicine), V12, V13, and V14 (with telemedicine), V15, V16, V18, V19, and 
V20 (with telemedicine), V21, V22, V23, V25 and V26. Any remote visit may have a telemedicine component added if needed.  With permission from the medical monitor and 
sponsor, other visits may be done remotely on a case-by-case extraordinary basis. 
a V2 should be scheduled as follows: 1 week after V1 for subjects whose anti-hypertensive medications in the absence of diuretics are documented to have been stable 
for at least 3 weeks prior to V1; 3 weeks after V1 in subjects whose stability of anti-hypertensive medications in the absence of diuretics is unknown or not 
documented.  However, in subjects who have an adjustment to anti-hypertensive medications or discontinuation of diuretics, V2 should be scheduled once the 
regimen is stable for 3 weeks, but no longer than 8 weeks after V1. 
b During the Follow-up Period, 3 visits should be scheduled over 4 weeks. Visit 25 cannot occur earlier than the 8th day (+3) after the last dose of study drug (V24). 
Visit 26 will occur 7-14 ±3 days after V25. Visit 27 is the last visit in this study and will occur 28±3 days after the last dose of study drug (V24). 
c Vital signs after the subject has been sitting for 5 minutes include heart rate, blood pressure, respiratory rate, and temperature at V1. At all subsequent visits include 
sitting heart rate and sitting blood pressure.  
d A full physical examination will be performed at V1 and V24/ET. A brief physical examination will be performed at V17 and V27. Additional physical examinations 
will be performed only for assessment of signs or symptoms reported by the subject that might require further evaluation. 
e Height will only be measured at V1. 
f Serum pregnancy test for WOCBP will be obtained at V1. Subsequently, urine pregnancy tests will be performed at V5, V11/Last Titration, V14, V17, V20, V24/ET 
and V27. All positive urine results will be confirmed by a serum pregnancy test. 
g  Chemistry blood samples and calculations: 
 
• Complete Chemistry Panel will be obtained at V1, V5, V11/Last Titration, V14, V17, V20, V24/ET, V27. If a subject required adjustment of blood pressure 
medications during Screening, then a repeat Complete Chemistry Panel will be performed at V2. 
 
• Liver Chemistry Panel will be obtained at V1, V3-V24/ET, and V27. If a subject requires adjustment of blood pressure medications during Screening, then a 
repeat Liver Chemistry Panel will be performed at V2. 
 
• Serum creatinine will be obtained at V3, V4, V25 and V26.  
 
 eGFR will be calculated and reported whenever serum creatinine is obtained either as part of the Complete Chemistry Panel or when serum creatinine alone is 
measured.  
 
• Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (Anti-HCV) will be obtained at V1 only. 
h Hematology blood samples will be obtained at V1, V5, V11/Last Titration, V17, V24/ET, and V27. 
i First morning, fasting urine specific gravity and osmolality (AM trough) will be obtained at V5, at every visit during the Lixivaptan Titration Period (except 
V11/Last Titration) and at V24 and V27.  Dispense container and review instructions (including not to take study drug on the morning of the next visit) with subject 
at V4-V9, V23, and V26. 
j Trough (7-10 AM prior to AM dose) plasma specimens for measurement of lixivaptan will be obtained at V5, at the final visit during the Titration Period (V11/Last 
Titration), and during the Maintenance Period if ALT levels >3 x ULN and/or total bilirubin >2 x ULN occur.  
k Utilizing a separate informed consent, all subjects will be asked to provide a DNA sample at the end of the Baseline Period (V5) to assess genetic variants associated 
with hepatic abnormalities (if and when feasible). 
l Serious adverse events (SAEs) will be collected throughout the study beginning with signing of informed consent.  All non-serious adverse events will be collected 
beginning at the start of the Titration Period. Adverse Events of Special Interest (AESI) include hepatic events and pregnancy and will be reported on special forms 
using the SAE pathway of reporting. 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
 
 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
 
 
ART 
anti-retroviral therapy 
AST 
aspartate aminotransferase 
BID 
twice per day 
BMI 
body mass index 
cAMP 
cyclic adenosine 3’,5’-monophosphate 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRO 
Contract Research Organization 
CS 
clinically significant 
CT 
computerized tomography 
DILI 
drug induced liver injury 
DILIN 
Drug Induced Liver Injury Network 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
eGFR 
estimated glomerular filtration rate 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C antibody 
HERC 
Hepatic Events Review Committee 
HgbA1c 
glycosylated hemoglobin 
HHC 
home healthcare clinician 


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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCS 
not clinically significant 
OTC 
over-the-counter 
PC1 
Polycystin 1 
PC2 
Polycystin 2 
PIN 
personal identification number 
PK 
Pharmacokinetic 
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 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
Uosm 
urine osmolality  
US 
United States 
WOCBP 
Women of childbearing potential 
 


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1 INTRODUCTION 
1.1 
Background 
Lixivaptan (also known as VPA-985, BIIB030, and CL 347,985) is a potent, non-peptide 
selective antagonist for the vasopressin V2 receptor, which is expressed primarily in the 
collecting duct of the nephron (Chan PS 1998).1  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 (Sosm) as well as restoring normal levels of intracellular 
cyclic adenosine 3’,5’-monophosphate (cAMP) (Chebib FT 2015).2   
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 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 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 renal cysts (Antignac C 2015).3  The progressive development and 
growth of numerous bilateral renal cysts results in fibrosis, renal 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, renal function loss and kidney failure 
(Antignac C 2015, Chapman AB 2015).3,4 
The most frequent extrarenal manifestation of ADPKD is polycystic liver disease, which is 
typically associated with increased renal 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 MC 2015).5  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 cause fever, right upper abdominal pain, and possible elevated CA19.9 
and alkaline phosphatase (ALP) levels.  


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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 FA 2004).6  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 VE 2005).7  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 VE 2012).12  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 O 2017).14  
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 
VE 2017b).15   
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 renal cAMP plays a pivotal role in the complex phenotypical 
manifestation of ADPKD (Belibi FA 2004),6 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.7  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 X 2008),8 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 (Gattone VH 2003)9  and tolvaptan (Wang X 2005),10 have proved efficacious in 
normalizing renal cAMP levels and correcting disease manifestations in preclinical rodent 
models of ADPKD.  In ADPKD patients, elevated levels of circulating copeptin, a marker for 


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serum vasopressin concentration, are associated with faster disease progression (Boertien WE 
2012).11 
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 renal 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 VE 2012, Torres VE 2017a).12,13  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 renal function during the study (Devuyst O 2017).14  
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 O 2017).14 
More recently, the results of REPRISE, a second pivotal Phase 3 trial with tolvaptan for the 
treatment of ADPKD, were published (Torres VE 2017b).15  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 (Wang X 
2005).10  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 renal volume increase, and delayed renal function decline.  These 
beneficial effects were accompanied by a reduction in renal cAMP levels, as expected.  


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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.   
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 subjects, ADPKD patients, and various 
other patient populations (patients with hypervolemic and euvolemic hyponatremia) 
demonstrated that treatment with lixivaptan readily suppresses urinary osmolality to levels 
below the target threshold of 300 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 O 2017).14   
Additional background information on the effect of lixivaptan on urine osmolality can be 
found in the IB. 
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. 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.  Four identified human metabolites of lixivaptan (WAY-
137930, 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.   
Studies using rodent genetic models have demonstrated that inhibiting vasopressin signaling 
is protective against the development of PKD.  Rats harboring a renal cyst-inducing PKD 
mutation genetically crossed to produce offspring with no circulating serum vasopressin do 
not develop cysts (Wang X 2008).8  In addition, the V2 vasopressin receptor antagonists 
mozavaptan and tolvaptan can normalize renal cAMP and correct disease manifestations in 
rodent models of ADPKD (Gattone II VH 2003, Wang X 2005).9,10  Similarly, lixivaptan 
reduces renal cAMP levels in rodent models of PKD and is also protective against the 
development of kidney disease manifestations, including reduced cystic burden, reduced 
renal volume increase, and delayed renal function decline.  Additional information regarding 
the nonclinical evaluation of lixivaptan can be found in the IB. 


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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 subjects, 10 Phase 2a studies, and 4 Phase 3 studies in subjects 
with hyponatremia.  More than 1600 subjects received at least one dose of lixivaptan as part 
of the hyponatremia development program, including 867 who participated in Phase 2 and 3 
studies.  The extent of exposure ranged from 1 day to 180 days with the average around 28 
days.  Total daily doses ranged from 1 mg to 800 mg with the average around 169 mg. 
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. 
Lixivaptan is being tested in ADPKD patients in the ongoing, open-label Phase 2 study, PA-
102.  This study is being conducted to directly 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 subjects with both ADPKD and CKD stage 1 (CKD1), 
stage 2 (CKD2), and stage 3 (CKD3).  At the dose of 200 mg BID, based on preliminary 
results, lixivaptan effectively reduced Uosm to dilute levels, i.e., levels below 300 mOsm/kg, 
throughout 24 hours.  The effect on Uosm was demonstrated in all severities of CKD tested in 
the study.  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 assess 
tolerability.  Lixivaptan was well tolerated by ADPKD subjects; the most common AEs 
reported in 3 or more subjects were dry mouth, headache, and nausea. No subject was 
discontinued because of an AE.  Additional information regarding the results of this study 
can be found in the IB. 
1.7 
Study Rationale 
This is a Phase 3, open-label, repeat dose study designed to assess hepatic safety, non-hepatic 
safety, and efficacy in subjects who previously experienced abnormal liver chemistry test 
results while treated with tolvaptan. Subjects who had to stop tolvaptan therapy due to 
abnormal liver chemistry test results do not currently have available therapeutic options.  In 
this study, such subjects will be treated with lixivaptan to determine if it is a safer alternative.  
Up to 50 subjects will be enrolled and treated.  Evaluations will 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.    
Lixivaptan as a safer alternative to tolvaptan  
Tolvaptan, a vasopressin V2 receptor antagonist, has been approved in many territories, to 
slow the progression of renal function deterioration in patients with autosomal dominant 
polycystic kidney disease (ADPKD).  However, drug-induced liver injury (DILI) occurs in a 


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certain percentage of subjects taking tolvaptan.  Acute liver failure requiring liver 
transplantation has also been reported (Endo M 2019).24  Subjects on tolvaptan require 
frequent testing of liver chemistry and discontinuation of the drug when the test results are 
elevated in order to prevent serious outcomes.   
DILI modeling has allowed for the assessment of potential abnormal liver chemistry tests 
prior to conducting large clinical trials (Woodhead JL 2017a).19  This is a Quantitative 
Systems Pharmacology model of drug-induced liver injury (DILIsymTM).  DILIsym 
integrates physiologically based pharmacokinetic (PBPK) and in vitro toxicity data of parent 
compound and its active metabolites.  Specific in vitro data incorporated into the model 
includes drug induced bile acid transporter inhibition, mitochondrial dysfunction, and 
oxidative stress which have been identified as putative mechanisms for DILI. 
DILIsym was employed to model tolvaptan-mediated liver injury (Woodhead JL 2017b).20  
DILIsym was able to successfully recapitulate the observed toxicity.  The frequency of 
predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split 
daily dosing, was 7.9% compared with clinical observations of 4.4-5.6% in ADPKD trials.  
The simulations also demonstrated that the in vivo hepatic exposure to tolvaptan and its 
metabolite, DM-4103, combined with alterations in bile acid disposition and inhibition of 
mitochondrial respiration were sufficient to account for the initiation of tolvaptan-mediated 
liver toxicity.  
This same platform was used to evaluate the potential of lixivaptan to cause liver toxicity 
(Woodhead JL 2019).21  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 2).  Additional information 
regarding the DILIsym evaluation of lixivaptan can be found in the IB.   
Table 2 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 
Study not yet 
conducted 
0/285 
Tolvaptan 
90/30 mg 
q AM/PM, 24 weeks 
4.4% 
18/229 
7.86% 
Therefore, compared to tolvaptan, in silico modeling and simulation have demonstrated that 
lixivaptan does not have the same potential for liver injury.   


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


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Figure 3.  Time course of ALT levels in relationship to dosing of lixivaptan in a patient 
with painful ADPKD 
 
These results strongly suggest that lixivaptan may represent a safer alternative to tolvaptan 
not only for the general patient population, but also for those subjects who experienced 
abnormal liver chemistry test results while receiving tolvaptan.  The intent of the PA-
ADPKD-303 study is to replicate the experience of hepatic safety with lixivaptan in a larger 
number of ADPKD patients previously treated with tolvaptan who discontinued the drug 
permanently because of abnormal liver chemistry test results. 
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 previous clinical studies conducted 
in healthy subjects, in subjects with hyponatremia of various etiologies, and in the PA-102 
study of subjects with ADPKD.   
The dose range selected for this study is 100 mg BID to 200 mg BID (with 50 mg BID as a 
starting dose).  Doses will be titrated in individual subjects to achieve an appropriate 
reduction in urine specific gravity (as a point-of-care surrogate for Uosm) and tolerability or 
the highest dose is achieved. The same dose range and dose titration scheme will be used in 
the Phase 3 pivotal study (PA-ADPKD-301) to assess the efficacy and tolerability of 
lixivaptan in subjects with ADPKD. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary Objectives 
The primary objectives of this study are: 
 To assess the effect of lixivaptan on hepatic safety in subjects with ADPKD who 
experienced abnormal liver chemistry test results on tolvaptan that resulted in 
permanent discontinuation of tolvaptan. 
2.1.2 Secondary Objectives 
The key secondary objectives of this study are 
 To characterize the non-hepatic safety and tolerability of lixivaptan in subjects with 
ADPKD who previously experienced abnormal liver chemistry test results while 
treated with tolvaptan. 
 To assess renal function (efficacy) in ADPKD subjects while on lixivaptan using 
change in estimated glomerular filtration rate (eGFR). 
2.1.3  Exploratory Objectives 
 To evaluate the relationship between abnormal liver chemistry test results and 
dose/exposure of lixivaptan as data permit. 
 To assess potential genetic risk factors for hepatic abnormalities (if and when 
feasible). 
2.2 
Study Endpoints 
2.2.1 Primary Endpoint 
Safety: 
 Proportion of subjects who develop ALT levels >3 x ULN during the Titration or 
Maintenance Periods that were assessed by the independent Hepatic Events Review 
Committee (HERC) to be at least probably related to lixivaptan and resulted in 
discontinuation of the study drug. 
2.2.2 Secondary Endpoints 
Safety: 
 Proportion of subjects who develop ALT levels >5 x ULN during the Titration or 
Maintenance Periods that were assessed by the independent HERC to be at least 
probably related to lixivaptan and resulted in discontinuation of the study drug. 
 Proportion of subjects who develop ALT levels >3 x ULN during the Titration or 
Maintenance Periods that were assessed by the independent HERC to be at least 
probably related to lixivaptan and resulted in dose reduction of the study drug. 


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 The safety and tolerability of lixivaptan assessed through evaluation of AEs, clinical 
laboratory findings (clinical chemistry including additional analyses of liver 
chemistry tests, hematology and urinalysis), vital signs, and 12-lead 
electrocardiograms (ECG). 
Efficacy:  
 Change in eGFR from baseline (mean of 3 eGFR determinations obtained during 
Screening and Baseline Periods) to final assessment (mean of 3 eGFR determinations 
obtained during the Follow-up Period). 
2.2.3 Exploratory Endpoints 
 Correlation of abnormal liver chemistry test results to plasma levels of lixivaptan. 
 Assessment of genetic variants (if and when feasible) to understand potential genetic 
risk factors for hepatic abnormalities. 


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3 INVESTIGATIONAL PLAN 
3.1 
Study Design 
3.1.1 Overview of Study Design 
This is a Phase 3, open-label, repeat dose study designed to assess hepatic safety, non-hepatic 
safety, and efficacy of lixivaptan in subjects who previously experienced abnormal liver 
chemistry test results while treated with tolvaptan that resulted in permanent discontinuation 
of tolvaptan for that reason.  Up to 50 subjects will be enrolled and treated.  Evaluations will 
include frequent testing of liver chemistry tests (every week during the Baseline and Titration 
Periods, every 4 weeks during the Maintenance Period, and at the final Follow-up Visit), 
physical examinations, vital signs, safety labs (non-hepatic serum chemistry, hematology, 
urinalysis), eGFR, urine osmolality determinations, and trough serum concentrations of 
lixivaptan. A DNA sample to assess genetic variants associated with hepatic abnormalities (if 
and when feasible) will be obtained under a separate biobanking informed consent at Visit 5 
or later in the study.  After meeting study entry criteria during a 1-3-week Screening Period 
that can extend up to 8 weeks (in subjects who need adjustment of anti-hypertensive 
medications), subjects will enter a 3-week no study drug Baseline Period to obtain baseline 
serum creatinine measurements (for eGFR determinations) and repeat liver chemistry tests to 
assess baseline variability, followed by a 3-6 week Titration Period during which lixivaptan 
administered twice daily will be titrated to a dose that is tolerated and results in a reduced 
trough urine specific gravity (or until the maximum dose level is reached) as described 
below.  The minimum dose to enter the Maintenance Period is Level 2 (100 mg BID). 
Treatment will continue for up to 52 weeks (12 months) after which study drug will be 
stopped, and final safety and efficacy assessments obtained during the Follow-up Period of 4 
weeks. The maximum study duration will be 73 weeks (16.8 months).  
All assessments and the relative timings are listed in the Schedule of Study Procedures (Table 
1). Certain visits may be conducted remotely with a home healthcare clinician (HHC), but 
Visits 1, 5, 17, 24, and 27 are to be conducted in the clinic (with only extraordinary 
exceptions at the discretion of the medical monitor and sponsor). Some of the remote visits 
will include a telemedicine component with the Investigator while other remote visits may 
have that option if deemed necessary for a medical reason.  Details are provided in Table 1. 
Study procedures by visit are outlined in Section 6.  A comprehensive description of study 
procedures can be found in Section 7.  Dosing procedures are outlined in Section 5.   
Note that the study may be interrupted at any time if safety issues compromise the safety of 
the subjects.  
The study schematic is depicted in Figure 1.   
 
3.1.2 Detailed Study Design 
Screening Period (Visits 1, 2): After obtaining Informed consent, screening assessments will 
be performed at Visit 1 to determine subject eligibility.  Subjects whose anti-hypertensive 
medications in the absence of diuretics are known and documented to have been stable 


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(unchanged) for at least 3 weeks prior to Visit 1 may proceed to Visit 2 in 1 week to confirm 
eligibility. Subjects for whom the stability of anti-hypertensive medications in the absence of 
diuretics is unknown or not documented must be observed for 3 weeks during the Screening 
Period to ensure stable dosing of these medications and then will be scheduled for Visit 
2.  For other subjects, diuretic therapy may be discontinued and/ or the antihypertensive 
therapy adjusted during the Screening Period; however, following any adjustments, the dose 
for these medications must remain stable for a minimum of 3 weeks prior to the completion 
of the Screening Period (Visit 2).  As such, the Screening Period (from Visit 1 to Visit 2) may 
be extended up to 8 weeks for those subjects who need to discontinue diuretic therapy and/or 
have their anti-hypertensive therapy optimized. 
Subjects who meet all the inclusion criteria and none of the exclusion criteria and achieve 
stability of background medications will be scheduled for end-of-screening assessments 
including body weight, vital signs, and a Complete Chemistry Panel (only if blood pressure 
medications were adjusted) at Visit 2 (which may be conducted remotely by a HHC with 
telemedicine to determine final eligibility).  Eligible subjects will then enter the Baseline 
Period immediately at the completion of Visit 2. Subjects who fail inclusion/exclusion 
criteria because of temporary or correctable reasons may be re-screened up to 2 times after 
obtaining new informed consents with the approval of the medical monitor and sponsor. 
Baseline Period (Visits 3 - 5): Following completion of all Screening assessments and 
establishment of background medication stability, subjects will enter the 3-week no study 
drug treatment Baseline Period during which time liver chemistry tests and serum creatinine 
(for eGFR determinations) will be assessed weekly to establish a baseline and assess 
individual variability.  Baseline trough spot urine specific gravity (as a point-of-care 
surrogate for urine osmolality) and Uosm will be determined only at Visit 5. Visits 3 and 4 
may be conducted remotely by a HHC. At the successful completion of the Baseline Period 
(Visit 5), subjects will be dispensed study drug and begin treatment.  This completes the 
Baseline Period and subjects will enter the Titration Period. 
Titration Period (Visits 6 - 11):  During a period of 3-6 weeks, the lixivaptan dose will be 
increased weekly according to the titration schedule (Table 4) to achieve a level that results in 
both a tolerable dose and reduced first morning (trough) spot urine specific gravity (as a 
point-of-care surrogate for urine osmolality) or until the maximum dose level (Level 4 [200 
mg BID]) is reached.  Dosing will be started at Level 1 (50 mg BID), but the minimum dose 
to enter the Lixivaptan Maintenance Period is Level 2 (100 mg BID).  In most circumstances, 
dose tolerability will be confirmed during an additional week of dosing before the subject 
advances to the Maintenance Period.  At the 2 highest dose levels (Level 3 and Level 4) 
where aquaretic effects may be problematic in certain subjects, there will be an opportunity 
to reduce the evening (PM) dose (Level 3a [150 mg AM/100 mg PM] and Level 4a [200 mg 
AM/150 mg PM]; see Section 5.2).  Liver chemistry tests will be assessed weekly during the 
Titration Period. Urine specific gravity and Uosm will be measured at all titration visits that 
occur except Visit 11.  All titration visits may be conducted remotely by a HHC with 
telemedicine.  
 


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Maintenance Period (Visits 12 - 24): Subjects will continue to receive lixivaptan at the dose 
achieved at the end of the Titration Period for up to 52 weeks (12 months).  The investigator 
will have the ability to lower the dose if necessary, to improve tolerability. Assessments, 
including liver chemistry tests, will be performed every 4 weeks during this period.  Visits 
12, 13, 14, 15, 16, 18, 19, 20, 21, 22, and 23 may be conducted remotely by a HHC.  If 
conducted remotely, Visits 14 and 20 will include telemedicine and the other visits may 
include telemedicine if deemed necessary by the Investigator. 
Follow-up Period (Visits 25 - 27): After the last dose of lixivaptan is given, the subjects will 
enter the Follow-up Period which will last 4 weeks.  Three assessments of serum creatinine 
to determine eGFR will be obtained starting as early as the 8th day after the final dose of 
study medication and continuing through the 28th day of the Follow-up Period.  Visits 25 and 
26 may be conducted remotely by a HHC (using telemedicine if deemed necessary by the 
Investigator).  Other routine safety assessments will be performed at the last visit (Visit 27).  
Study assessments including clinical laboratory tests, spot urine collections, physical 
examination findings, vital signs, ECGs, trough PK sampling, and monitoring of AEs will be 
performed at the timepoints presented in the Schedule of Procedures (Table 1).  Serious AEs 
(SAEs) will be recorded from the time the subject signs the Informed Consent Form (ICF) 
until exit from the study.  All other AEs will be recorded from the start of the Titration Period 
until exit from the study.  
The maximum study duration is 73 weeks (16.8 months).  Note that the study may be 
interrupted at any time if safety issues compromise the safety of the subjects.  
3.2 
Rationale for Study Design 
This study design is similar to the study design used to assess the safety of ambrisentan in 
subjects with pulmonary arterial hypertension (PAH) who had discontinued endothelin 
receptor antagonist therapy due to abnormal liver chemistry test results (McGoon MD 
2009).22  Subjects in this study will have previously discontinued tolvaptan permanently due 
to abnormal liver chemistry test results.  The rationale for selecting a similar design is 
twofold.  
1) Selection of an enriched population of subjects 
It is only in the ADPKD population that abnormal liver chemistry tests resulting in drug 
discontinuation have been observed with tolvaptan.  Liver injury has not been detected 
following exposure to tolvaptan in non-ADPKD patients including subjects with cirrhosis, 
congestive heart failure, or hyponatremia (Watkins PB 2015).23  Although other factors might 
have contributed to tolvaptan’s toxicity, it is possible that subjects with ADPKD may be more 
susceptible to tolvaptan-associated liver injury (Watkins PB 2015).23  Because the liver injury 
may be severe, tolvaptan is no longer a treatment option for ADPKD subjects experiencing 
this side effect of tolvaptan.  Therefore, subjects who discontinue from tolvaptan due to liver 
injury are a higher risk population where the hepatic safety profile of lixivaptan may be 
appropriately tested and where the potential benefit of vaptan therapy may be provided in the 
absence of other therapeutic choices.  


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2) Sample size consideration  
The sample size of up to 50 subjects selected for this study is similar to that used in the 
ambrisentan hepatic safety study (McGoon MD 2009).22  Although, a placebo-controlled, 
double-blind assessment of lixivaptan is the preferred study design, a placebo-controlled trial 
would not be feasible in this patient population due to the low frequency of patients with 
abnormal liver chemistry test results following treatment with tolvaptan.  Conversely, a 52-
week placebo-controlled, double-blind trial with an additional 52 weeks of open-label 
lixivaptan treatment to assess the efficacy and safety of lixivaptan for the treatment of 
ADPKD (PA-ADPKD-301) in a broader patient population will be conducted approximately 
in parallel to this study.  The number of subjects planned to be enrolled in the PA-ADPKD-
301 trial is 1200.  A comparison of the frequency of serum ALT elevations between the 
lixivaptan and placebo arms of that trial will provide complementary data to support the 
hepatic safety profile of lixivaptan.  Additionally, subjects in the placebo arm of the double-
blind phase of that study will receive lixivaptan during the open-label phase and be studied 
for an additional 52 weeks, thus, providing further hepatic safety information. Safety data 
from the pivotal efficacy and safety trial (PA-ADPKD-301) and this hepatic safety study (PA-
ADPKD-303) will be used to support the predicted hepatic safety profile of lixivaptan. 
Therefore, both studies will contribute to understanding the safety of lixivaptan in ADPKD 
patients, particularly any effects on liver chemistry tests.   


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4 SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1 
Selection of Study Population 
Approximately 100-200 subjects will be screened in order to enroll and treat up to 
approximately 50 subjects at up to approximately 25 sites globally.  An eligibility review and 
discussion between the Investigator and the medical monitor will be conducted before each 
subject is enrolled (completes Visit 3) at each site.  Subjects will be enrolled only if they 
meet all the inclusion criteria and none of the exclusion criteria. With the approval of the 
medical monitor and sponsor, subjects who fail inclusion/exclusion criteria due to temporary 
or correctable reasons may be re-screened up to 2 times after re-consenting each time. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety.  Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 Inclusion Criteria 
In order to qualify for enrollment in this study, each subject must meet the following 
inclusion criteria: 
1. Male or female, between 18 and 65 years of age (inclusive) at the time of Screening.  
2. Female subjects must: 
a. not be pregnant, lactating, or breastfeeding.   
b. be either postmenopausal (defined as amenorrhea for ≥12 months), surgically 
sterile (defined as having undergone hysterectomy and/or bilateral 
oophorectomy), or if of child-bearing potential (WOCBP) must agree to 
practice appropriate methods of birth control or remain abstinent (only if this 
is the usual and preferred lifestyle of the participant) during the study and for 
30 days after the last dose of study drug. Acceptable forms of contraception 
include any of the following: 
 hormonal contraceptives (i.e., oral, intravaginal, transdermal, 
injectable, implantable) 
 double barrier methods of non-hormonal contraception are permitted 
in this study.  
o male or female condom with spermicide (cream, spray, gel, 
suppository, contraceptive sponge, or polymer film) 
o diaphragm, cervical cap, or contraceptive sponge with 
spermicide (with or without a condom) 
 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 


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count 
 bilateral tubal ligation 
 Essure® procedure (tubal occlusion). 
3. Male subjects and their female partners of childbearing potential must also use the 
contraceptive methods listed above or remain abstinent (only if this is the usual and 
preferred lifestyle of the participant) during the study and for 30 days after the last 
dose of study drug. 
4. Diagnosis of ADPKD confirmed by previous treatment with tolvaptan specifically for 
that indication and supported by evidence from any imaging modality or genetic 
analysis. 
5. Screening eGFR ≥20 ml/min/1.73m2. 
6. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) at the time of 
Screening. 
7. Documented history of: 
a. Based on upper limit of normal (ULN): at least 2 elevated alanine 
aminotransferase (ALT) levels, 1 ALT level >2 times (x) the ULN and 1 ALT 
level >3 x ULN while the subject was receiving tolvaptan, or within 4 weeks 
after tolvaptan discontinuation, with no other explanation for the ALT 
elevations.  The 2 elevated ALT measurements could be recorded during the 
same instance of liver injury or during distinct instances;  
OR 
b. Based on the subject’s stable baseline as determined by the Investigator: at 
least 2 elevated ALT levels, 1 ALT level >2 x the subject’s stable baseline 
level and 1 ALT level >3 x the subject’s stable baseline level while the subject 
was receiving tolvaptan, or within 4 weeks after tolvaptan discontinuation, 
with no other explanation for the ALT elevations; provided that at least one 
ALT elevation was >2 x ULN.  The 2 elevated ALT measurements could be 
recorded during the same instance of liver injury or during distinct instances; 
OR 
c. A pattern of ALT elevations deemed by the Investigator to be consistent with 
tolvaptan liver injury with no other explanation for the ALT elevations and the 
agreement of the medical monitor and sponsor.   
8. Permanent discontinuation of prior tolvaptan treatment because of the abnormal liver 
chemistry test results. 
9. The subject may or may not have been re-challenged with tolvaptan.  If re-challenge 
was performed, the ALT level should have increased to >2 x ULN upon rechallenge 
or the ALT level was increasing but tolvaptan was stopped for patient safety reasons 
before it reached > 2 x ULN after having previously normalized. 
10. Appropriate control of hypertension including an angiotensin converting enzyme 
inhibitor or angiotensin receptor blocker (unless not considered appropriate for the 
subject) without the use of a diuretic in concert with KDIGO “Clinical Practice 


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Guideline for the Management of Blood Pressure in Chronic Kidney Disease”.17  
11. 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 
Subjects meeting any of the following exclusion criteria are not eligible for study enrollment. 
1. Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan 
and related compounds. 
2. Hypovolemia on physical examination at Screening. 
3. Abnormal serum sodium concentration at Screening. 
4. Subjects who have taken any investigational drug or used an investigational device 
within 30 days, or 5 half-lives, whichever is longer, prior to Screening.  
5. Subjects who are taking, have taken within the 2 weeks prior to Screening, 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. 
6. Simvastatin at total daily doses >10 mg or amlodipine at total daily doses >5 mg. 
7. Prior use of tolvaptan within the 3 months prior to Screening OR until a previously 
elevated ALT level has returned to ≤1 x ULN for at least 3 months.  
8. Prior use of lixivaptan or participation in a clinical study with lixivaptan within the 3 
months of Screening. 
9. Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, 
etc.), metformin (allowed for diabetes mellitus), nicotinamide, bardoxolone, 
venglustat, demeclocycline, or mTOR kinase inhibitors (e.g., everolimus, sirolimus, 
etc.) to treat ADPKD within the 3 months prior to Screening. 
10. Requirement for chronic diuretic use. 
11. History of advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or 
glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine], 
retinopathy), other significant renal disease, transplanted kidney, recent kidney 
surgery within the 6 months prior to Screening (including cyst drainage or 
fenestration) or acute kidney injury within 6 months prior to Screening. 
12. Clinically significant incontinence, overactive bladder, or urinary retention (e.g., 
benign prostatic hyperplasia). 
13. New York Heart Association Functional Class 3 or 4 heart failure or other significant 
cardiac or ECG findings that could pose a safety risk to the subject. 
14. Clinically significant liver disease or impairment or active chronic hepatitis at 
Screening. 
15. Positive test results for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV) 
antibody. 
16. History of infection with human immunodeficiency virus (HIV) unless the subject is 
stable and doing well on a non-CYP interacting anti-retroviral therapy (ART) regimen 
and who has not required more than 2 changes in their ART regimen. 


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17. ALT or aspartate aminotransferase (AST) values >1.5 x ULN during 
Screening/Baseline. 
18. Total bilirubin values >1.0 x ULN during Screening/Baseline. 
19. History of drug or alcohol abuse in the 2 years prior to Screening.  
20. Any malignancy within the 5 years prior to Screening except for basal cell carcinoma 
successfully treated with local therapy. 
21. Medical history or findings that preclude safe participation in the study or who are 
likely to be non-compliant with study procedures in the opinion of the Investigator or 
medical monitor. 
4.2 
Completion and Withdrawal of Subjects from the Study 
4.2.1 Definition of Completed Subjects 
A completed treatment subject is one who has completed the procedures beginning with 
Screening through the last Maintenance Period visit (Visit 24). A completed study subject is 
one who has completed the procedures beginning with Screening through the last Follow Up 
Period visit (Visit 27).  The end of the study is defined as the last subject’s last visit. 
4.2.2 Screening and Baseline Failures  
Subjects 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 and Baseline Periods, subjects who withdraw their consent or fail to 
meet all the entry criteria to participate in the study will be designated as “Screen failures” or 
“Baseline failures”, respectively.  Screen or Baseline failure subjects will be recorded as such 
on the electronic Case Report Form (eCRF) and do not need to enter the Follow-up Period 
unless a SAE is ongoing, in which case they will be scheduled for Visit 27 in 4 weeks. Screen 
failure subjects who do not meet study entry requirements due to temporary or correctable 
reasons may be re-screened up to 2 times with the written approval of the medical monitor 
and sponsor. 
4.2.3 Subject Withdrawal Criteria 
A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
administrative reasons.  
Subjects who discontinue or are discontinued after the Baseline Period will be considered as 
a withdrawal, regardless of whether they have received study drug. A subject that withdraws 
from study drug will be treated as a study withdrawal unless they are being followed for 
safety reasons. 
All premature discontinuations and their causes must be carefully documented in the eCRF, 
and in the AE form (if applicable).  


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Subjects not completing the entire study on study drug should be encouraged to continue 
with the visit schedule, a modified visit schedule, or telephone follow-up as agreed between 
the subject and the Investigator. At a minimum, subjects should be encouraged to complete 
the Early Termination Visit (Visit 24 – in the clinic) at the time of study drug discontinuation 
and the Follow-up Visits (Visits 25 – 27) over the 4 weeks after the last dose of study drug.  
Subjects with ongoing SAEs or AEs believed to be at least possibly related to study 
medication will continue to be followed until resolution or for 28 days as warranted by the 
nature of the AE. If the AE is related to abnormal liver chemistry test results, see Section 
7.3.7 for additional follow-up requirements.  
4.2.4 Reasons for Withdrawal 
Reasons for withdrawal (subjects who refuse to return for any remaining study visits) or 
discontinuation (subjects who prematurely stop the treatment) at any time during the study 
may include, but are not limited, to the following: 
1. No longer meet the protocol inclusion or exclusion criteria, e.g., require a prohibited 
concomitant medication. 
2. Noncompliance with the protocol. 
3. Lack of efficacy. 
4. A serious or intolerable AE that, in the Investigator’s opinion, requires withdrawal 
from the study, including but not limited to laboratory safety assessments that reveal 
clinically significant (CS) hematological or biochemical changes from the baseline 
values, other than changes that are expected for vasopressin antagonists, and 
symptoms of an intercurrent illness that justifies withdrawal. If the AE is related to 
abnormal liver chemistry test results, see Section 7.3.7 for additional follow-up 
requirements.  Mild elevations in serum creatinine or serum sodium are known 
pharmacodynamic effects of vasopressin antagonists like lixivaptan and are transient 
and reversible.  Therefore, subjects should not be withdrawn from study participation 
solely due to mildly elevated serum creatinine or serum sodium.  Cases where eGFR 
has declined by 25% or more from baseline should be discussed with the medical 
monitor and sponsor. 
5. Death 
6. Lost to follow-up. 
7. Other (e.g., pregnancy, study burden, development of contraindication to use of study 
drug). 
8. Withdrawal of consent (partial or complete). 
9. Investigator’s or Sponsor’s decision to discontinue the subject’s participation in the 
study. 
10. Sponsor termination of the study. 
Upon occurrence of an SAE or intolerable AE, the Investigator will confer with the medical 
monitor and Sponsor.  If a subject is discontinued from study drug because of an AE, the 


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event will be followed until it is resolved or stable or up to 28 days as determined by the 
Investigator.  Any subject may withdraw his or her consent at any time.  Subjects’ safety will 
be closely monitored throughout the study, and the study will be conducted following Good 
Clinical Practices (GCP).  The entire study may be stopped at any time at the discretion of 
the Sponsor. 
4.2.5 Methods to Prevent Lost to Follow-up 
The Investigator must make every attempt to follow-up subjects who have withdrawn from 
the study at any time and for any reason. When a subject 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 subject 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 subject cannot be reached, they should be identified as “lost to follow-up” in 
the eCRF. 
4.2.6 Replacements 
Subjects who withdraw from the study will not be replaced. 
4.2.7 Withdrawals Due to Abnormal Liver Chemistry Test Results 
Guidance for management of abnormal liver chemistry test results is provided in Section 
7.3.7.  In some cases, it will be advisable to discontinue the study drug and under other 
circumstances dose reduction might be appropriate.  These actions in response to abnormal 
liver chemistry test results must be discussed with the medical monitor and sponsor prior to 
taking any action (except in an emergency).  If study drug is withdrawn, re-starting study 
drug should generally be encouraged after discussion with the medical monitor and sponsor, 
when liver chemistry tests have normalized or stabilized, and in conjunction with a plan for 
increased frequency of liver chemistry test monitoring.  In certain circumstances described in 
Section 7.3.7.2, restarting study drug should only occur when the HERC believes the 
relationship between the abnormal liver chemistry test results and the study drug is less than 
50% according to the DILIN criteria, modified, Section 13.2  (Fontana RJ 2009).18 
 


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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 3. 
Table 3.  Investigational Product 
 
Lixivaptan 
Strength 
50 mg 
Formulation 
Capsules, packaged 30 per bottle 
Inactive ingredients 
Polyethylene glycol 400, NF/EP; Polyethylene glycol 1000, 
NF/EP; Povidone (K-17), USP/EP; Polysorbate 80, NF/EP; 
Butylated hydroxytoluene; Butylated hydroxyanisole 
 
Manufacturer 
PMRS, Inc. 
202 Precision Road  
Horsham, PA 19044 
Packager 
PCI Pharma Services 
4545 Assembly Drive 
Rockford, IL 61109 
 
5.1.2 Route of Administration 
The study drug (lixivaptan capsule) is intended to be taken orally, i.e., to be swallowed whole 
with water. The capsule should NOT be opened.   
5.1.3 Study Drug Packaging, Labeling, and Storage 
Study drug will be packaged and labeled by PCI Pharma Services, Rockford, IL, USA 
according to all local legal requirements. The study drug will be labeled in accordance with 
applicable regulatory requirements. 
All study drug supplies should be stored at the study site in its original packaging in a secure, 
locked area under the responsibility of the Investigator or other authorized individual. At the 
study site, lixivaptan should be stored in accordance with the specifications detailed in the 
study pharmacy manual.  Once lixivaptan is dispensed, the subject should be instructed to 
store it in its original packaging and in accordance with lixivaptan treatment labelling at all 
times until ready to take.  For subjects who utilize remote visits, study drug will be dispensed 
and shipped from the study site to the subject’s home, or to an alternate location pre-specified 
by the subject, via an experienced courier approved by the Sponsor.  Subjects will be 
provided with written instructions to securely store the study drug in its original packaging 
under the conditions described above and not to open the package until the HHC arrives. 
 


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5.1.4 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 and used by each subject 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 drug 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. During the Lixivaptan Titration 
Period, 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 4. 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 subjects’ tolerability at either the 150 mg BID or 200 mg 
BID dose levels, respectively.  Titration will stop when a tolerable dose level is reached that 
achieves the goal of lowering trough (first AM) fasting spot urine specific gravity to ≤1.005 
(as a point-of-care surrogate for Uosm) or the highest dose (Level 4 or 4a) is achieved 
(regardless of trough urine osmolality).  Subjects tolerating the drug at Level 2, 3, and 3a, but 
not achieving the urine specific gravity goal may be allowed to continue in the study after 
consultation with the medical monitor and sponsor.   
Table 4  Dosing Levels during the Lixivaptan Titration Period 
Dose Level 
AM Dose 
PM Dose* 
1† 
50 mg (1 capsule) 
50 mg (1 capsule) 
2 
100 mg (2 capsules) 
100 mg (2 capsules) 
3 
150 mg (3 capsules) 
150 mg (3 capsules) 
3a‡ 
150 mg (3 capsules) 
100 mg (2 capsules) 
4 
200 mg (4 capsules) 
200 mg (4 capsules) 
4a# 
200 mg (4 capsules) 
150 mg (3 capsules) 
*PM dose to be administered approximately 10 hours after the AM dose. 
†Dose Level 1 is only for initiation of treatment. 
‡Subjects having difficulty with aquaretic effects at Dose Level 3 can drop back to 150 mg in the AM 
and 100 mg in the PM (Dose Level 3a: 150/100 mg). 
#Subjects having difficulty with aquaretic effects at 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 and reduced trough urine specific gravity are achieved (or tolerability and 
maximum dose), subjects will stay on that dose for 1 additional week to confirm tolerability 
(except when the dose is reduced to Level 3a or Level 4a after 2 weeks of dosing at Level 3 


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or Level 4, respectively, when a single final week at the lower dose level is sufficient; see 
Table 5).  The most common dosing scenarios that can be advanced to the Maintenance 
Period are shown in Table 5.  With concurrence of the medical monitor and the sponsor, some 
subjects may be allowed to enter the Maintenance Period at a lower dose (but not less than 
100 mg BID) if tolerability is an issue after trying a higher dose (regardless of specific 
gravity result at the lower dose): 
Table 5. Dosing Diagram in the Lixivaptan Titration Period 
Dose Level 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
2 
50 mg 
BID 
100 mg 
BID 
100 mg 
BID 
 
 
 
3 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
150 mg BID 
 
 
3a 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
150/100 mg 
(AM/PM) 
150/100 mg 
(AM/PM) 
 
3a (when 2nd 
week of Level 
3 is not 
tolerated) 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
150 mg BID 
150/100 mg 
(AM/PM) 
 
4 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
200 mg BID 
200 mg BID 
 
4a 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
200 mg BID 
200/150 mg 
(AM/PM) 
200/150 mg 
(AM/PM) 
4a (when 2nd 
week of Level 
4 is not 
tolerated) 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
200 mg BID 
200 mg BID 
200/150 mg 
(AM/PM) 
 
Subjects will continue to adhere to the recommended fluid intake regimen outlined in Section 
5.8. 
Subjects who tolerate their optimized dose will then enter the Maintenance Period during 
which time they will continue at the lixivaptan dose level achieved at the end of the Titration 
Period.  During the Maintenance Period, the dose may be adjusted downward at the 
Investigator’s discretion if needed to manage non-hepatic side effects and may also be 
increased back to the dose achieved at the end of the Titration Period.  The Investigator may 
instruct the subject to hold the study drug for up to 7 days, if necessary, to manage acute 
intercurrent illness, tolerability issues, surgical procedures or life situations, e.g., airplane 
travel, etc.  Additionally, subjects who have a longer interruption due to illness, including 
COVID-19, or other reasons may be able to re-start study drug when medically stable after 
discussion with the medical monitor and sponsor.  Temporary or permanent study drug 
discontinuation for management of abnormal liver chemistry test results is described further 
in Section 7.3.7. 
5.3 
Method of Assigning Subjects to Identification Numbers 
Each investigator will be assigned a unique 5-digit site number (XXXXX). This site number 
will be concatenated with a leading protocol number (303) and a following 3-digit subject 


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number to assure that each subject will be uniquely identified in the clinical database. Thus, a 
prototypical subject number in this study will look like 303-XXXXX-YYY.  As subjects are 
screened, the next subject qualified chronologically at a site will be assigned the next number 
in ascending numerical order.  Thus, the subject identification number for the first subject 
screened at the first site activated will be 303-10001-001.  The first subject screened at the 
second site activated will be 303-10002-001 and so on. The subject identification number 
assigned at Screening will be used for that subject throughout the study, including if the 
subject re-screens. 
5.4 
Blinding 
This will be an open-label study. 
5.5 
Randomization and Treatment Assignment 
This study will not be randomized.  
5.6 
Treatment Compliance 
Dispensing of study drug and reconciliation will be done at each visit during the Titration 
Period and every 4 weeks during the Maintenance Period.  A final reconciliation will be done 
by the site once each subject completes study drug dosing. Subject compliance will be 
monitored by capsule counts as study drug is returned. 
The dates of all study medication dosing, including interruptions, missed doses or overdose, 
must be recorded in the eCRF. If the subject 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 subject should be re-
educated regarding the correct study drug doses to be administered. However, if the 
Investigator, medical monitor, and sponsor have agreed to a treatment interruption (Section 
5.2), then this period of non-compliance will not be considered a protocol deviation.   
5.7 
Prior and Concomitant Therapy 
Subjects will be allowed to take their medications to treat chronic conditions unless excluded 
by the protocol (Section 5.7.1.2) and provided that their chronic medication therapy meets 
the conditions outlined in Section 5.7.1.1, including remaining constant throughout the 
duration of the study (unless there is a documented medical reason to change the dose).  
Use of all prior medications within 1 month prior to study drug administration will be 
recorded in the subject’s eCRF. However, for those medications specified in Exclusion 
Criteria 7, 8, and 9 it will be necessary to check medical records during the prior 3 months.  
The minimum requirement is that drug name and 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 subject’s eCRF. 
Any concomitant medication deemed necessary for the well-being of the subject during the 
study may be given at the discretion of the Investigator after consideration of the clinical 
situation.  The Investigator is responsible for ensuring that details regarding concomitant 


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medication use are recorded in the eCRF.  For each concomitant medication administered the 
following details will be documented and recorded in the subject’s eCRF: name of 
medication, dose administered, dates and time of administration, and reason for medication 
use. 
Upon entering the study, each subject will be instructed about the importance of not taking 
any medication (including herbal supplements and OTC medications) without consulting the 
Investigator. 
5.7.1.1 Permitted Therapy 
Allowed medications include those typically prescribed to treat ADPKD, CKD, and their 
complications such as hypertension.  These include angiotensin II receptor blockers (e.g., 
valsartan, candesartan, telmisartan, irbesartan) and angiotensin-converting enzyme inhibitors 
(e.g., enalapril, lisinopril).  However, certain medications are prohibited.  Those are detailed 
in Section 5.7.1.2 below.    
Acetaminophen, at doses ≤3 g per day, is permitted for use any time during the study in 
subjects who usually take acetaminophen to control episodic pain.  Because of their effect on 
renal function, use of non-steroidal anti-inflammatory drugs should be minimized. 
Non-sedating antihistamines (other than loratadine) and decongestants are permitted on an 
as-needed basis.  Low-dose aspirin (up to 325 mg per day) is permitted.   
Chronic use of other concomitant medications that are required to treat a medical condition 
may be permitted unless otherwise prohibited (Sections 4.1.2 and 5.7.1.2).  All medications 
should be stable for at least 3 weeks before and/or during the Screening Period.  
Subsequently, doses of such medications should remain as stable as possible allowing for 
minor adjustments per the standard of care to treat medical conditions.  The stability of 
certain drugs, such as insulin and warfarin, should be based on the standard of care rather 
than on a stable dose.   
As lixivaptan has the potential to inhibit the metabolism of CYP3A4 and CYP2C8 substrates, 
care should be exercised when administering lixivaptan in combination with these substrates 
(Section 5.7.1.2) due to the potential for drug-drug interactions.  Caution should be exercised 
when concomitantly administering simvastatin or amlodipine with lixivaptan.  In order to 
minimize the potential for AEs, the Investigator should consider potential dose adjustments 
or alternative therapeutic options that are not CYP3A4 or CYP2C8 substrates (e.g. 
rosuvastatin to replace simvastatin) or that have a high therapeutic index.  If subjects are 
receiving simvastatin as background medication and it is not possible to replace simvastatin 


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with rosuvastatin, the dose of simvastatin should be decreased to ≤10 mg daily.  If 
amlodipine is needed for clinical care, the dose should not exceed 5 mg daily. 
5.7.1.2 Prohibited Therapy 
Subjects should not be entered into the study until all abnormal liver chemistry test results 
related to tolvaptan have resolved for at least 3 months prior to the first Screening Visit. 
The following medications are prohibited during the 3 months prior to Screening Visit 1 and 
throughout the study: 
 Conivaptan 
 Somatostatin analogs (e.g. lanreotide, pasireotide, octreotide, etc.) 
 Metformin (for ADPKD; allowed for diabetes mellitus) 
 Nicotinamide (for ADPKD) 
 Bardoxolone 
 Venglustat 
 Demeclocycline  
 mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.) 
 SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.)  
 HIF-PH inhibitors 
 Any investigational drug or device. 
The following medications are excluded within 2 weeks of Screening Visit 1 (except 
diuretics) and prohibited throughout the study: 
 Diuretics (which should be discontinued during the Screening Period when anti-
hypertensive medications are being adjusted); 
 Strong or moderate CYP3A4 or CYP2C8 inhibitors, including aprepitant, boceprevir, 
clarithromycin, chloramphenicol (not eye drops), cimetidine, ciprofloxacin, 
clopidogrel, clotrimazole (if used orally), cobicistat and cobicistat-containing 
products, crizotinib, cyclosporine, danazol, deferasirox, diltiazem, dronedarone, 
erythromycin, fluconazole, fluvoxamine, gemfibrozil, HIV protease inhibitors, 
imatinib, isoniazid, itraconazole, josamycin, ketoconazole, nefazodone, posaconazole, 
quinupristin/dalfopristin, remdesivir, ritonavir and ritonavir-containing products, 
telaprevir, teriflunomide, tofisopam, troleandomycin, verapamil, and voriconazole; 
 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. 
5.8 
Diet, Fluid, Activity, and Lifestyle Considerations 
Restriction of excess dietary sodium and cooked meat protein may prove beneficial to 
subjects 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. 


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Subjects 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 subjects with ADPKD.  Given the potential for 
dehydration with lixivaptan treatment, all subjects 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 Titration Period, all subjects 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 Investigator.  This 
recommendation should start at the beginning of the Titration Period and continue through 
the end of the study.  Additionally, subjects 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 subject self-assessment of 
symptoms such as lightheadedness or dizziness.  Starting at the end of the Baseline Period 
(Visit 5) and continuing during the Titration Period, subjects will be weighed weekly at their 
visits.  Acute decreases of >3% of body weight over any 7-day period should be noted by the 
staff and the subject should be counseled to increase fluid intake.   
Daily activity including exercise should remain stable during the study and subjects should 
avoid heavy lifting or intense physical exertion on the day before scheduled serum creatinine 
measurements. 
Consumption of alcohol should be limited to 1 alcoholic drink equivalent per day in women 
and 2 alcoholic drink equivalents per day in men.  An alcoholic drink equivalent is 12 ounces 
(360 ml) of regular beer, or 5 ounces (150 ml) of wine, or 1.5 ounces (45 ml) of distilled 
spirits. 


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6 TIMING OF STUDY PROCEDURES  
The timing of study procedures is presented in Table 1. Certain visits must occur in the 
clinic.  Other visits may occur in the clinic or remotely by a HHC (if available). 
6.1 
Screening Period 
To determine subject eligibility, informed consent will be obtained, and screening 
assessments will be performed during Visit 1.  It will be particularly important to review 
previous treatment history with tolvaptan and documentation of all liver chemistry tests 
during and after treatment with that drug.  Subjects not known to the Investigator should be 
prepared to bring medical records.  Such documentation must include evidence of the 
decision to discontinue tolvaptan permanently on the basis of prior abnormal liver chemistry 
test results.  
Following Visit 1, subjects whose anti-hypertensive medications in the absence of diuretics 
are known and documented to have been stable (unchanged) for at least 3 weeks prior to Visit 
1 may proceed to Visit 2 in 1 week to confirm eligibility. Subjects for whom the stability of 
anti-hypertensive medications in the absence of diuretics is unknown or not documented 
must be observed for 3 weeks during the Screening Period to ensure stable dosing of these 
medications and then will be scheduled for Visit 2.  At Visit 2 (which may be conducted 
remotely by a HHC and telemedicine to determine eligibility) screening test results will be 
reviewed, and additional assessments obtained as per the Schedule of Procedures. 
Subjects who need to have diuretics discontinued or anti-hypertensive regimens intensified 
will undergo those changes and be monitored as medically appropriate.  Once the doses of 
those medications have been stabilized for 3 weeks, the subject will be scheduled for Visit 2.  
Under these circumstances, the Screening Period should not exceed 8 weeks. 
Subjects who successfully complete the Screening Period will immediately enter the Baseline 
Period.  Subjects who fail inclusion/exclusion criteria will be discontinued but may be re-
screened and new informed consents obtained with the approval of the medical monitor and 
sponsor at a later time up to 2 times if the screen failure reason was temporary or correctable. 
6.1.1 Visit 1  
Visit 1 will be conducted at the clinical site.  Subjects will undergo informed consent and 
after signing the informed consent form the following screening procedures will be 
performed: 
 Collect and review demographic information 
 Collect and review medical history information (including documented history of 
abnormal liver chemistry test results while taking tolvaptan resulting in 
discontinuation for that reason) 
 Collect and review prior and concomitant medication information with particular 
emphasis on collection of prior tolvaptan use and dosing and protocol-prohibited 
medications 
 Perform a complete physical examination 
 Collect body weight and height measurements  


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 Check vital signs (includes sitting blood pressure, heart rate, respiratory rate, and 
temperature)  
 Perform a 12-lead ECG 
 Collect blood samples for  
o Complete Chemistry Panel  
o Liver Chemistry Panel 
o Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCV Ab) 
o Hematology 
o Serum pregnancy testing for WOCBP 
 Collect urine for urinalysis 
 Determine whether the subject is eligible to participate in the study based on meeting 
all the Inclusion Criteria (Section 4.1.1) and none of the Exclusion Criteria (Section 
4.1.2) except for those related to diuretic use and BP control. 
 Contact the IRT to assign the subject an identification number as described in Section 
5.3.  The Investigator or designee must use his or her own user identification and 
personal identification number (PIN) when contacting the IRT. PIN must not be 
shared between users and should be maintained in a secure location. 
 If no medication changes are necessary and anti-hypertensive medications in the 
absence of diuretics have been stable for at least 3 weeks prior to Visit 1, schedule 
Visit 2 one (1) week later (with an extension of up to 2 weeks for scheduling 
purposes). 
 If no medication changes are necessary but it is unknown or undocumented whether 
anti-hypertensive medications in the absence of diuretics have been stable for at least 
3 weeks prior to Visit 1, instruct the subject to maintain stable medications and 
schedule Visit 2 three (3) weeks later (with an extension of up to 2 weeks for 
scheduling purposes).   
 For subjects who need medication changes (discontinuation of diuretics or revision of 
anti-hypertensive medications), proceed with those changes per medical standard of 
care.  The subject should then be observed on stable medications for 3 weeks and 
Visit 2 should be scheduled.  The full duration of screening should not exceed 8 
weeks. 
6.1.2 Visit 2  
Subjects will either report to the clinic for Visit 2 or be scheduled for a remote visit with a 
HHC to review tests from Visit 1 and finalize screening assessments. Telemedicine will be 
used to determine final eligibility by the investigator. 
The following procedures will be performed at Visit 2: 
 Collect and review any additional medical history since prior visit 
 Collect and review concomitant medication information  
 Determine if any SAE occurred since the prior visit 
 Collect body weight 


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 Check vital signs (sitting blood pressure and heart rate)  
 Only for those subjects who had extended screening to allow for adjustment of blood 
pressure medications, collect a blood sample for the following laboratory testing:  
o Complete chemistry panel  
o Liver Chemistry Panel 
 Determine whether the subject is still eligible to participate in the study. 
o If the subject is not eligible to participate, the site will record the subject as a 
Screen Failure and contact the IRT to discontinue the subject from the study 
and complete the appropriate eCRFs. Subjects 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 and sponsor.   
o If the subject is eligible to participate, contact the IRT to update the subject’s 
status, instruct the subject not to change any concomitant medications, and 
Schedule Visit 3 for 1 week later.  
6.2 
Baseline Period 
The 3-week Baseline Period begins at the conclusion of Visit 2 and consists of 3 visits – 
Visits 3, 4, and 5. It is designed to collect baseline data to record variability of each subject’s 
liver chemistry test results and to obtain 3 serum creatinine values to determine baseline renal 
function (eGFR) according to the CKD-EPI equation.  Visits will be weekly (Visits 3 and 4 
may be done remotely if available), and no study drug will be administered during this time. 
6.2.1 Visit 3 
Prior to Visit 3 the eligibility review by the medical monitor will be completed for each 
subject. Subjects will either report to the clinic for Visit 3 or be scheduled for a remote visit 
with a HHC.  The following procedures will be performed at Visit 3: 
 Collect and review concomitant medication information  
 Check SAEs 
 Check vital signs (sitting blood pressure and heart rate) 
 Collect a blood sample for the following laboratory testing: 
o Liver Chemistry Panel 
o Serum creatinine 
 Contact the IRT to record the visit 
 Schedule the subject for Visit 4 to occur in 1 week. 
6.2.2 Visit 4 
Subjects will either report to the clinic for Visit 4 or be scheduled for a remote visit with a 
HHC. The following procedures will be performed at Visit 4: 
 Collect and review concomitant medication information  


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 Check SAEs 
 Check vital signs (sitting blood pressure and heart rate) 
 Collect a blood sample for the following laboratory testing: 
o Liver Chemistry Panel 
o Serum creatinine 
 Contact the IRT to record the visit 
 Provide the subject with a urine collection container and written instructions (See 
Section 7.2.1 for more detailed information) to produce a first morning, fasting (8 
hours except for water) spot urine specimen to be brought in at Visit 5 for specific 
gravity and Uosm determination.  
 Schedule the subject to return to the clinic for Visit 5 to occur in 1 week. 
6.2.3 Visit 5  
Subjects will report to the clinic in the morning of Visit 5 (after a minimum 8-hour overnight 
fast) to complete the Baseline Period and begin the Lixivaptan Titration Period.  
The following procedures will be performed at Visit 5: 
 Collect and review concomitant medication information  
 Check SAEs 
 Check vital signs (Sitting blood pressure and heart rate) 
 Measure body weight 
 Process an aliquot of first AM spot urine for specific gravity  
 Send the remaining AM spot urine for Uosm determination 
 Collect urine to conduct a pregnancy test in WOCBP  
 Collect a blood sample for:  
o Complete chemistry panel 
o Liver Chemistry Panel 
o Hematology 
o DNA sample (to be obtained under a separate informed consent for the 
purposes of biobanking to assess genetic variants associated with hepatic 
abnormalities [if and when feasible]. This may be obtained at any later visit if 
the subject initially declines permission but agrees at a later time.) 
 Collect a plasma sample for measurement of lixivaptan. Note date and time of sample 
on the requisition form. The sample must be collected before the first dose of 
lixivaptan is administered.  
 Perform a 12-lead ECG 
 If all study entry criteria are met, contact the IRT to complete subject’s participation 
in the Baseline Period, obtain kit assignment, and enter the subject into the Titration 
Period and proceed as follows:   
o Dispense lixivaptan (Level 1) and have subject take the first dose when they 
return home from the clinic. Instruct the subject to take 1 capsule twice a day 
approximately 10 hours apart, e.g., 8 AM and 6 PM. 


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o Educate the subject to expect aquaretic effects and to maintain fluid intake to 
prevent dehydration. 
 Provide subject with a urine collection container and written instructions to produce a 
first morning, fasting (8 hours except for water) spot urine specimen to be brought in 
at Titration Period Visit 6 or provided to the HHC if the visit will be conducted 
remotely for specific gravity and Uosm determination. 
 Schedule the subject for Visit 6 to occur in 1 week.  Provide the subject with an 
appointment reminder card and any written instructions. 
 If the subject does not meet the study entry criteria, contact the IRT to discontinue the 
subject. No follow-up visit is needed unless an SAE is ongoing. 
6.3 
Titration Period 
The Titration Period will last from 3 to 6 weeks.  Subjects will self-administer lixivaptan at 
home.  All subjects will start at Level 1 (50 mg BID) and will be increased weekly over 2-5 
weeks 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 4. If aquaretic effects limit a subject’s 
tolerability at Level 3 (150 mg BID) or Level 4 (200 mg BID), dose levels can be adjusted to 
Level 3a and Level 4a, respectively, which reduce the evening (PM) dose by 50 mg (from 
150 mg to 100 mg for Level 3 to 3a, and from 200 mg to 150 mg for Level 4 to 4a).  Titration 
will stop when a tolerable dose level is reached that achieves the goal of lowering trough 
(first morning, fasting except for water) urine specific gravity to ≤1.005 or the highest dose 
(Level 4 or 4a) is achieved (regardless of trough urine osmolality).  The minimum dose to 
enter the Lixivaptan Maintenance Treatment Period is Level 2. Once tolerability and reduced 
trough urine specific gravity are achieved (or tolerability and maximum dose), subjects will 
stay on that dose for 1 additional week under most circumstances to confirm tolerability 
(Table 5).  Subjects will then proceed to Visit 11/Last Titration Visit.   
6.3.1 Visits 6 to 10  
Visits 6, 7, 8, 9, and 10 will occur weekly ± 3 days as needed for titration and may be 
conducted remotely by a HHC.  Subjects will either report to the clinic or interact with a 
HHC in the morning for their visits (after a minimum 8-hour overnight fast except for water) 
to undergo Titration Period assessments. Note that telemedicine will be utilized at these visits 
for the Investigator to assess the subject’s status and tolerability of the study drug and to 
make a titration decision.  Any other issues may also be discussed with the subject.   
 
Subjects should bring into the clinic, or provide to the HHC, any remaining study drug.  
Remind the subjects not to take their morning dose of lixivaptan on the morning of the visit 
in order to obtain a trough PK sample should they advance to Visit 11 procedures. 
The following procedures will be performed at each visit unless otherwise noted: 
 Collect and review concomitant medication information  
 Review study drug compliance/reconciliation 
 Assess study drug tolerability by asking the subject, “Are you able to continue this 
dose for the next 12 months?” 
 Review lab results from prior visit 


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o For subjects exhibiting an increase in ALT or AST during the Titration Period 
(>3 x ULN) or total bilirubin (>2 x ULN), follow the instructions in Section 
7.3.7. 
 Check AEs and SAEs 
 Assess clinically for liver dysfunction (symptoms, signs [if a clinic visit]) in 
accordance with the checklist and instructions in Appendix 4 (Section 13.4). 
 Check vital signs (sitting blood pressure and heart rate) 
 Measure body weight and counsel subject to increase fluid intake if weight decreases 
>3% 
 Process an aliquot of first morning, fasting urine for specific gravity and assess if 
≤1.005 has been reached (except if Level 4 or 4a) 
 Send the remaining first morning, fasting urine for Uosm determination 
 Collect a blood sample: 
o Liver Chemistry Panel  
 Follow the flowchart in Figure 4 to determine whether to increase the dose, decrease 
the dose, advance the subject to Visit 11 procedures to initiate the Maintenance 
Period, or discontinue the subject. For remote visits, the HHC will call the 
Investigator to receive direction on this decision. The Investigator may want to utilize 
telemedicine to interact with the subject. 
o Based on the decision made from the flowchart, contact the IRT to receive the 
kit assignment for the next period of time 
o Dispense study drug and instruct subject how many capsules to take based on 
the dose level guide in Table 4 
o For remote visits, the site will contact the IRT sufficiently in advance of the 
scheduled visit day to obtain kit assignment and to allow sufficient time for 
study drug to be shipped to arrive at subject’s home prior to the visit date. 
 At each visit, remind the subject to take adequate fluids, provide a urine collection 
container, and instruct the subject to collect a first morning, fasting (8 hours except 
for water) urine specimen on the morning of their next visit, which they will bring 
with them (if a clinic visit) or provide to the HHC if a remote visit is conducted. 
 Provide the subject with an appointment reminder card and any written instructions. 


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Figure 4. Titration Flowchart  
 


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6.3.2 Visit 11/Last Titration Visit 
Visit 11/Last Titration Visit is intended to confirm that the subject tolerates lixivaptan at the 
dose determined during the Titration Period and to collect additional data before entering the 
Maintenance Period.  The procedures specified for Visit 11 may be performed at an earlier 
titration visit if the subject qualifies to enter the Maintenance Period at that time.  The last 
titration visit may be in the office or conducted remotely by a HHC.  If conducted remotely, 
telemedicine will be used for the Investigator to interact with the subject and confirm that the 
subject can continue into the Maintenance Period. 
Subjects will either report to the clinic in the morning or interact with the HHC, if a remote 
visit is conducted, to undergo the assessments for the last visit of the Titration Period.  
Subjects should bring any remaining study drug into the clinic or provide to the HHC.  
Remind the subjects not to take their morning dose of lixivaptan on the morning of the visit.  
Dosing instructions will occur during the visit. 
The following procedures will be performed: 
 Collect and review concomitant medication information  
 Review study drug compliance/reconciliation  
 Assess study drug tolerability 
 Check AEs and SAEs 
 Assess clinically for liver dysfunction (symptoms, signs [if a clinic visit]) in 
accordance with the checklist and instructions in Appendix 4 (Section 13.4).  
 Review lab results from prior visit 
o For subjects exhibiting an increase in ALT or AST during the Titration Period 
(>3 x baseline) or total bilirubin (>2 x ULN), follow the instructions in 
Section 7.3.7 
 Measure body weight and counsel subject to increase fluid intake if weight decreases 
>3% 
 Check vital signs (sitting blood pressure and heart rate) 
 Collect urine to conduct a pregnancy test in WOCBP  
 Collect blood for the following laboratory testing:  
o Complete chemistry panel  
o Liver chemistry panel 
o Hematology  
 Collect a trough blood sample for measurement of lixivaptan. Note date and time of 
last dose from the previous day and the date and time of the sample on the requisition. 
The sample must be collected before the dose of lixivaptan is administered. 
 The site will contact the IRT to complete subject’s participation in the Titration 
Period, obtain new kit assignment, and enter the subject into the Maintenance Period 
and proceed as follows:   
o Dispense new kits. Have the subject take the first dose at home.  Instruct the 
subject to take the appropriate dose twice a day approximately 10 hours apart, 
e.g., 8 AM and 6 PM. 


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o For remote visits, the site will contact the IRT sufficiently in advance of the 
scheduled visit day to obtain kit assignment and to allow sufficient time for 
study drug to be shipped to arrive at subject’s home prior to the visit date. 
 Schedule the subject for their next visit to occur in 4 weeks and remind the subject to 
take adequate fluids.  Provide the subject with an appointment reminder card and any 
written instructions. Note that the next visit may be conducted remotely (if available). 
6.4 
Maintenance Period 
The Maintenance Period will last 52 weeks (Visit 12 to Visit 24).  If available, the following 
visits may be done remotely: Visits 12, 13, 14 (with telemedicine), 15, 16, 18, 19, 20 (with 
telemedicine), 21, 22, and 23. Note that telemedicine may be added to any other visit if the 
Investigator judges that additional interaction or information is needed to assess the subject’s 
status. 
6.4.1 Visits 12 to 23  
Visits 12 to 23 will occur every 4 weeks ± 3 days.  For visits not done remotely, subjects will 
report to the clinic in the morning or afternoon on visit days.  Subjects should bring any 
remaining study drug into the clinic or provide to the HHC.  
The following procedures will be performed at each visit unless otherwise noted: 
 Check vital signs (sitting blood pressure and heart rate) 
 Review lab results from prior visit 
o For subjects exhibiting an increase in ALT or AST during the Maintenance 
Period (>3 x ULN) or total bilirubin (>2 x ULN), follow the instructions in 
Section 7.3.7. 
 Check AEs and SAEs and inquire about tolerability of the study drug 
 Assess clinically for liver dysfunction (symptoms, signs [if a clinic visit]) in 
accordance with the checklist and instructions in Appendix 4 (Section 13.4) 
 Review study drug compliance/ reconciliation  
 Collect and review concomitant medication information  
 Perform a brief physical exam (Visit 17) 
 Perform a 12-lead ECG (Visit 17) 
 Collect urine to conduct a pregnancy test in WOCBP (Visits 14, 17, and 20 only). 
 Collect a blood sample for the following laboratory testing:  
o Complete Chemistry Panel (Visits 14, 17, and 20 only)  
o Liver Chemistry Panel (all visits)   
o Hematology (Visit 17) 
 Collect a plasma sample for trough measurement of lixivaptan if ALT > 3 x ULN 
and/or total bilirubin > 2 x ULN. Note date and time of last dose from the previous 
day and the date and time of the sample on the requisition form.  


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 At Visit 23, provide subject 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 24 for specific gravity and Uosm determination. 
 The site will contact the IRT at each visit to obtain kit number assignment and 
complete the visit.  Dispense assigned kits to subject for the next 4 weeks.  Instruct 
the subject to take the appropriate dose twice a day approximately 10 hours apart, 
e.g., 8 AM and 6 PM. 
 For remote visits, the site must contact the IRT sufficiently in advance of the 
scheduled visit day to obtain kit assignment and to allow sufficient time for drug to be 
shipped to arrive at subject’s home prior to the visit date. 
 Schedule the subject to return for their next visit or confirm if visit will be done 
remotely.  The visit is to occur in 4 weeks.  Provide the subject with an appointment 
reminder card and any written instructions. 
6.4.2 Visit 24/Early Termination  
Visit 24 will occur at Week 52 ± 3 days.   
Subjects will report to the clinic in the morning to undergo last Maintenance Visit 
assessments. These procedures will also be conducted on subjects that terminate the study 
early (Section 6.5.4).  
Subjects should bring in any remaining study drug with them.  
The following procedures will be performed: 
 Collect and review concomitant medication information  
 Review study drug compliance/reconciliation and collect all remaining study drug 
 Review lab results from prior visit 
o For subjects exhibiting an increase in ALT or AST during the Maintenance 
Period (>3 x ULN) or total bilirubin (>2 x ULN), follow the instructions in 
Section 7.3.7. 
 Check AEs and SAEs 
 Assess clinically for liver dysfunction (symptoms, signs) in accordance with the 
checklist and instructions in Appendix 4 (Section 13.4).  
 Perform a full physical examination 
 Measure body weight 
 Check vital signs (sitting blood pressure and heart rate) 
 Perform a 12-lead ECG 
 Process an aliquot of first morning, fasting urine for specific gravity  
 Send the remaining first morning, fasting for Uosm determination 
 Collect urine for urinalysis 
 Collect urine sample for a urine pregnancy test in WOCBP 
 Collect blood for the following laboratory testing:  
o Complete chemistry panel  


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o Liver chemistry panel 
o Hematology  
 Collect a plasma sample for trough measurement of lixivaptan if ALT > 3 x ULN 
and/or total bilirubin > 2 x ULN. Note date and time of last dose from the previous 
day and the date and time of the sample on the requisition form.  
 Contact the IRT to complete the visit. 
 Schedule the subject to return to the clinic for the first follow-up visit (Visit 25) or 
schedule as a remote visit if available. 
6.5 
Follow-up Period  
The Follow-up Period will last 28 days and include 3 visits (Visit 25, Visit 26, and Visit 27).  
If available, Visits 25 and 26 may be done remotely by a HHC (with telemedicine if 
necessary). 
6.5.1 Visit 25 
Visit 25 will occur no earlier than 8 (+ 3) days after Visit 24.  The following procedures will 
be performed at Visit 25: 
 Check AEs and SAEs 
 Review lab results from prior visit 
o For subjects exhibiting an increase in ALT or AST (>3 x ULN) or total 
bilirubin (>2 x ULN) at the prior visit, follow the instructions in Section 7.3.7. 
 Assess clinically for liver dysfunction (symptoms, signs [if a clinic visit]) in 
accordance with the checklist and instructions in Appendix 4 (Section 13.4). 
 Collect and review concomitant medication information  
 Collect a blood sample: 
o Serum creatinine  
 Schedule the subject to return to the clinic for V26, in 7-14±3 days or confirm if it 
will be done remotely 
 The site will contact the IRT to complete the visit 
6.5.2 Visit 26 
Visit 26 will occur 7-14±3 days after Visit 25.  The following procedures will be performed 
at Visit 26: 
 Check AEs and SAEs 
 Collect and review concomitant medication information  
 Collect a blood sample: 
o Serum creatinine  
 Schedule the subject to return to the clinic for V27, 28±3 days after V24 (last dose of 
study drug) and provide a urine collection container and instructions for first 
morning, fasting (8 hours except for water) urine specific gravity and Uosm 
determination 


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 The site will contact the IRT to complete the visit 
6.5.3 Visit 27 (End of Study Visit) 
Visit 27 is the last visit in this study and will occur 28±3 days after the last dose of study drug 
(Visit 24).  The visit will be conducted in the clinic.  The following procedures will be 
performed at Visit 27: 
 Check vital signs (sitting blood pressure and heart rate) 
 Perform a brief physical exam 
 Perform a 12-lead ECG 
 Check AEs and SAEs 
 Collect and review concomitant medication information  
 Process an aliquot of first morning, fasting urine for specific gravity  
 Send the remaining first morning, fasting urine for Uosm determination 
 Collect urine for urinalysis 
 Collect urine sample for a urine pregnancy test in WOCBP 
 Collect a blood sample for the following laboratory testing:  
o Complete chemistry panel 
o Liver chemistry panel 
o Hematology 
 Contact the IRT to complete subject’s participation in PA-ADPKD-303 
6.5.4 Early Termination Procedures 
Subjects who terminate the study during the Screening or Baseline Periods will not have 
follow up unless there is an ongoing SAE.  See Section 4.2.2. 
Subjects who terminate the study during the Titration or Maintenance Periods will have final 
procedures and follow up performed as described in Section 4.2.3. 


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7 DESCRIPTION OF STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study procedures, all potential subjects will sign the primary ICF.   
Separate informed consent will be obtained at the end of Baseline or later in the study to 
allow biobanking of a DNA sample to assess genetic variants associated with hepatic 
abnormalities (if and when feasible).  Subjects will have the opportunity to have any 
questions answered before signing the ICFs.  The Investigator must address all questions 
raised by the subject. 
The study assessments to be performed at each visit are specified in the study Schedule of 
Procedures (Table 1).  
Visits that occur following an overnight fast (8 hours except for water) will occur in the 
morning.  Other visits may occur in the morning or afternoon.  To avoid aquaretic effects 
while traveling, study drug will be administered at home.   
7.1 
Efficacy Assessments 
7.1.1 eGFR 
The eGFR values reported to Investigators from the central laboratory will be calculated 
according to the CKD-EPI formula from the serum creatinine concentrations taken at 
Screening and at the visits specified in the Schedule of Procedures (Table 1) when either the 
Complete Chemistry Panel or serum creatinine is listed.  During the Baseline Period, serum 
creatinine assessments will be used to determine the average eGFR. The averaged value will 
be used as the eGFR baseline. 
Alteration in the metabolism of creatinine based on changes in meat intake and exercise may 
impact accuracy of serum creatinine and determination of eGFR.  Measures to reduce 
variability are provided in Section 5.8.   
7.2 
Pharmacodynamic Assessments 
7.2.1 Specific Gravity and Urine Osmolality  
First AM, fasting urine collections will be obtained at the timepoints specified in the 
Schedule of Procedures (Table 1).  An 8-hour overnight fast (except for water, which is 
encouraged to satisfy thirst and replace any overnight urine production) is required prior to 
collection.  Morning medications should not be taken until the urine collection has been 
obtained.  Subjects will be provided a urine collection container and instructions in advance 
of each visit where specific gravity and Uosm are determined. Subjects will be asked to 
completely empty their bladders upon arising in the morning and then provide a spot urine 
specimen within the next 20-40 minutes for the determination of specific gravity and Uosm.  
They will either bring that specimen to their clinic visit or provide to a HHC if a remote visit 
is conducted, where specific gravity will be measured by dipstick using an automated device.  
The remainder of the urine specimen will be sent to the central laboratory for Uosm 
determination. 


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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 study Schedule of 
Procedures (Table 1).  Assessment windows are presented in Table 1. 
7.3.1 Body Height, Weight, and BMI 
Body height (inches or centimeters) and weight (pounds or kilograms) will be measured at 
Screening 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 (Table 1). 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 subject wearing shoes. 
7.3.2 Demographics and Medical History  
Medical history and demographic data, including initials, sex, age, race, and ethnicity will be 
recorded at the Screening Visit 1 (Table 1).  
Medical and medication history will be assessed as related to the eligibility criteria in Section 
4.1.  Medical history will include documented history of abnormal liver chemistry test results 
while on tolvaptan, history of permanent discontinuation of tolvaptan due to abnormal liver 
chemistry test results, history of any re-challenge with tolvaptan or development of DILI on 
tolvaptan. As data permit, information on the duration of tolvaptan use prior to 
discontinuation should be included.  
Other than tolvaptan, medication history will include all medications taken within 30 days 
prior to Screening (except for the longer periods specified for Exclusion Criteria 7, 8, and 9; 
see Section 5.7) and history of drug, alcohol, and tobacco use.     
An update to medical history, including medication review, will be performed at Screening 
Visit 2 to verify subject eligibility. 
7.3.3 Physical Examinations  
A complete physical examination will be performed during Screening Visit 1 and the final 
Maintenance/Early Termination Visit (Visit 24).  Brief physical examination will 
subsequently be performed at the timepoints specified in the study Schedule of Procedures 
(Table 1).  
Complete physical examinations will include, at a minimum, height and weight (Visit 1 only, 
Visit 24 will include weight only), 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 


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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 and Baseline 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 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 subjects experiencing AEs. 
7.3.4 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 study Schedule of 
Procedures (Table 1).  Respiratory rate and body temperature will be measured once at 
Screening. 
Subjects will remain at rest in a seated position for a minimum of 5 minutes before vital sign 
measurements are obtained.  For all subjects, 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 must be recorded as medical history during the Screening and Baseline 
Periods and as an AE after the start of study drug.  If other procedures are scheduled at the 
same timepoint, vital signs should be obtained first, before an ECG and/or blood draw. 
7.3.5 12-Lead ECGs 
Standard 12-lead ECGs will be performed at the timepoints specified in the study Schedule 
of Procedures (Table 1).   
Safety 12-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 subject throughout the study.  
ECGs will be obtained with the subject remaining in a supine or semi-recumbent position 
following 5 minutes of rest.  All ECGs throughout the study for a given subject should be 


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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.   
For all subjects, ECGs will be reviewed, signed, and dated by the Investigator or a qualified 
designee.  The ECGs will be classified as being in one of three categories:  normal, abnormal 
but not clinically significant (NCS), or abnormal and CS.  All CS findings will be reported as 
medical history during the Screening and Baseline Periods and as AEs after the start of study 
drug. 
Additional ECGs may be performed if deemed medically appropriate. 
7.3.6 Clinical Laboratory Tests 
Blood and urine specimens will be collected for the clinical laboratory (hematology, clinical 
chemistry, and urinalysis) and pregnancy tests (all female subjects of child-bearing potential) 
at the timepoints specified in the study Schedule of Procedures (Table 1). Except where 
noted, all laboratory testing will be performed at the central laboratory, which will return 
results with normal ranges to the clinical sites.   A confirmatory assessment through the 
central lab should be obtained as soon as possible for any CS abnormal laboratory parameter 
if deemed necessary by the Investigator.  Repeat testing for abnormal liver chemistry tests is 
described in Section 7.3.7.1.  Any other repeat laboratory testing for values that are not CS 
should be discussed first by the Investigator with the medical monitor before such tests are 
ordered. All routine testing will be conducted in the morning after an overnight fasted state 
(minimum of 8 hours except for water).  Mild elevations in serum creatinine or serum sodium 
are known pharmacodynamic effects of vasopressin antagonists like lixivaptan, therefore 
confirmatory assessments for serum creatinine and serum sodium will be at the Investigator's 
discretion.   
Clinical laboratory parameters for analysis are presented in Table 6. 
Macroscopic urinalysis will be performed via dipstick. Microscopic examination is needed 
only if macroscopic results are positive for blood or protein.   
Additional liver chemistry tests should be collected if the subject experiences liver chemistry 
test abnormalities of concern or has suspicious symptom or sign of liver dysfunction (Section 
7.3.7).  


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Table 6  Clinical Laboratory Parameters 
Complete Chemistry Panel 
Hematology 
Urinalysis 
Albumin 
Hematocrit 
pH 
Blood urea nitrogen (urea) 
Hemoglobin 
Specific gravity 
Calcium 
Red blood cell count 
Protein 
Chloride 
Quantitative platelet count 
Glucose 
CO2 
WBC count  
Ketones 
Creatinine 
with differential (total and %) only if  
Bilirubin 
Glucose 
 WBC count is abnormal: 
Blood 
Phosphorous 
   Neutrophils 
Urobilinogen 
Potassium 
   Lymphocytes 
Leukocytes 
Protein 
   Monocytes 
Nitrite 
Sodium 
   Eosinophils 
Microscopic examination (if  
Uric acid 
   Basophils 
  positive for blood, protein, 
 
 
  nitrite, or leukocytes) 
Liver Chemistry Panel 
Other Tests 
 
Alanine aminotransferase 
Urine specific gravity (local to guide 
 
Alkaline phosphatase 
titration) 
 
Aspartate aminotransferase 
Urine osmolality 
 
Bilirubin Total and Direct 
Urine or serum pregnancy test 
 
 
  (female subjects) 
 
 
Specimen for potential DNA analysis 
 
Abbreviations: CO2 = carbon dioxide; WBC = white blood cell. 
 
7.3.6.1 Sample Collections 
Instructions regarding the collection, processing, and shipment of laboratory samples are 
detailed in a separate laboratory manual.  All samples will be given a unique identifier.  The 
sample collection date and time will be entered into the eCRF. 
7.3.7 Assessment of Liver Symptoms, Signs, or Test Abnormalities 
Testing for hepatic transaminase (ALT/AST), alkaline phosphatase, and total and direct 
bilirubin will be performed at the timepoints as specified in the Schedule of Procedures 
(Table 1). 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 4 (Section 13.4) in a subject at any time during the study should trigger prompt 
testing of liver chemistry tests (i.e., within 48 hours). 
7.3.7.1 Requirements for Additional Liver Chemistry Testing 
To determine when repeat liver chemistry testing is necessary, follow the instructions in 
Table 7: 


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Table 7  Additional Liver Chemistry Testing and Other Testing 
Subjects with Liver Chemistry Values 
Exceeding Eligibility Requirements at 
Screening or Baseline 
Subjects with Eligible Liver Chemistry 
Values at Screening or Baseline 
Subjects with transaminase (ALT/AST) or 
total bilirubin values above the values in 
the exclusion criteria (>1.5 x ULN and 
>1.0 x ULN, respectively) during the 
Screening or Baseline Periods will not 
proceed further in the study.  Any required 
follow up should be part of routine 
clinical care.  However, if evaluation 
indicates a reversible cause of liver 
disease, such subjects may be re-screened 
in consultation with the medical monitor 
and sponsor when such liver chemistry 
test results return to values allowing entry 
into the study. 
Any transaminase value >3 x ULN or total 
bilirubin >2 x ULN during the Titration or 
Maintenance Periods requires immediate 
retesting within 48 hours.  Local laboratory 
testing is acceptable with collection of a 
concurrent central laboratory sample for 
confirmation whenever possible.  During 
the time that values remain elevated, testing 
should be done at least weekly for the first 
month, gradually returning to monthly as 
indicated by the results. Individual cases 
that either resolve quicker or slower should 
be discussed with the medical monitor and 
sponsor.  The medical monitor will discuss 
with the Investigator any additional 
laboratory testing or imaging depending on 
the case circumstances. Examples of such 
testing are shown in Appendix 3 (Section 
13.3). 
   
7.3.7.2 Changes in Study Drug Dosing if Liver Chemistry Test 
Abnormalities Occur During the Titration or Maintenance Periods 
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 transaminase 
levels >3 x ULN or total bilirubin levels >2 x ULN are observed during the Titration or 
Maintenance Periods.  All elevations meeting these thresholds will be assessed the HERC.   
In the case of study drug interruption, re-starting study drug should be encouraged (see 
exception below) after discussion with the medical monitor and sponsor, when liver 
chemistry tests have normalized or stabilized, and in conjunction with a plan for increased 
frequency of liver chemistry test monitoring. 
In the presence of such liver chemistry test abnormalities, additional clinical testing 
(examples listed in Appendix 3 (Section 13.3) may be recommended by the medical monitor 
and sponsor and those results reported according to local guidelines. 
Treatment with study drug cannot be resumed in subjects when: 
 transaminase levels >8 x ULN at any time, 
 transaminase levels >5 x ULN for more than 2 weeks, or 
 concurrent elevations of transaminase levels >3 x ULN and total bilirubin >2 x ULN 


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except under these circumstances: 
Subjects with these levels of abnormality may be re-challenged with study drug if 
abnormalities were adjudicated as having a ≤50% likelihood of being related to study 
drug (per DILI Network [DILIN] probability criteria, modified, Section 13.2 (Fontana 
RJ 2009)18 by the HERC, and the Investigator, medical monitor, and sponsor agree to 
an intensive monitoring plan to mitigate risk.  The subject must also be willing to 
comply with these monitoring measures, be informed of the potential risks, and 
consent to study drug re-challenge. 
Liver chemistry test increases of a lesser extent should be discussed with the medical 
monitor.  They may be related to the underlying variability of such tests in ADPKD patients.  
Generally, dosing should continue, but the frequency of laboratory testing should increase, 
particularly during the Maintenance Period.  Slowing of titration may also be considered if 
the abnormalities occur during the Titration Period. 
7.3.7.3 Special Reporting of Liver Events 
A liver dysfunction details eCRF will be utilized during the study.  The type of information 
needed to complete it is provided in Appendix 4 (Section13.4).  The purpose of the liver 
dysfunction details eCRF and additional testing is to facilitate review of each subject who 
develops liver chemistry test abnormalities and/or signs or symptoms of liver dysfunction 
during the study to determine the probable cause(s) of these abnormalities.  The review will 
be performed by an independent HERC using DILIN probability criteria, modified (0 to 5% 
= unrelated; 6 to 25% = unlikely, 25% to 50% = possibly, 51% to 75% = probably, 76% to 
95% = very likely, >95% = definite) (Fontana RJ 2009).18 The HERC will independently 
decide attribution and will communicate in writing with the sponsor. The results of the 
HERC review will be used in assessing the primary and secondary endpoints.  The result of 
these analyses may be presented separately from the final clinical study report (CSR). 
The Investigator must complete the liver dysfunction details eCRF and submit it within 24 
hours of awareness through the SAE reporting pathway (described in Section 7.3.8.3) for any 
subject who develops an Adverse Event of Special Interest (AESI) related to abnormal liver 
chemistry test results or clinical signs or symptoms. Specifically, any subject who 
 develops any signs or symptoms of hepatic dysfunction (see Appendix 4 [Section 
13.4]) 
 discontinues treatment due to a liver-related AE, 
 reports a serious liver-related AE, 
 develops ALT or AST levels >3 × ULN, 
 develops total bilirubin levels >2 × ULN.  
The AESI report form should be updated as new information becomes available. 


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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 7.3.8.2 below. 
An AE is defined as any untoward medical occurrence in a subject 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-subject 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 
subject 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 SAEs will be recorded from the time the ICF is signed until study completion.  Non-
serious AEs will be recorded from the start of study treatment until study completion.  Other 
changes in health or new symptoms occurring during the Screening or Baseline Periods will 
be recorded as medical history. 
At every study visit, subjects will be asked a standard non-leading question to elicit any 
medically related changes in their well-being.  They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject 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. 


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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 subject is screened or during baseline, 
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 subject’s condition, are not 
to be reported as AEs or SAEs. 
For the purpose of this study, liver events are considered to be AESIs.  Liver events will be 
reported directly from the electronic data capture [EDC] system.  
Pregnancy events will need to be reported on special pregnancy forms to ICON PVSS. 
Any AE that meets SAE or AESI criteria will be reported to ICON Pharmacovigilance & 
Safety Services (PVSS) immediately (i.e., within 24 hours) after site personnel first learn 
about the event.  Investigators should record all SAE/AESI details available, including 
Investigator causality assessment, on an Adverse Event eCRF or appropriate AESI forms and 
submit the report via the electronic data capture (EDC) system within 24 hours of becoming 
aware of the event.  Notification of SAE/AESI entry will be generated and sent to ICON 
PVSS via the EDC system. Pregnancy events will also be reported to ICON PVSS within 24 
hours of recognition of the event, but on the special forms provided. 
In the event the EDC system is unavailable, a completed SAE Report Form should be 
submitted to ICON PVSS as an email attachment or by fax to the email address / fax number 
below. The EDC system must be updated with the information on the paper report as soon as 
the EDC is available. The preferred method of reporting on paper is via email: 
ICON PVSS Email Address: ICON-Safety-CentralReceipt@iconplc.com 
or via fax to: 
ICON PVSS Fax: 1-215-616-3096 (within US) 
ICON PVSS Fax: +44 (0)208 100 5005 (outside US) 
Should the site have questions or concerns regarding SAE report submission, the site may 
elect to call the ICON PVSS SAE Hotline number. The site will be asked to provide the 
following information: protocol number, site number, subject identifiers, event term, study 
drug information, relationship of the event to study drug. 
 ICON PVSS SAE Hotline Number: +1-888-426-8801 (within US) – Toll Free 
Number or +1-281-295-4889 (outside of US) 


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In a study-related health emergency, for discussion of urgent protocol medical-related 
questions when the assigned medical monitor for a study cannot be reached, an on-call 
physician can be reached 24 hours per day, 7 days per week via an ICON Call-Center:  
 
Telephone: +1 857-957-5013  
(chargeable telephone number allowing a global reach from both landlines and mobile 
phones)  
 https://icophone.iconplc.com/24-7-Medical.pdf  
On this internet page, a list of country-specific toll-free telephone numbers is provided. It 
should be noted that not all countries globally have access to toll-free numbers as indicated 
on the “24/7 Medical Help desk” index. Countries without toll-free numbers need to dial the 
chargeable number as indicated above. Furthermore, there may be restrictions when dialling 
toll-free numbers from a mobile phone. 
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. 
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 8. 


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Table 8  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 subject'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 subject’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 subject’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 Follow-Up of Subjects 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 subject is considered to be stable. 
7.3.8.7 Overdose Management 
An overdose is any dose of study drug given to a subject or taken by a subject that exceeds 
the dose described in the protocol.  Any overdose, with or without associated AEs, must be 
promptly reported to the Investigator and also reported to the Sponsor.  Overdoses without 
signs or symptoms do not need to be recorded as AEs; in case of any AEs associated with the 
overdose, these should be reported on relevant AE/SAE sections in the eCRF.  In the event of 
suspected overdose, the appropriate supportive clinical care including fluid replacement 
should be instituted at the discretion of the Investigator or as dictated by the subject’s clinical 
status. 
7.3.8.8 Pregnancy 
Pregnancy is not regarded as an AE unless there is a medical/surgical complication.  Any 
pregnancy of a subject or the partner of a subject that occurs during study participation must 
be reported using a clinical study pregnancy reporting form.  To ensure subject safety, each 
pregnancy must be reported through this mechanism to ICON PVSS 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 subject was discontinued from the study.  Pregnancy 


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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 subject has completed the study, and considered by the Investigator as possibly 
related to the study treatment, must be promptly reported to ICON PVSS. 
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 subject’s condition, are not 
to be reported as AEs or SAEs. 
7.3.10 Hepatic Events Review Committee (HERC) 
The HERC consists of 3-4 expert hepatologists who will review demographic, medical and 
medication history, safety data, PK data and any other relevant data as available on subjects 
who develop liver abnormalities of concern during the study.  
This committee will independently determine the probable causality for instances of 
suspected liver dysfunction and liver chemistry test abnormalities of concern (Section 7.3.7) 
and of relatedness to lixivaptan.   
The results of these reviews will be captured on an eCRF and used for analysis of the 
primary and secondary safety endpoints. A full report may be provided separately from the 
clinical study report. 
The HERC will also assess the relationship to tolvaptan of prior instances of liver 
dysfunction and liver chemistry test abnormalities that occurred while enrolled subjects were 
previously receiving tolvaptan. 
7.4 
Pharmacokinetic Assessments 
Blood samples will be obtained to measure plasma levels of lixivaptan. 
7.4.1 Pharmacokinetic Blood Sampling 
Blood samples for PK will be taken for determination of plasma lixivaptan concentrations.  A 
4 mL plasma sample will be collected at the timepoints specified in the study Schedule of 
Procedures (Table 1) and here: 
 Baseline 
 At trough (between 7-10 AM prior to AM dosing) at the last titration visit (Visit 11).   
 At trough (between 7-10 AM prior to AM dosing) at the time of a liver chemistry test 
abnormality (any transaminase value >3 x ULN or total bilirubin >2 x ULN).  


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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 to the central clinical laboratory for storage. Detailed 
handling and shipping instructions are in the laboratory manual. 
Blood samples for the PK analysis of lixivaptan concentrations will be collected and handled 
according to the specifications in the laboratory manual.   


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8 STATISTICAL AND ANALYTICAL PLAN 
The statistical and analytical plan for this clinical study is summarized below.  Further details 
are provided separately in the Statistical Analysis Plan (SAP). 
8.1 Sample Size 
Up to 50 subjects will be enrolled and treated.  This is based on a similar study conducted 
with ambrisentan in subjects who had previous liver chemistry test abnormalities on other 
endothelin receptor antagonists for the treatment of pulmonary arterial hypertension 
(McGoon MD 2009).22   
8.2 Populations for Analysis 
The following populations will be used for analyzing the data: 
The Enrolled Population is defined as all subjects who meet inclusion/exclusion criteria 
during the Screening Period and complete Visit 3.  All general summaries, except safety and 
efficacy analyses are based on the Enrolled Population, unless specified otherwise. 
The Safety Population is a subset of the Enrolled Population defined as those subjects who 
received at least 1 dose of lixivaptan.  This population will be utilized for all safety analyses. 
The Efficacy Population is a subset of the Safety Population defined as those subjects who 
have at least 1 eGFR determination during the Baseline Period and have at least 1 eGFR 
determination during the Follow-up Period.  This population will be used for all efficacy 
analyses. 
The Pharmacokinetic (PK) Population is a subset of the Safety Population defined as those 
subjects who had at least 1 on-therapy evaluable PK measurement. 
The Pharmacodynamic (PD) Population is a subset of the Enrolled Population defined as 
those subjects who have at least 1 set of urine specific gravity and urine osmolality 
measurements from the same specimen. 
8.3 Analysis of Demographic and Baseline Characteristics 
Descriptive statistics for demographic (e.g., age, race, and sex) and baseline (e.g., eGFR) 
characteristics will be presented for the Safety and Efficacy Populations.  
8.4 Safety Analyses 
8.4.1 Primary Hepatic Safety Endpoint  
Descriptive statistics (n, percentage, 95% confidence interval) will be used to summarize the 
proportion of subjects who develop ALT levels >3 x ULN that were assessed by the 
independent HERC to be at least probably related to lixivaptan and resulted in 
discontinuation of the study drug during the Titration or Maintenance Periods.   
8.4.2 Secondary Hepatic Safety Endpoints 
Similarly, descriptive statistics (n, percentage, 95% confidence interval) will be utilized to 
present the 2 secondary endpoints:  
The proportion of subjects who develop ALT levels >5 x ULN that were assessed by 
the independent HERC to be at least probably related to lixivaptan and resulted in 


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discontinuation of the study drug during the Titration or Maintenance Periods; and  
The proportion of subjects who develop ALT levels >3 x ULN that were assessed by 
the independent HERC to be at least probably related to lixivaptan and resulted in 
lixivaptan dose reduction during the Titration or Maintenance Periods. 
8.4.3 Additional Hepatic Safety Endpoints 
The proportion of subjects who develop the following abnormalities during the Titration and 
Maintenance Periods will be tabulated and presented descriptively: 
 >3 x, 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 
 ALT or AST levels >2 x their baseline 
 Any elevation of total bilirubin (TBL) >2 x ULN 
 Any elevation of alkaline phosphatase (ALP) >2 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. 
8.4.4 Adverse Events 
The number and percentage of subjects and the number of events during the Titration and 
Maintenance Periods will be presented for TEAEs, SAEs, treatment-related TEAEs, and 
TEAEs leading to premature withdrawal according to the system organ class (SOC) and 
preferred term (PT) assigned to the event using MedDRA.  In addition, TEAEs will also be 
summarized by SOC, and PT separately by maximum severity and relationship to study drug.  
Listings of deaths and serious TEAEs will be provided.  Similarly, number and percentage of 
subjects will be presented for TEAEs, SAEs, and treatment-related TEAEs during the Follow 
Up Period. 
All AE data will be listed for all subjects.  Both the Investigator’s verbatim terms and the 
MedDRA preferred terms will be listed for each subject.  Listings will also include the SAEs, 
start and end time and 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.     
8.4.5 Clinical Laboratory Tests 
Descriptive statistics (n, mean, standard deviation [SD], median, minimum, and maximum) 
for clinical laboratory data and changes from baseline will be presented for each scheduled 
time point. 
The baseline value is the last value observed prior to first administration of study drug and 
any information taken after first administration of study drug is regarded as post-baseline 


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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 scheduled time point.  For categorical data, 
change from baseline will be summarized using frequency and proportion at each scheduled 
timepoint. 
Individual data listings of clinical laboratory results will be presented for each subject.  
Values outside of the clinical laboratory's reference range (i.e., those with low or high values) 
will be flagged in the clinical laboratory listings. 
For all continuous clinical laboratory variables, a shift table comparing the baseline value 
(normal, low, and high) to last observation on treatment will be presented. 
For urinalysis, a shift table comparing the baseline value to the maximum value will be 
presented (using number of subjects with results of negative, trace, or positive). 
8.4.6 ECGs 
Observed values and changes from baseline for continuous ECG parameters including heart 
rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), and QTcF 
interval will be summarized over each scheduled timepoint in terms of absolute values using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  In addition, a 
summary shift table comparing baseline interpretation (normal, abnormal - NCS, abnormal - 
CS) to the Investigator interpretation at each time point will also be presented. 
A listing will be provided for Investigator-identified ECG abnormalities from safety ECGs.  
Overall evaluation of safety ECGs will be summarized using frequency counts and 
percentage of subjects as normal or abnormal, and the relevance of the abnormality will be 
summarized by CS or NCS. 
8.4.7 Vital Signs 
Changes from baseline in vital signs at each scheduled timepoint will be summarized using 
descriptive statistics (n, mean, SD, median, minimum, and maximum).  The baseline value is 
defined as the last value observed prior to first administration of study drug.  The change 
from baseline is defined as the post-baseline value minus the baseline value.   
8.5 Efficacy Analysis 
Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be presented for 
observed values at baseline and endpoint, as well as change from baseline in eGFR at the 
endpoint.  Baseline eGFR is defined as the mean of the 3 eGFR assessments obtained during 
the Baseline Period.  However, if any values are missing, the remaining values will be used 
to determine the baseline eGFR.  The endpoint eGFR is defined as the mean of 3 eGFR 
assessments obtained during the Follow-up Period.  However, if any values are missing, the 
remaining values will be used to determine the endpoint eGFR 
8.6 Exploratory Analyses 
8.6.1 Relationship of Liver Chemistry Test Abnormalities to Drug Levels 
Trough levels of lixivaptan will be listed.  Any possible relationships between liver chemistry 
test abnormalities and trough levels of lixivaptan collected during the study will be explored 


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if sufficient data exist.  Details will be provided in the statistical analysis plan. 
8.6.2 Assessment of Genetic Variants 
In the event that specific genetic variants confirming increased or decreased risk to hepatic 
abnormalities in subjects with DILI become known during the time of the study, testing for 
such variants may be performed on stored specimens of those individuals who provided 
consent. 
8.6.3 Pharmacodynamic Assessments 
Relationships between urine specific gravity and Uosm will be explored.   Details will be 
provided in the statistical analysis plan. 
8.7 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS® software Version 9.4 or higher.  All 
continuous variables will be summarized using the following descriptive statistics: number of 
non-missing observations (n), mean, SD, median, minimum, and maximum.  Categorical 
variables will be summarized using the following descriptive statistics: frequency counts and 
percentages and 95% confidence intervals for the primary and secondary safety endpoints.  
All data will be listed in data listings. 
Further details of the statistical analyses, methods, and data conventions are described in the 
SAP.  The SAP may modify the plans outlined in the protocol; however, any major 
modifications of the primary analysis will also be reflected in a protocol amendment.  
Additional statistical analyses other than those described in this section may be performed if 
deemed appropriate in the plan. 
8.8 Data Quality Assurance 
Standard operating procedures are available for all activities performed at the study sites 
relevant to the quality of this study.  Designated study site personnel will be responsible for 
maintaining quality assurance and quality control to ensure that the study conduct as well as 
data collection and documentation are performed in compliance with the study protocol, GCP 
requirements, and applicable regulatory requirements. 
All clinical data will undergo source document verification by the Clinical Research 
Associate and data review by Data Management prior to database lock.  Programmed edit 
checks are also implemented to check for missing data, data inconsistencies, data ranges, etc.  
Corrections are made prior to database lock.  Electronic CRFs can be printed directly from 
the database.  Each eCRF will be reviewed and signed electronically by the Investigator. 
8.8.1 Data Management 
An eCRF is required and should be completed for each included subject. The completed 
original eCRFs are the sole property of the Sponsor and should not be made available in any 
form to third parties, except for authorized representatives of the Sponsor or appropriate 
regulatory authorities, without written permission from the Sponsor. 
As part of the responsibilities assumed in conducting the study, the Investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 


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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 subject 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 subject data into eCRFs using the EDC system 
designated by the sponsor.  The analysis data sets will be a combination of these data and 
data from other sources (e.g., laboratory data) and follow Clinical Data Interchange 
Standards Consortium (CDISC) standard. 
Clinical data management will be performed in accordance with applicable standards and 
data cleaning procedures of the contract research organization (CRO) to ensure the integrity 
of the data, e.g., removing errors and inconsistencies in the data.  Adverse events and 
concomitant medication terms will be coded using the MedDRA and World Health 
Organization Drug Dictionaries, respectively. 
After database lock, each study site will receive all site-specific eCRF data for the study, 
including full discrepancy and audit history.  Additionally, a copy of all the study site’s data 
from the study will be created and sent to the Sponsor for storage.  The CRO will maintain a 
duplicate copy for their records.  In all cases, subject initials will not be collected or 
transmitted to the Sponsor. 


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9 ETHICS 
9.1 
Institutional Review Board (IRB)/Ethics Committee (EC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, ICFs, and other relevant documents, e.g., written subject instructions, 
recruitment advertisements, if applicable, from the IRB/EC before participation of human 
subjects 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 subjects. 
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 
Subject Information and Consent 
Written informed consents in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each subject before entering the study, upon re-
screening, and when performing any unusual or non-routine procedure that involves risk to 
the subject.  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 subjects must sign the 
revised form. 
Before recruitment and enrollment, each prospective subject 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 subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject or legal guardian. 


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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 and the CRO’s medical 
monitor are listed on the cover page of this protocol.  Contact information for other sponsor 
personnel, ICON Clinical Research Limited, the designated CRO, and other vendors are 
listed in the Investigator Site File provided to each site. 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines.  Changes will be reported to the IRB 
but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subjects’ confidentiality.  All records will be kept in a secure 
storage area with limited access.  Clinical information will not be released without subjects’ 
(or legal guardians’) written permission, except as necessary for monitoring and auditing by 
the Sponsor, its designee, the FDA, or the IRB/EC. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study.  Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54.  In addition, the Investigator must provide to the Sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the Sponsor nor Sponsor’s representatives is financially responsible for further 
testing or treatment of any medical condition that may be detected during the screening 
process.  In addition, in the absence of specific arrangements, neither the Sponsor nor 
Sponsor’s representatives is financially responsible for further treatment of the subject’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: 
 IRB/EC written approval and any other local approval, as appropriate 


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


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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 Sponsor will be 
responsible for these activities and will work with the Investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues.  The Sponsor has final approval authority over all 
such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization 
from the Sponsor, but data and publication thereof will not be unduly withheld. 


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


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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 
subject or Investigator that results in a significant, additional risk to the subject.  Major 
deviations can include not adhering to inclusion or exclusion criteria, enrollment of the 
subject without prior Sponsor approval, or not adhering to FDA regulations or ICH GCP 
guidelines, and will lead to the subject being withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the Clinical Monitor throughout the course of 
monitoring visits.  Investigators will be notified in writing by the monitor of deviations.  The 
IRB/EC should be notified of all protocol deviations in a timely manner. 
11.3 Study Termination 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the final end 
of study assessment. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
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 subjects, as appropriate.  The study results will be posted on publicly 
available clinical trial registers. 


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12  REFERENCE LIST 
1. Chan PS, Coupet J, Park HC, Lai F, Hartupee, D, Cervoni P, Dusza JP, Albright JD, 
Ru X, Mazandarani H, Tanikella T, Shepherd C, Ochalski L, Bailey T, Lock YYW, 
Ning X, Taylor JR, Spinelli W. 1998. VPA-985, a nonpeptide orally active and 
selective vasopressin V2 receptor antagonist. Adv Exp Med Biol. 449:439-443. 
2. Chebib FT, Sussman CR, Wang X, Harris PC, Torres VE. 2015. Vasopressin and 
disruption of calcium signaling in polycystic kidney disease. Nat Rev Nephrol. 
11(8):451-464. 
3. 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. 
4. 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 
5. 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. 
6. 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. 
7. Torres VE. 2005. Vasopressin antagonists in polycystic kidney disease. Kidney Int. 
68(5):2405-2418. 
8. 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. 
9. 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. 
10. 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. 
11. 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. 


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12. 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. 
13. 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. 
14. 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. 
15. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang 
J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O. 2017b. Tolvaptan in later-
stage autosomal dominant polycystic kidney disease. N Engl J Med. 377:1930-1942. 
16. 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. 
17. 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.  
18. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon 
J; DILIN Study Group. 2009. Drug-Induced Liver Injury Networ k (DILIN) 
prospective study: rationale, design and conduct. Drug Saf. 32(1):55-68. 
19. 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.    
20. 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. 
21. Woodhead JL, Pellegrini L, Shoda LKM, Howell BA. 2019.  Comparison of the 
Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic 
Kidney Disease Using Quantitative Systems Toxicology Modeling.  Pharm Res., in 
press. 
22. McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, 
McLaughlin VV, Gerber MJ, DuftonC, Despain DJ, Rubin LJ. 2009. Ambrisentan 
therapy in patients with pulmonary arterial hypertension who discontinued bosentan 
or sitaxsentan due to liver function test abnormalities. Chest 135:122-129.  


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23. Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, 
Ouyang J, Torres VE, Czerwiec, 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. 
24. 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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13 APPENDICES 
13.1 Appendix 1: Chronic Kidney Disease Classification Criteria 
This study uses the 2009 CKD-EPI creatinine equation (Levey A,16 which is recommended 
by the KDIGO Clinical Practice Guidelines for Management of Chronic Kidney Disease. 
The CKD-EPI equation is: 
𝑒𝐺𝐹𝑅ൌ141 ൈ 𝑚𝑖𝑛൬𝑆𝑐𝑟
κ , 1൰
஑
ൈmax ൬𝑆𝑐𝑟
κ , 1൰
ିଵ.ଶ଴ଽ
ൈ0.993୅୥ୣൈ1.018 ሺif femaleሻൈ1.159 ሺif blackሻ,   
where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females 
and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr or 1. 
13.2 Appendix 2: DILI Network Causality Criteria, modified 
Causality assessment scoring in the Drug-Induced Liver Injury Network (DILIN) prospective 
study, modified (Fontana RJ et al)18 
Causality score 
Likelihood 
(%) 
Description 
1 = definite 
>95 
Liver injury is typical for drug or herbal product 
(‘signature’ or pattern of injury, timing of onset, 
recovery). 
The evidence for causality is “beyond a reasonable 
doubt”. 
2 = highly likely 
75-95 
The evidence for causality is ‘clear and convincing’ but 
not definite. 
3 = probable 
50-74 
The causality is supported by ‘the preponderance of 
evidence’ as implicating the drug but the evidence cannot 
be considered definite or highly likely. 
4 = possible 
25-49 
The causality is not supported by ‘the preponderance of 
evidence’; however, one cannot definitely exclude the 
possibility. 
5 = unlikely 
6-24 
The evidence for causality is ‘highly unlikely’ based 
upon the available information. 
6 = unrelated 
0-5 
An alternate cause was clearly established. 
7 = insufficient data 
Not 
applicable 
Key elements of the drug exposure history, initial 
presentation, alternative diagnoses and/or diagnostic 
evaluation prevent one from determining a causality 
score. 
 


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


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13.4 Appendix 4: Liver Dysfunction Checklist 
The following items will be included in a checklist to be completed by the HHC for remote 
visits (Part 1 only) and by the site for clinic visits (Part 1 and Part 2) when directed by the 
protocol.  For remote visits where there are findings on Part 1 of the checklist, telemedicine 
will be utilized to determine if a clinic visit is needed to complete Part 2.   
 
Part 1 - Symptoms 
Did the subject 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 subject develop the following signs since the last visit? 
 
Sign 
Jaundice 
Ascites 
Rash 
Fever 
Right upper quadrant tenderness or liver 
enlargement 
Encephalopathy 
 
Any symptoms, signs, or an associated diagnosis deemed clinically significant based on 
information entered in Part 1 or Part 2 during either a remote visit or a clinic visit will be 
entered in the eCRF by the site as adverse events. The Investigator will determine whether a 
constellation of symptoms and signs in the context of all available information including 


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laboratory data indicate the potential presence of liver dysfunction.  Otherwise, individual 
symptoms and signs need to be recorded as other AEs or as an alternative diagnosis.  For 
example, fatigue alone may be a non-specific AE with no clear cause.  As another example, 
fatigue, weakness, and vomiting occurring together may indicate a gastroenteritis. Liver 
dysfunction should only be considered when the totality of the evidence makes that a 
plausible diagnosis. 
  
If liver dysfunction is suspected, the Investigator will communicate with the medical monitor 
and additional testing detailed in Section 7.3.7.1 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 subject’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 subject 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 subject’s country of birth?  
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           1 
 
Study PA-ADPKD-303: The ALERT Study 
Clinical Study Protocol Version 4 Dated November 17, 2021 
Summary of Changes 
 
This Summary of Changes document reflects revisions incorporated into Protocol Amendment 3, Version 4 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 to Version 3 are shown in Track Changes. Minor editorial and document formatting revisions have not 
been summarized. 
 
Administrative Changes 
This section lists administrative changes, including changes of names or roles of companies or personnel and/or contact information. No 
changes listed here affect clinical decision making or consent. 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
26 
List of 
Abbreviations 
ACEi        angiotensin converting enzyme 
inhibitors 
….. 
ARB        angiotensin receptor blocker 
ACEi        angiotensin converting enzyme 
inhibitors 
….. 
ARB        angiotensin receptor blocker 
These abbreviations 
are no longer used in 
text and have been 
removed from the List 
of Abbreviations. 
48 
5.1.1 Identity 
of the 
Investigational 
Product 
The investigational product, lixivaptan 
capsule, is formulated as a white hard 
gelatin capsule with a clear band (without 
markings) containing 50 mg of lixivaptan 
and the inactive ingredients listed in Table 
3. 
 
The investigational product, lixivaptan 
capsule, is formulated as a white, banded, 
hard gelatin capsule with a clear band 
(without markings) containing 50 mg of 
lixivaptan and the inactive ingredients 
listed in Table 3. 
 
Investigational 
product description 
revised to allow for 
multiple drug lots to 
be used, which may 
differ in capsule 
banding. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           2 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
93 
References 
17. 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. 
17. 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. 
Reference updated to 
reflect current 
guidelines (2021). 
 
 
Text Clarifications 
This section lists text changes for consistency or other clarifications. These changes do not affect clinical decision making or consent. 
Page(s) Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
13 
SYNOPSIS 
Subject 
Population 
9. If re‐challenge with tolvaptan was 
performed, the ALT level should 
have increased to >2 x ULN upon 
re‐challenge or the ALT level was 
increasing but tolvaptan was 
stopped for patient safety 
reasons before it reached > 2 x 
ULN after having previously 
normalized. 
 
9. The subject may or may not have 
been re‐challenged with tolvaptan.  
If re‐challenge with tolvaptan was 
performed, the ALT level should 
have increased to >2 x ULN upon 
re‐challenge or the ALT level was 
increasing but tolvaptan was 
stopped for patient safety reasons 
before it reached > 2 x ULN after 
having previously normalized. 
Text has been 
updated to make 
consistent with 
wording in 
Inclusion #9 in 
Section 4.1.1 
14 
SYNOPSIS 
Subject 
Population 
11. History of advanced diabetes 
(e.g., glycosylated hemoglobin 
[HgbA1c] >7.5%, and/or 
glycosuria by dipstick, significant 
proteinuria [>300 mcg 
11. History of advanced diabetes (e.g., 
glycosylated hemoglobin [HgbA1c] 
>7.5%, and/or glycosuria by 
dipstick, significant proteinuria 
[>300 mcg albumin/mg 
creatinine], retinopathy), other 
Text has been 
updated to make 
consistent with 
wording in 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           3 
Page(s) Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
albumin/mg creatinine]), other 
significant renal disease, 
transplanted kidney, recent 
kidney surgery within the 6 
months prior to Screening 
(including cyst drainage or 
fenestration) or acute kidney 
injury within 6 months prior to 
Screening. 
significant renal disease, 
transplanted kidney, recent kidney 
surgery within the 6 months prior 
to Screening (including cyst 
drainage or fenestration) or acute 
kidney injury within 6 months 
prior to Screening. 
 
Exclusion #11 in 
Section 4.1.2 
44 
Section 4.1.1 
Inclusion Criteria 
10. Appropriate control of 
hypertension including an ACEi or 
ARB (unless not considered 
appropriate for the subject) 
without the use of a diuretic in 
concert with KDIGO “Clinical 
Practice Guideline for the 
Management of Blood Pressure in 
Chronic Kidney Disease”.17  
 
10. Appropriate control of 
hypertension including an ACEi 
angiotensin converting enzyme 
inhibitor or ARB angiotensin 
receptor blocker (unless not 
considered appropriate for the 
subject) without the use of a 
diuretic in concert with KDIGO 
“Clinical Practice Guideline for the 
Management of Blood Pressure in 
Chronic Kidney Disease”.17  
Abbreviation 
removed and 
replaced with 
complete text for 
consistency 
61 
Figure 4. 
Titration 
Flowchart 
Visit 9: Level 3a; Tolerated?; No 
Visit 9: Level 3a; Tolerated?; No/Yes 
Flowchart updated 
to reflect all dosing 
options at Visit 9. 
 
 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           4 
 
Clinically-relevant Changes 
This section describes changes that affect the type or frequency of protocol procedures, or the addition of information to the protocol that 
influences clinical decision making or consent. 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
11 
 
SYNOPSIS 
Subject 
Population 
2. Female subjects must: 
a. not be pregnant, lactating, 
or breastfeeding.   
b. be either postmenopausal 
(defined as amenorrhea for 
≥12 months), surgically 
sterile (defined as having 
undergone hysterectomy 
and/or bilateral 
oophorectomy), or if of 
child‐bearing potential 
(WOCBP) must agree to 
practice appropriate 
methods of birth control or 
remain abstinent during the 
study and for 30 days after 
the last dose of study drug. 
Acceptable forms of 
contraception include any 
of the following: 
i. oral contraceptives 
ii. double barrier 
methods of non‐
2. Female subjects must: 
a. not be pregnant, lactating, 
or breastfeeding.   
b. be either postmenopausal 
(defined as amenorrhea for 
≥12 months), surgically 
sterile (defined as having 
undergone hysterectomy 
and/or bilateral 
oophorectomy), or if of 
child‐bearing potential 
(WOCBP) must agree to 
practice appropriate 
methods of birth control or 
remain abstinent (only if 
this is the usual and 
preferred lifestyle of the 
participant) during the 
study and for 30 days after 
the last dose of study drug. 
Acceptable forms of 
contraception include any 
of the following: 
 hormonal 
List of contraceptive 
methods has been 
aligned with global 
standard for 
“acceptable methods” 
of contraception. 
Abstinence, as a 
method of birth 
control, has been 
clarified.  


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           5 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
hormonal 
contraception are 
permitted in this 
study:  
1. female 
condom with 
spermicide 
(cream, 
spray, gel, 
suppository, 
contraceptive 
sponge, or 
polymer film) 
2. diaphragm 
with 
spermicide 
(with or 
without a 
condom) 
3. cervical cap 
with 
spermicide 
(with or 
without a 
condom) 
4. male sexual 
partner who 
agrees to use 
a male 
contraceptives (i.e., 
oral, intravaginal, 
transdermal, 
injectable, 
implantable) 
i. oral contraceptives 
● double barrier 
methods of non‐
hormonal 
contraception are 
permitted in this 
study:  
1.○  male or female 
condom with 
spermicide (cream, 
spray, gel, 
suppository, 
contraceptive sponge, 
or polymer film) 
2. ○  diaphragm, 
cervical cap, or 
contraceptive sponge 
with spermicide (with 
or without a condom) 
3.cervical cap with 
spermicide (with or 
without a condom) 
4.male sexual partner 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           6 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
condom in 
addition to 
female 
subject’s use 
of spermicide 
(cream, 
spray, gel, 
suppository, 
contraceptive 
sponge, or 
polymer film) 
iii. intrauterine device 
(IUD), including 
progestin‐containing 
intrauterine devices 
iv. 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 
v. bilateral tubal 
ligation 
vi. Essure® procedure. 
3. Male subjects and their female 
partners of childbearing potential 
who agrees to use a 
male condom in 
addition to female 
subject’s use of 
spermicide (cream, 
spray, gel, suppository, 
contraceptive sponge, 
or polymer film) 
iii. ● intrauterine device 
(IUD), including 
progestin‐containing 
intrauterine devices 
 intrauterine 
hormone‐releasing 
system (IUS) 
iv. ● 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 
v. ● bilateral tubal 
ligation 
vi. ● Essure® procedure 
(tubal occlusion). 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           7 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
must also use the contraceptive 
methods listed above during the 
study and for 30 days after the last 
dose of study drug. 
3.   Male subjects and their female 
partners of childbearing potential must 
also use the contraceptive methods listed 
above or remain abstinent (only if this is 
the usual and preferred lifestyle of the 
participant) during the study and for 30 
days after the last dose of study drug. 
 
41 
4.1.1 Inclusion 
Criteria 
2.   Female subjects must: 
a. not be pregnant, lactating, or 
breastfeeding.   
b. be either postmenopausal 
(defined as amenorrhea for ≥12 
months, surgically sterile 
(defined as having undergone 
hysterectomy and/or bilateral 
oophorectomy), or if of child‐
bearing potential (WOCBP) must 
agree to practice appropriate 
methods of birth control or 
remain abstinent during the 
study and for 30 days after the 
last dose of study drug. 
Acceptable forms of 
contraception include any of the 
following: 
 oral contraceptives 
 double barrier 
2.   Female subjects must: 
a. not be pregnant, lactating, or 
breastfeeding.   
b. be either postmenopausal 
(defined as amenorrhea for ≥12 
months), surgically sterile 
(defined as having undergone 
hysterectomy and/or bilateral 
oophorectomy), or if of child‐
bearing potential (WOCBP) 
must agree to practice 
appropriate methods of birth 
control or remain abstinent 
(only if this is the usual and 
preferred lifestyle of the 
participant) during the study 
and for 30 days after the last 
dose of study drug. Acceptable 
forms of contraception include 
any of the following: 
 hormonal 
List of contraceptive 
methods has been 
aligned with global 
standard for 
“acceptable methods” 
of contraception. 
Abstinence, as a 
method of birth 
control, has been 
clarified.  


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           8 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
methods of non‐
hormonal 
contraception are 
permitted in this 
study.  
o female 
condom with 
spermicide 
(cream, 
spray, gel, 
suppository, 
contraceptive 
sponge, or 
polymer film) 
o diaphragm 
with 
spermicide 
(with or 
without a 
condom) 
o cervical cap 
with 
spermicide 
(with or 
without a 
condom) 
o male sexual 
partner who 
agrees to use 
contraceptives (i.e., 
oral, intravaginal, 
transdermal, 
injectable, 
implantable) 
 oral contraceptives 
 double barrier 
methods of non‐
hormonal 
contraception are 
permitted in this 
study.  
o male or 
female 
condom with 
spermicide 
(cream, 
spray, gel, 
suppository, 
contraceptive 
sponge, or 
polymer film) 
o diaphragm, 
cervical cap, 
or 
contraceptive 
sponge with 
spermicide 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           9 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
a male 
condom in 
addition to 
female 
subject’s use 
of spermicide 
(cream, 
spray, gel, 
suppository, 
contraceptive 
sponge, or 
polymer film) 
 intrauterine device 
(IUD), including 
progestin‐containing 
intrauterine devices 
 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 
 bilateral tubal 
ligation 
 Essure® procedure 
(with or 
without a 
condom) 
o cervical cap 
with 
spermicide 
(with or 
without a 
condom) 
o male sexual 
partner who 
agrees to use 
a male 
condom in 
addition to 
female 
subject’s use 
of spermicide 
(cream, 
spray, gel, 
suppository, 
contraceptive 
sponge, or 
polymer film) 
 intrauterine device 
(IUD), including 
progestin‐containing 
intrauterine devices 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           10 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
 3. Male subjects and their female partners 
of childbearing potential must also use the 
contraceptive methods listed above during 
the study and for 30 days after the last 
dose of study drug. 
 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 
 bilateral tubal 
ligation 
 Essure® procedure 
(tubal occlusion). 
 3. Male subjects and their female partners 
of childbearing potential must also use the 
contraceptive methods listed above or 
remain abstinent (only if this is the usual 
and preferred lifestyle of the participant) 
during the study and for 30 days after the 
last dose of study drug. 
48 
5.1.3 Study 
Drug 
Packaging, 
Labeling, and 
Storage 
All study drug supplies should be stored at 
the study site in its original packaging in a 
secure, locked area under the 
responsibility of the Investigator or other 
authorized individual. At the study site, the 
study drug should be stored refrigerated 
All study drug supplies should be stored at 
the study site in its original packaging in a 
secure, locked area under the 
responsibility of the Investigator or other 
authorized individual. At the study site, 
lixivaptan should be stored in accordance 
Drug storage details 
revised based on 
updated CMC data; 
details will be 
reflected in the 
pharmacy manual. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           11 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
(between 2‐8°C [35‐46°F]) and protected 
from extreme conditions of temperature, 
light, and humidity. Once study drug is 
dispensed, the subject should be 
instructed to store it in its original 
packaging at refrigerated temperatures 
between 2‐8°C [35‐46°F]), protected from 
extreme conditions of temperature, light, 
and humidity. 
with the specifications detailed in the 
study pharmacy manual. At the study site, 
the study drug should be stored 
refrigerated (between 2‐8°C [35‐46°F]) and 
protected from extreme conditions of 
temperature, light, and humidity. Once 
study drug lixivaptan is dispensed, the 
subject should be instructed to store it in 
its original packaging at refrigerated 
temperatures between 2‐8°C [35‐46°F]), 
protected from extreme conditions of 
temperature, light, and humidity and in 
accordance with lixivaptan treatment 
labelling at all times until ready to take. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                        Clinical Study Protocol Version 4 dated November 17, 2021 
Confidential                       
 
 
 
 
 
           12 
Page Section 
Version 3 dated September 2, 2020 
Version 4 
Explanation 
53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.7.1.2 
Prohibited 
Therapy 
The following medications are prohibited 
during the 3 months prior to Screening 
Visit 1 and throughout the study: 
 Conivaptan 
 Somatostatin analogs (e.g. 
lanreotide, pasireotide, octreotide, 
etc.) 
 Metformin (for ADPKD; allowed for 
diabetes mellitus) 
 Nicotinamide (for ADPKD) 
 Bardoxolone 
 Venglustat 
 Demeclocycline  
 mTOR kinase inhibitors (e.g., 
everolimus, sirolimus, etc.) 
 Any investigational drug or device. 
The following medications are prohibited 
during the 3 months prior to Screening 
Visit 1 and throughout the study: 
 Conivaptan 
 Somatostatin analogs (e.g. 
lanreotide, pasireotide, octreotide, 
etc.) 
 Metformin (for ADPKD; allowed for 
diabetes mellitus) 
 Nicotinamide (for ADPKD) 
 Bardoxolone 
 Venglustat 
 Demeclocycline  
 mTOR kinase inhibitors (e.g., 
everolimus, sirolimus, etc.) 
 SGLT2 inhibitors (e.g., canagliflozin, 
dapagliflozin, empagliflozin, etc.)  
 HIF‐PH inhibitors 
 Any investigational drug or device. 
The list of prohibited 
medications has been 
revised to reflect 
additional 
medications that may 
confound safety or 
efficacy assessments 
in this study. 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           1 
 
Study PA-ADPKD-303: The ALERT Study 
Clinical Study Protocol Version 3 Dated September 2, 2020 
Summary of Changes 
 
This Summary of Changes document 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 are shown in Track Changes. 
Administrative Changes 
This section lists administrative changes, including changes of names or roles of companies or personnel and/or contact information. No 
changes listed here affect clinical decision making or consent. 
Page 
Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
1 
2 
 
3 
 
10 
Title Page 
Protocol approval – 
Sponsor Signature 
Declaration of 
Investigator 
Protocol Synopsis 
An Open-label Study of Lixivaptan in 
Subjects with Autosomal Dominant 
Polycystic Kidney Disease Who 
Previously Experienced Abnormal 
Liver Chemistry Test Results While 
Receiving Tolvaptan  
Protocol Number: PA-ADPKD-303: 
The ALERT Study 
An Open-label Study of Lixivaptan in 
Subjects with Autosomal Dominant 
Polycystic Kidney Disease Who 
Previously Experienced Abnormal 
Liver Chemistry Test Results While 
Receiving Tolvaptan: The ALERT 
Study  
Protocol Number: PA-ADPKD-303: 
The ALERT Study 
Corrects a placement error 
of the acronym “The ALERT 
Study”  
1 
Title Page 
Sponsor Contact – no email address 
Email: 
NShusterman@palladiobio.com 
Added email address 
1 
Title Page 
Medical Monitor – no affiliation 
David Frid, MD 
ICON Clinical Research 
Added medical monitor’s 
employment affiliation 
1 
Title page 
Version of Protocol: 2 
Version of Protocol: 23 
Updates protocol version 
1 
Title page 
Date of protocol: June 18, 2020 
Date of protocol: June 18, 
2020September 2, 2020 
Updates protocol date 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           2 
Page 
Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
2 
Protocol approval – 
Sponsor signature 
Protocol Version 2 
Protocol Version: 23 
Updates protocol version 
2 
Protocol approval – 
Sponsor signature 
Protocol date: June 18, 2020 
Protocol date: June 18, 
2020September 2, 2020 
Updates protocol date 
2 
Protocol approval – 
Sponsor signature 
Signature date: June 18, 2020 
Signature date: June 18, 
2020September 2, 2020 
Updates protocol date 
84 
8.8.1. Data 
Management 
Clinical data management will be 
performed in accordance with 
applicable standards and data 
cleaning procedures of the CRO)… 
Clinical data management will be 
performed in accordance with 
applicable standards and data 
cleaning procedures of the contract 
research organization (CRO)… 
Defines “CRO” at its first 
appearance in document. 
All 
Footer 
18-Jun-2020 
18-Jun-202002-Sep-2020 
Updates protocol date 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           3 
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(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
4-9 
Tables of 
Contents, 
Listings, and 
Figures 
N/A 
N/A 
Updated page 
numbers (change 
not tracked) 
11 
Synopsis – 
Subject 
Population 
An eligibility review and discussion 
between the Investigator and the medical 
monitor will be conducted before the first 
subject is enrolled at each site 
At Visits 1 and 2, subjects must meet all of 
the Inclusion criteria and none of the 
Exclusion criteria.  An eligibility review and 
discussion between the Investigator and 
the medical monitor will be conducted 
before the firsteach subject is enrolled 
(prior to Visit 3) at each site. 
Clarifies text 
14 
 
80 
Synopsis – Study 
design 
8.1 Sample Size 
Up to 50 subjects will be enrolled. 
Up to 50 subjects will be enrolled and 
treated. 
Clarifies text 
15 
 
 
 
39 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
3.1.2 Detailed 
Study Design 
Subjects […] and then will return for Visit 
2. 
Subjects […] and then will be scheduled 
return for Visit 2. 
Clarifies text 
16 
 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
After successful completion of the 
Baseline Period, subjects will begin study 
drug and will enter the Titration Period.  
 
After successful completion of Visit 5 
assessments in the clinicthe Baseline 
Period, subjects will be dispensed study 
drug and begin taking study 
drugtreatment. This completes the 
Baseline Period and subjects, begin 
Clarifies 
procedures 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           4 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
taking study drug and will enter the 
Titration Period. 
16 
 
 
 
38 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
3.1.2 Detailed 
Study Design 
Liver chemistry tests, urine specific 
gravity and Uosm will be measured weekly 
throughout the Titration Period. 
Liver chemistry tests will be assessed 
weekly during the Titration Period.  uUrine 
specific gravity and Uosm will be measured 
weekly throughout the Titration Period  at 
all titration visits that occur except Visit 11.  
All titration visits may be conducted 
remotely by a HHC with telemedicine. 
Clarification of 
other testing during 
titration and use of 
remote visits. 
16 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
Subjects will continue to receive 
lixivaptan at the dose level achieved at 
the end of the Titration Period for up to 
52 weeks (12 months).   
Following successful completion of the 
Titration Pperiod, Ssubjects will continue 
to receive lixivaptan in the Maintenance 
Period at the dose level achieved at the 
end of the Titration Period for up to 52 
weeks (12 months).   
Clarifies 
procedures 
17 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
Serum creatinine to determine final 
eGFR, will be obtained starting the 8th 
day after the final dose of study drug and 
continuing through the 28th day of the 
Follow-up Period.   
Three (3) visits to assess Sserum 
creatinine, to determine final eGFR, will be 
obtained over three (3) visits starting the 
8th day after the final dose of study drug 
and continuing through the 28th day of the 
Follow-up Period.   
Clarifies text 
20 
Synopsis – 
Statistical 
Methods 
Up to 50 subjects will be enrolled based 
on the design of a similar study with a 
different drug. 
Up to 50 subjects will be enrolled and 
treated based on the design of a similar 
study with a different drug. 
Clarifies text 
20 
 
 
83 
Synopsis – 
Statistical 
Methods 
8.7 Statistical 
Analysis 
Methodology 
[…] descriptive statistics and upper 95% 
confidence interval […] 
[…] descriptive statistics (n and 
percentage) and upper 95% confidence 
interval […] 
Rectifies error (the 
entire 95% 
confidence interval 
will be calculated) 
26 
List of 
abbreviations 
-- 
ART: anti-retroviral therapy 
HHC: home healthcare clinician 
Added 
abbreviations 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           5 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
32 
1.6 Summary of 
Clinical Studies 
the most common AEs were dry mouth, 
headache, and nausea 
the most common AEs reported in 3 or 
more subjects were dry mouth, headache, 
and nausea. 
Clarifies text 
32 
 
38 
1.7 Study 
rationale 
3.1.1 Overview of 
Study Design 
Up to 50 subjects will be enrolled. 
Up to 50 subjects will be enrolled and 
treated. 
Clarifies text 
34 
1.7 Study 
rationale 
Analysis of the Phase 2 ADPKD study 
also did not show any hepatic AEs. 
An interim aAnalysis of the Phase 2 
ADPKD study also did not show any 
hepatic AEs. 
Updates 
information 
34 
1.7 Study 
rationale 
At the time of this writing, there has been 
no evidence of increased ALT values in 
this subject after 7.5 months of therapy 
with lixivaptan (Error! Reference source 
not found.) 
At the time of this writing, there has been 
no evidence of increased ALT values in 
this subject after 7.514 months of therapy 
with lixivaptan (Error! Reference source 
not found.) 
Updates 
information from 
version 2 
35 
Figure 3 
-- 
Figure 3 updated with recent data 
Updates 
information from 
version 2 
38 
3.1.1 Overview of 
Study Design 
A DNA sample to assess genetic 
variants associated with hepatic 
abnormalities (if and when feasible) will 
be obtained under a separate biobanking 
informed consent at the Baseline Period 
or later in the study.   
A DNA sample to assess genetic variants 
associated with hepatic abnormalities (if 
and when feasible) will be obtained under 
a separate biobanking informed consent 
at the end of the Baseline PeriodVisit 5 or 
later in the study.   
Adds some more 
precision 
42 
4.1 Selection of 
Study Population 
Approximately 100-200 subjects will be 
screened in order to enroll up to 
approximately 50 subjects at up to 
approximately 25 sites globally.  An 
eligibility review and discussion between 
the Investigator and the medical monitor 
will be conducted before the first subject 
is enrolled at each site.  Subjects will be 
Approximately 100-200 subjects will be 
screened in order to enroll and treat up to 
approximately 50 subjects at up to 
approximately 25 sites globally.  An 
eligibility review and discussion between 
the Investigator and the medical monitor 
will be conducted before  the firsteach 
subject is enrolled (completes Visit 3) at 
Clarifies enrollment 
of subjects and 
rescreening 
procedures 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           6 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
enrolled only if they meet all the inclusion 
criteria and none of the exclusion criteria. 
With the approval of the medical monitor 
and sponsor, subjects who fail 
inclusion/exclusion criteria due to 
temporary or correctable reasons may be 
re-screened up to 2 times. 
each site.  Subjects will be enrolled only if 
they meet all the inclusion criteria and 
none of the exclusion criteria. With the 
approval of the medical monitor and 
sponsor, subjects who fail 
inclusion/exclusion criteria due to 
temporary or correctable reasons may be 
re-screened up to 2 times after re-
consenting each time. 
45 
4.1.2 Exclusion 
criteria 
20. Any malignancy within 5 years prior 
to Screening except for basal cell 
carcinoma successfully treated with local 
therapy. 
20. Any malignancy within the 5 years 
prior to Screening except for basal cell 
carcinoma successfully treated with local 
therapy. 
Corrects grammar 
46 
4.2.3 Subject 
Withdrawal 
Criteria 
At a minimum, subjects should be 
encouraged to complete the Early 
Termination Visit (Visit 24) at the time of 
[…] 
At a minimum, subjects should be 
encouraged to complete the Early 
Termination Visit (Visit 24 – in the clinic) at 
the time of […] 
Adds details on 
Visit 24 
47 
4.2.7 
Withdrawals Due 
to Abnormal Liver 
Chemistry Test 
Results 
In certain circumstances described in 
Section Error! Reference source not 
found., restarting study drug should only 
occur when the HERC believes the 
relationship between the abnormal liver 
chemistry test results and the study drug 
is 50% or less according to the DILIN 
criteria, modified, Section Error! 
Reference source not found. 
In certain circumstances described in 
Section Error! Reference source not 
found., restarting study drug should only 
occur when the HERC believes the 
relationship between the abnormal liver 
chemistry test results and the study drug 
is less than 50% or less according to the 
DILIN criteria, modified, Section Error! 
Reference source not found. 
Corrects error 
48 
5.1.3 Study Drug 
Packaging, 
Labeling, and 
Storage – Table 
3 
 
Lixivaptan 
Strength 
50 mg 
Formulation 
Capsules, packaged 30 
per bottle 
 
Lixivaptan 
Strength 
50 mg 
Formulation 
Capsules, packaged 30 
per bottle 
Clarifies that 
Palladio does not 
have a role in the 
manufacturing of 
the study drug.  
Palladio as 
sponsor of the 
study is well 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
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Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
Inactive 
ingredients 
Polyethylene glycol 400, 
NF/EP; Polyethylene 
glycol 1000, NF/EP; 
Povidone (K-17), 
USP/EP; Polysorbate 80, 
NF/EP; Butylated 
hydroxytoluene; 
Butylated hydroxyanisole 
 
Supplier/ 
manufacturer 
Palladio 
Biosciences 
5 Walnut 
Grove Drive 
Suite 120 
Horsham 
PA 19044 
PMRS, 
Inc. 
202 
Precision 
Road  
Horsham, 
PA 19044 
Packager 
PCI Pharma Services 
4545 Assembly Drive 
Rockford, IL 61109 
 
Inactive 
ingredients 
Polyethylene glycol 400, 
NF/EP; Polyethylene 
glycol 1000, NF/EP; 
Povidone (K-17), 
USP/EP; Polysorbate 
80, NF/EP; Butylated 
hydroxytoluene; 
Butylated 
hydroxyanisole 
 
Supplier/ 
mManufacturer 
Palladio 
Biosciences 
5 Walnut 
Grove Drive 
Suite 120 
Horsham 
PA 19044 
PMRS, 
Inc. 
202 
Precision 
Road  
Horsham, 
PA 19044 
Packager 
PCI Pharma Services 
4545 Assembly Drive 
Rockford, IL 61109 
 
documented in the 
protocol. 
49  
5.1.3 Study Drug 
Packaging, 
Labeling, and 
Storage 
All study drug supplies should be stored 
in its original packaging in a secure, 
locked area under the responsibility of 
the Investigator or other authorized 
individual. 
All study drug supplies should be stored at 
the study site in its original packaging in a 
secure, locked area under the 
responsibility of the Investigator or other 
authorized individual. 
Clarifies that this 
instruction applies 
to storage at 
clinical sites. 
56 
6.1.1 Visit 1 
Assign the subject an identification 
number and contact the IRT. The 
Investigator or designee will contact the 
IRT and enter the subject identification 
number as described in Section Error! 
Reference source not found. 
Contact the IRT to Aassign the subject an 
identification number and contact the IRT. 
The Investigator or designee will contact 
the IRT and enter the subject identification 
number as described in Section Error! 
Reference source not found. 
Simplifies the text 
57 
57 
58 
58 
60 
6.1.2 Visit 2 
6.1.3 Visit 3 
6.2.2 Visit 4 
6.2.3 Visit 5 
 Collect and review concomitant 
medication information and update the 
CRF 
 Collect and review concomitant 
medication information and update the 
eCRF 
Remove useless 
text (CRF is 
always updated) 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           8 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
 
62 
6.3.1 Visits 6 to 
10 
6.3.2 Visit 
11/Last Titration 
Visit 
57 
6.2 Baseline 
Period 
The 3-week Baseline Period beginning 
with Visit 3 is designed to collect 
baseline data […] 
The 3-week Baseline Period begins at the 
conclusion of Visit 2 and consists of 3 
visits – Visits 3, 4, and 5. beginning with 
Visit 3It is designed to collect baseline 
data […] 
Clarifies the 
Baseline Period 
57 
59 
6.2.1 Visit 3 
6.2.3 Visit 5 
 Schedule the subject to return for Visit 
[…] to occur in 1 week. 
 Schedule the subject to return for Visit 
[…] to occur in 1 week. 
Remove useless 
text 
58 
6.2.2 Visit 4 
 Schedule the subject to return for Visit 
5 to occur in 1 week 
 Schedule the subject to return to the 
clinic for Visit 5 to occur in 1 week 
Clarifies text 
58 
6.2.3 Visit 5 
 Collect a plasma sample for 
measurement of lixivaptan. Note date 
and time of sample on the requisition 
form and the CRF. 
 Collect a plasma sample for 
measurement of lixivaptan. Note date 
and time of sample on the requisition 
form and the eCRF. 
Rectifies text 
63 
6.3.2 Visit 
11/Last Titration 
Visit 
 Investigator or designee contact the 
IRT […]   
 The Investigator or designeesite will 
cContact the IRT […] 
Clarifies text 
63 
6.3.2 Visit 
11/Last Titration 
Visit 
 Schedule the subject to return for their 
next visit to occur in 4 weeks and 
remind the subject to take adequate 
fluids.  Provide the subject with an 
appointment reminder card and any 
written instructions. Note that the next 
visit may be conducted remotely (if 
available and when necessary). 
 Schedule the subject to return for their 
next visit to occur in 4 weeks and remind 
the subject to take adequate fluids.  
Provide the subject with an appointment 
reminder card and any written 
instructions. Note that the next visit may 
be conducted remotely (if available and 
when necessary). 
Clarifies text 
63 
 
65 
6.4.1 Visits 12 to 
23 
6.5.1 Visit 25 
 Contact the IRT […] 
 For remote visits, the IRT should be 
contacted sufficiently […] 
 The site will Ccontact the IRT […] 
Clarifies text 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           9 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
66 
6.5.2 Visit 26 
 For remote visits, the site must contact 
the IRT should be contacted sufficiently 
[…] 
65 
6.4.2 Visit 
24/Early 
Termination 
 Collect a plasma sample […] on the 
requisition form and the CRF.  
 […] 
 Schedule the subject to return […] as a 
remote visit if available and when 
necessary. 
 Collect a plasma sample […] on the 
requisition form and the eCRF.  
 […] 
Schedule the subject to return […] as a 
remote visit if available and when 
necessary. 
Rectifies text 
65 
6.5 Follow-up 
Period 
The Follow-up Period will last 28 days 
and include 3 visits (Visit 25, Visit 26, 
and Visit 27).  If available and when 
necessary, Visits 25 and 26 may be done 
remotely. 
The Follow-up Period will last 28 days and 
include 3 visits (Visit 25, Visit 26, and Visit 
27).  If available and when necessary, 
Visits 25 and 26 may be done remotely by 
a HHC. 
Clarifies and 
rectifies text 
68 
7.3.3 Physical 
Examination 
Brief physical examination will 
subsequently be measured at the 
timepoints specified 
Brief physical examination will 
subsequently be measured performed at 
the timepoints specified 
Corrects grammar 
71 
7.3.7 
Assessment of 
Liver Symptoms, 
Signs, or Test 
Abnormalities 
Management of hepatic and liver 
chemistry test abnormalities are 
discussed below.  The appearance of 
any suspicious symptoms or signs of 
liver dysfunction in a subject at any time 
during the study should trigger prompt 
testing of liver chemistry tests (i.e., within 
48 hours). 
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 4 (Section Error! 
Reference source not found.) in a 
subject at any time during the study 
should trigger prompt testing of liver 
chemistry tests (i.e., within 48 hours). 
Provides link to list 
of symptoms and 
signs 
73 
7.3.7.3 Special 
Reporting of 
Liver Events 
A liver disease eCRF will be utilized 
during the study. The purpose of the liver 
disease eCRF and additional testing is to 
facilitate review of each subject who 
develops liver chemistry test 
abnormalities during the study to 
A liver dysfunction detailsisease eCRF will 
be utilized during the study. The type of 
information needed to complete it is 
provided in Appendix 4 (SectionError! 
Reference source not found.). The 
purpose of the liver dysfunction 
detailsisease eCRF and additional testing 
(4 corrections) 
Clarifies text and 
describes use of a 
checklist 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           10 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
determine the probable cause(s) of these 
abnormalities. 
is to facilitate review of each subject who 
develops liver chemistry test abnormalities 
and/or signs or symptoms of liver 
dysfunction during the study to determine 
the probable cause(s) of these 
abnormalities.  
73 
7.3.7.3 Special 
Reporting of 
Liver Events 
The Investigator must complete a liver 
disease eCRF and submit it within 24 
hours of awareness through the SAE 
reporting pathway… 
The Investigator must complete a the liver 
disease dysfunction details eCRF and 
submit it within 24 hours of awareness 
through the SAE reporting pathway 
(described in Section Error! Reference 
source not found.)… 
Clarifies how to 
submit liver 
dysfunction events 
73 
7.3.7.3 Special 
Reporting of 
Liver Events 
 
develops any signs or symptoms of 
hepatic dysfunction (e.g. nausea, 
vomiting, right upper quadrant pain, 
malaise, jaundice) 
 
develops any signs or symptoms of 
hepatic dysfunction (see Appendix 4 
[Section Error! Reference source 
not found.]e.g. nausea, vomiting, 
right upper quadrant pain, malaise, 
jaundice) 
Refers reader to 
complete list of 
signs and 
symptoms 
73 
7.3.7.3 Special 
Reporting of 
Liver Events 
The liver eCRF and AESI report form 
should be updated as new information 
becomes available. 
The liver eCRF and AESI report form 
should be updated as new information 
becomes available. 
Clarifies the forms 
to use to report 
new information 
75 
7.3.8.3 Reporting 
AEs, SAEs, and 
AEs of Special 
Interest 
For the purpose of this study, 
pregnancies and liver events are 
considered to be AESIs.  Liver events 
will be reported directly from the EDC 
system; however, pregnancy events will 
need to be reported on special 
pregnancy forms to ICON PVSS.  
Any AE that meets SAE or AESI criteria 
will be reported to ICON 
Pharmacovigilance & Safety Services 
(PVSS) immediately (i.e., within 24 
hours) after site personnel first learn 
For the purpose of this study, pregnancies 
and liver events are considered to be 
AESIs.  Liver events will be reported 
directly from the electronic data capture 
(EDC) system; however, . 
Ppregnancy events will need to be 
reported on special pregnancy forms to 
ICON PVSS. 
Any AE that meets SAE or AESI criteria 
will be reported to ICON 
Pharmacovigilance & Safety Services 
(PVSS) immediately (i.e., within 24 hours) 
Clarifies that 
pregnancy is not 
an AE of Special 
Interest but will be 
reported prompted 
through ICON’s 
pharmacovigilance 
department using a 
paper-based 
reporting form. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           11 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
about the event.  Investigators should 
record all SAE/AESI details available, 
including Investigator causality 
assessment, on an Adverse Event eCRF 
or appropriate AESI forms and submit 
the report via the electronic data capture 
(EDC) system within 24 hours of 
becoming aware of the event.  
Notification of SAE/AESI entry will be 
generated and sent to ICON PVSS via 
the EDC system. 
after site personnel first learn about the 
event.  Investigators should record all 
SAE/AESI details available, including 
Investigator causality assessment, on an 
Adverse Event eCRF or appropriate AESI 
forms and submit the report via the 
electronic data capture (EDC) system 
within 24 hours of becoming aware of the 
event.  Notification of SAE/AESI entry will 
be generated and sent to ICON PVSS via 
the EDC system. Pregnancy events will 
also be reported to ICON PVSS within 24 
hours of recognition of the event, but on 
the special forms provided. 
78 
7.3.10 HERC 
This committee will independently 
determine the probable causality for liver 
chemistry test abnormalities of concern 
(Section Error! Reference source not 
found.) and of relatedness to lixivaptan. 
This committee will independently 
determine the probable causality for 
instances of suspected liver dysfunction 
and liver chemistry test abnormalities of 
concern (Section Error! Reference 
source not found.) and of relatedness to 
lixivaptan. 
Explicitly states 
that episodes of 
liver dysfunction as 
well as liver 
chemistry 
abnormalities will 
be reviewed by the 
HERC. 
81 
8.4.3 Additional 
Hepatic Safety 
Endpoints 
>3 x, 5 x, >10 x, and 20 x ULN elevations 
for ALT 
>3 x, 5 x, >10 x, and 20 x ULN elevations 
for ALT 
Correction of 
typographical error 
84 
8.8.1 Data 
Management 
Investigative site personnel will enter 
subject data into eCRFs using the [EDC 
system name] program.   
Investigative site personnel will enter 
subject data into eCRFs using the [EDC 
system name] programdesignated by the 
sponsor. 
Correction of 
template language 
86 
10 Investigator’s 
Obligations  
10 INVESTIGATOR’S OBLIGATIONS 
 
10 INVESTIGATOR’S OBLIGATIONS 
AND STUDY PERSONNEL 
 
Clarifies 
sponsorship of 
study and 
identification of 
CRO. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           12 
Page(s) Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
The study will be conducted by qualified 
investigators under the sponsorship of 
Palladio Biosciences, Inc. (the sponsor). 
 
The contact information for the sponsor’s 
Chief Medical Officer and the CRO’s 
medical monitor are listed on the cover 
page of this protocol.  Contact information 
for other sponsor personnel, ICON Clinical 
Research Limited, the designated CRO, 
and other vendors are listed in the 
Investigator Site File provided to each site 
94 
13.2 Appendix 2: 
DILI Network 
Causality 
Criteria, modified 
Causality 
score 
Likelihood 
(%) 
Description 
4 = 
possible 
25-49 
The causality 
is not 
supported by 
‘the 
preponderance 
of evidence’ as 
implicating the 
drug but the 
evidence 
cannot be 
considered 
definite or 
highly likely 
 
Causality 
score 
Likelihood 
(%) 
Description 
4 = 
possible 
25-49 
The causality 
is not 
supported by 
‘the 
preponderance 
of evidence’; 
however, one 
cannot 
definitively 
exclude the 
possibility as 
implicating the 
drug but the 
evidence 
cannot be 
considered 
definite or 
highly likely 
 
Cut-and-paste 
error from source 
document 
corrected 
 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           13 
 
Clinically-relevant Changes 
This section describes changes that affect the type or frequency of protocol procedures, or the addition of information to the protocol that 
influences clinical decision making or consent. 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
14 
 
 
44 
Synopsis – 
Exclusion Criteria 
 
4.1.2 Exclusion 
Criteria 
16. History of infection with human 
immunodeficiency virus (HIV). 
16. History of infection with human 
immunodeficiency virus (HIV) unless the 
subject is stable and doing well on a 
non-CYP interacting anti-retroviral 
therapy (ART) regimen and who has not 
required more than 2 changes in their 
ART regimen. 
Allows subjects into the 
study with HIV infection 
under specified conditions. 
15 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
- 
Certain visits may be conducted 
remotely with a home healthcare 
clinician (HHC), but Visits 1, 5, 17, 24, 
and 27 are to be conducted in the clinic 
(with only extraordinary exceptions at 
the discretion of the medical monitor 
and sponsor). Some of the remote visits 
will include a telemedicine component 
with the Investigator.  Details are 
provided in Error! Reference source 
not found.. 
Increases the number of 
remote visits with a HHC 
from 13 to 22 
15 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
Subjects who meet all the inclusion 
criteria and none of the exclusion 
criteria and achieve stability of 
background anti-hypertensive 
medications in the absence of 
diuretics will return to the clinic for 
end-of-screening assessments at Visit 
2, including body weight, vital signs, 
and serum chemistry testing (if 
Subjects who meet all the inclusion 
criteria and none of the exclusion criteria 
and achieve stability of background anti-
hypertensive medications in the 
absence of diuretics will either return to 
the clinic or be scheduled for a remote 
visit with thea HHC  for Visit 2 end-of-
screening assessments at Visit 2, 
including body weight, vital signs, and 
Adds the use of a remote 
visit with a HCC and 
telemedicine 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           14 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
diuretics were discontinued or anti-
hypertensive medications were 
adjusted).   
serum chemistry testing (if diuretics 
were discontinued or anti-hypertensive 
medications were adjusted) and final 
eligibility determination (utilizing 
telemedicine if a remote visit).   
16 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
Subjects who fail inclusion/exclusion 
criteria due to temporary or 
correctable reasons may be re-
screened (up to 2 additional times) 
after consultation with the medical 
monitor and sponsor.  Subjects will 
enter the Baseline Period. 
 
Subjects 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 
and sponsor.  Immediately following 
successful completion of Visit 2, 
Ssubjects who successfully complete 
the Screening Period will enter the 
Baseline Period. 
 
Clarifies that reconsent is 
necessary if a subject re-
screens (after previously 
screening failing) 
16 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
-- 
Visits 3 and 4 may be conducted 
remotely by a HHC.  
 
Adds the use of remote 
visits with a HCC for Visits 
3 and 4 
16 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
-- 
All titration visits may be conducted 
remotely by a HHC with telemedicine. 
Adds the use of remote 
visits with a HCC for Visits 
6-11 
16-
17 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
-- 
Visits 12, 13, 14 , 15, 16, 18, 19, 20, 21, 
22, and 23 may be conducted remotely 
by a HHC.  If conducted remotely, Visits 
14 and 20 will include telemedicine and 
all other remote maintenance visits may 
Adds the use of remote 
visits with a HCC for Visits 
12-23 and telemedicine for 
Visits 14 and 20 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           15 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
include a telemedicine component if 
deemed necessary by the Investigator. 
17 
Synopsis - Study 
Period 
Description and 
Estimated 
Duration 
-- 
Visits 25 and 26 may be conducted 
remotely by a HHC (using telemedicine 
if necessary). 
Adds the use of remote 
visits with a HCC for Visits 
25 and 26 
19 
 
 
 
50 
 
 
Synopsis - Study 
Drug, Dosage, 
and Route of 
Administration 
5.2 Dose 
Administered 
The Investigator may temporarily hold 
the drug for up to 7 days, if 
necessary, to manage intercurrent 
illness, tolerability issues, planned or 
unplanned surgical procedures or life 
situations, e.g., airplane travel, etc.  
The Investigator may temporarily hold 
the drug for up to 7 days, if necessary, 
to manage acute intercurrent illness, 
tolerability issues, planned or 
unplanned surgical procedures or life 
situations, e.g., airplane travel, etc. 
Additionally, subjects who have a 
longer interruption due to illness, 
including COVID-19, or other reasons 
may re-start study drug when medically 
stable after discussion with the medical 
monitor and sponsor. 
Adds provisions for long 
interruption of study drug 
treatment 
19 
 
 
20 
 
 
 
36 
Synopsis – 
Criteria for 
Evaluation 
Synopsis – 
Analysis of 
Primary and 
Secondary 
Endpoints 
2.2.1 Primary 
Endpoint 
Proportion of subjects who develop 
ALT levels >3 x ULN during the 
Titration and Maintenance Periods 
that were assessed by the Investigator 
in consultation with the medical 
monitor and sponsor and adjudicated 
by the independent Hepatic Events 
Review Committee (HERC) to be 
related to lixivaptan and resulted in 
discontinuation of the study drug. 
Proportion of subjects who develop ALT 
levels >3 x ULN during the Titration and 
or Maintenance Periods that were 
assessed by the Investigator in 
consultation with the medical monitor 
and sponsor and adjudicated by the 
independent Hepatic Events Review 
Committee (HERC) to be at least 
probably related to lixivaptan and 
resulted in discontinuation of the study 
drug. 
Delegation of determining 
relationship to the 
independent HERC and 
clarification of the 
causality assessments 
that are clinically 
meaningful. 
19 
 
 
Synopsis – 
Criteria for 
Evaluation 
Proportion of subjects who develop 
ALT levels >5 x ULN during the 
Titration and Maintenance Periods 
Proportion of subjects who develop ALT 
levels >5 x ULN during the Titration and 
or Maintenance Periods that were 
Delegation of determining 
relationship to the 
independent HERC and 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           16 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
20-
21 
 
 
 
36-
367 
Synopsis – 
Analysis of 
Primary and 
Secondary 
Endpoints 
2.2.2 Secondary 
Endpoint 
that were assessed by the Investigator 
in consultation with the medical 
monitor and sponsor and adjudicated 
by the independent HERC to be 
related to lixivaptan and resulted in 
discontinuation of the study drug. 
Proportion of subjects who develop 
ALT levels >3 x ULN during the 
Titration and Maintenance Periods 
that were assessed by the Investigator 
in consultation with the medical 
monitor and sponsor and adjudicated 
by the HERC to be related to 
lixivaptan and resulted in dose 
reduction of the study drug. 
assessed by the Investigator in 
consultation with the medical monitor 
and sponsor and adjudicated by the 
independent HERC to be at least 
probably related to lixivaptan and 
resulted in discontinuation of the study 
drug. 
Proportion of subjects who develop ALT 
levels >3 x ULN during the Titration and 
or Maintenance Periods that were 
assessed by the Investigator in 
consultation with the medical monitor 
and sponsor and adjudicated by the 
independent HERC to be at least 
probably related to lixivaptan and 
resulted in dose reduction of the study 
drug. 
clarification of 
“relatedness” for the other 
secondary endpoints.  
20 
 
 
80 
Synopsis – 
Statistical 
Methods 
8.2 Populations 
for Analysis 
Populations for Analysis: 
The Safety Population is defined as 
those subjects who received at least 1 
dose of lixivaptan.  This population will 
be utilized for all safety analyses. 
The Efficacy Population is defined as 
those subjects who received at least 1 
dose of lixivaptan and have at least 1 
eGFR determination during the 
Follow-up Period.  This population will 
be used for all efficacy analyses. 
Populations for Analysis: 
The Enrolled Population is defined as all 
subjects who meet inclusion/exclusion 
criteria during Screening Period and 
complete Visit 3. All general summaries, 
except safety and efficacy analyses are 
based on the Enrolled Population, 
unless specified otherwise. 
The Safety Population is a subset of the 
Enrolled Population defined as those 
subjects who received at least 1 dose of 
lixivaptan.  This population will be 
utilized for all safety analyses. 
The Efficacy Population is a subset of 
the Safety Population defined as those 
subjects who received at least 1 dose of 
lixivaptan have at least 1 eGFR 
Updates analysis 
populations definitions and 
defines 3 new populations 
based on discussions 
during the preparation of 
the statistical analysis plan 
(SAP) 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           17 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
determination during the Baseline 
Period and have at least 1 eGFR 
determination during the Follow-up 
Period.  This population will be used for 
all efficacy analyses. 
The Pharmacokinetic (PK) Population is 
a subset of the Safety Population 
defined as those subjects who had at 
least 1 on-therapy evaluable PK 
measurement. 
The Pharmacodynamic (PD) Population 
is a subset of the Enrolled Population 
defined as those subjects who have at 
least 1 set of urine specific gravity and 
urine osmolality measurements from the 
same specimen. 
24 
Table 1. 
Schedule of 
Procedures 
Assess for liver dysfunction: shown 
from Visit 6 to Visit 24 
Added assessment for liver dysfunction 
to Visit 25 
Lab results from Visit 24 
needed to be checked as 
Visit 25 
24 
Table 1. 
Schedule of 
procedures 
-- 
 
Footnote d. A brief physical 
examination will be performed at V11 
and V27. 
ECGs and physical examination: 
Removed at V11, added at V17 
Footnote d. A brief physical examination 
will be performed at V11 V17 and V27. 
Changes ECG and brief 
physical examination 
schedule to a visit that will 
be in the clinic 
25 
Table 1. 
Schedule of 
procedures 
footnotes 
(second bullet) 
Remote visits (if available) may occur 
at V3, V4, V12, V13, V15, V16, V18, 
V19, V21, V22, V23, V25 and V26. 
Remote visits (if available and when 
necessary) may occur at V2 (with 
telemedicine), V3, V4, V6 – V11 (each 
with telemedicine), V12, V13, and V14 
(with telemedicine), V15, V16, V18, V19, 
and V20 (with telemedicine), V21, V22, 
V23, V25 and V26. Any remote visit may 
have a telemedicine component added if 
needed.  With permission fromof the 
Reflects the increase in 
the number of remote 
visits  


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           18 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
medical monitor and sponsor, other 
visits may be done remotely on a case-
by-case extraordinary basis. 
38 
3.1.1 Overview of 
Study Design 
All assessments and the relative 
timings are listed in the Schedule of 
Study Procedures (Table 1). 
All assessments and the relative timings 
are listed in the Schedule of Study 
Procedures (Table 1). Certain visits may 
be conducted remotely with a home 
healthcare clinician (HHC), but Visits 1, 
5, 17, 24, and 27 are to be conducted in 
the clinic (with only extraordinary 
exceptions at the discretion of the 
medical monitor and sponsor). Some of 
the remote visits will include a 
telemedicine component with the 
Investigator while other remote visits 
may have that option if deemed 
necessary for a medical reason. Details 
are provided in Error! Reference 
source not found.. 
Details remote visits with a 
HHC and telemedicine 
versus in-clinic visits 
39 
3.1.2 Detailed 
Study Design – 
Screening Period 
Subjects who meet all the inclusion 
criteria and none of the exclusion 
criteria and achieve stability of 
background medications will return to 
the clinic for end-of-screening 
assessments including body weight, 
vital signs, and a Complete Chemistry 
Panel (only if blood pressure 
medications were adjusted) at Visit 2.  
Eligible subjects will then enter the 
Baseline Period at the completion of 
Visit 2. Subjects who fail 
inclusion/exclusion criteria because of 
temporary or correctable reasons may 
be re-screened up to 2 times with the 
Subjects who meet all the inclusion 
criteria and none of the exclusion criteria 
and achieve stability of background 
medications will return to the clinicbe 
scheduled for end-of-screening 
assessments including body weight, 
vital signs, and a Complete Chemistry 
Panel (only if blood pressure 
medications were adjusted) at Visit 2 
(which may be conducted remotely by a 
HHC with telemedicine to determine 
final eligibility).  Eligible subjects will 
then enter the Baseline Period 
immediately at the completion of Visit 2. 
Subjects who fail inclusion/exclusion 
Explains that Visit 2 can 
be done remotely 
Explains that new ICF is 
needed for re-screening 
 
 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           19 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
approval of the medical monitor and 
sponsor. 
criteria because of temporary or 
correctable reasons may be re-screened 
up to 2 times after obtaining new 
informed consents with the approval of 
the medical monitor and sponsor. 
39 
3.1.2 Detailed 
Study Design – 
Baseline Period 
After completion of the Baseline 
Period, subjects will enter the Titration 
Period. 
Visits 3 and 4 may be conducted 
remotely by a HHC. After At the 
successful completion of the Baseline 
Period (Visit 5), subjects will be 
dispensed study drug and begin 
treatment  enter the Titration Period.  
This completes the Baseline Period and 
subjects will enter the Titration Period. 
Details transition between 
Baseline Period and 
Titration Period 
39 
3.1.2 Detailed 
Study Design – 
Titration Period 
Liver chemistry tests, urine specific 
gravity, and Uosm will be measured 
weekly during the Titration Period. 
Liver chemistry tests will be assessed 
weekly during the Titration Period,. 
uUrine specific gravity and Uosm will be 
measured weekly during the Titration 
Periodat all titration visits that occur 
except Visit 11.  All titration visits may 
be conducted remotely by a HHC with 
telemedicine. 
Clarifies when certain labs 
are obtained and adds the 
use of remote visits with 
telemedicine for titration 
visits. 
40 
3.1.2 Detailed 
Study Design – 
Maintenance 
Period 
Assessments, including liver 
chemistry tests, will be performed 
every 4 weeks during this period. 
Assessments, including liver chemistry 
tests, will be performed every 4 weeks 
during this period.  Visits 12, 13, 14, 15, 
16, 18, 19, 20, 21, 22, and 23 may be 
conducted remotely by a HHC.  If 
conducted remotely, Visits 14 and 20 
will include telemedicine and the other 
visits may include telemedicine if 
deemed necessary by the Investigator.. 
Adds the use of remote 
visits with a HCC and 
telemedicine for Visits 12-
23 
40 
3.1.2 Detailed 
Study Design – 
Follow-up Period 
Three assessments of serum 
creatinine to determine eGFR will be 
obtained starting as early as the 8th 
Three assessments of serum creatinine 
to determine eGFR will be obtained 
starting as early as the 8th day after the 
Adds the use of remote 
visits with a HCC for Visits 
25 and 26 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           20 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
day after the final dose of study 
medication and continuing through 
the 28th day of the Follow-up Period. 
final dose of study medication and 
continuing through the 28th day of the 
Follow-up Period.  Visits 25 and 26 may 
be conducted remotely by a HHC (using 
telemedicine if deemed necessary by 
the Investigator).   
48 
5.1.3 Study Drug 
Packaging, 
Labeling, and 
Storage 
Once study drug is dispensed, the 
subject should be instructed to store it 
in its original packaging at 
temperatures between 2-25°C [35-
77°F]), but protected from extreme 
conditions of temperature, light, and 
humidity. 
Once study drug is dispensed, the 
subject should be instructed to store it in 
its original packaging at temperatures 
between 2-25°C [35-77°F]), but 
protected from extreme conditions of 
temperature, light, and humidity.  For 
subjects who utilize remote visits, study 
drug will be dispensed and shipped from 
the study site to the subject’s home or to 
an alternate location pre-specified by 
the subject, via an experienced courier 
approved by the Sponsor.  Subjects 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 health clinician 
arrives. 
Provides the ability to ship 
study drug to the subject 
using an approved, 
experienced courier when 
the subject elects to have 
remote visits at home. 
51 
5.6 Treatment 
Compliance 
The dates of all study medication 
dosing, including interruptions, 
missed doses or overdose, must be 
recorded in the eCRF. If the subject 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 
The dates of all study medication 
dosing, including interruptions, missed 
doses or overdose, must be recorded in 
the eCRF. If the subject 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 subject 
should be re-educated regarding the 
Added text to handle 
situation of prolonged 
treatment interruption that 
does not represent non-
compliance. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           21 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
subject should be re-educated 
regarding the correct study drug 
doses to be administered. 
correct study drug doses to be 
administered.  However, if the 
Investigator, medical monitor, and 
sponsor have agreed to a treatment 
interruption (Section Error! Reference 
source not found.), then this will not be 
considered a protocol deviation. 
53 
5.7.1.2 Prohibited 
Therapy 
Strong or moderate CYP3A4 or 
CYP2C8 inhibitors, including […] 
Strong or moderate CYP3A4 or 
CYP2C8 inhibitors, including […] 
remdesivir […] 
Adds remdesivir (COVID-
19 treatment which is a 
3A4 inhibitor) to the list of 
prohibited medications 
55 
6 Timing of Study 
Procedures 
Certain visits must occur in the clinic.  
Other visits may occur in the clinic or 
through an at-home visiting nurse (if 
available). 
Certain visits must occur in the clinic.  
Other visits may occur in the clinic or 
remotely by a HHC through an at-home 
visiting nurse (if available). 
Switches from at-home 
nurse visits to remote 
visits 
55 
6.1 Screening 
Period 
Subjects […] will return for Visit 2.  At 
Visit 2, screening test results will be 
reviewed […] 
Subjects […] will return be scheduled 
for Visit 2.  At Visit 2 (which may be 
conducted remotely by a HHC and 
telemedicine to determine eligibility) 
screening test results will be reviewed 
[…] 
Explains that Visit 2 can 
be conducted remotely 
55 
6.1 Screening 
Period 
Subjects who successfully complete 
the Screening Period will enter the 
Baseline Period.  Subjects who fail 
inclusion/exclusion criteria will be 
discontinued but may be re-screened  
with the approval […] 
Subjects who successfully complete the 
Screening Period will immediately enter 
the Baseline Period.  Subjects who fail 
inclusion/exclusion criteria will be 
discontinued but may be re-screened 
and new informed consents obtained 
with the approval […] 
Explains the need to redo 
an informed consent if 
subjects are re-screened 
55 
6.11 Visit 1 
Subjects will undergo informed 
consent… 
Visit 1 will be conducted at the clinical 
site.  Subjects will undergo informed 
consent… 
Restates that Visits 1 is an 
in-clinic visit 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           22 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
56 
6.1.2 Visit 2 
Subjects will report to the clinic for 
Visit 2 to review tests from Visit 1 and 
finalize screening assessments.  
Subjects will either report to the clinic for 
Visit 2 or be scheduled for a remote visit 
with a HHC to review tests from Visit 1 
and finalize screening assessments. 
Telemedicine will be used to determine 
final eligibility by the investigator. 
Adds that Visit 2 can be in 
clinic or remote 
57 
6.1.2 Visit 2 
Determine whether the subject is still 
eligible to participate in the study. 
o If the subject is not eligible to 
participate, record the subject as a 
Screen Failure and contact the 
IRT to discontinue the subject from 
the study and complete the 
appropriate eCRFs. 
 
Determine whether the subject is still 
eligible to participate in the study. 
o If the subject is not eligible to 
participate, the site will record the 
subject as a Screen Failure and 
contact the IRT to discontinue the 
subject from the study and complete 
the appropriate eCRFs. Subjects 
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 
and sponsor.   
 
Details re-screening 
procedures 
57 
6.2.1 Visit 3 
-- 
Prior to Visit 3 the eligibility review by 
the medical monitor will be completed 
for each subject. Subjects will either 
report to the clinic for Visit 3 or be 
scheduled for a remote visit with a HHC.   
Adds eligibility procedures 
before Visit 3 and states 
that Visit 3 can be 
conducted remotely 
58 
6.2.2 Visit 4 
-- 
Subjects will either report to the clinic for 
Visit 4 or be scheduled for a remote visit 
with a HHC. 
States that Visit 4 can be 
conducted remotely 
59 
6.2.3 Visit 5 
Provide subject with a urine collection 
container […] to be brought in at Visit 
Provide subject with a urine collection 
container […] to be brought in at 
Titration Period Visit 6 or provided to the 
Explains how the urine 
sample is collected if the 
visit is done with an HCC 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           23 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
6 (titration Period) for specific gravity 
and Uosm determination. 
HHC if the visit will be conducted 
remotely (Titration Period) for specific 
gravity and Uosm determination 
59 
6.3.1 Visits 6 to 
10 
Visits 6, 7, 8, 9, and 10 will occur 
weekly ± 3 days as needed for 
titration.  All titration visits will be 
conducted in the clinic. Subjects will 
report to the clinic in the morning for 
their visits (after a minimum 8-hour 
overnight fast except for water) to 
undergo Titration Period 
assessments.  
Subjects should bring in any 
remaining study drug with them.   
 
Visits 6, 7, 8, 9, and 10 will occur weekly 
± 3 days as needed for titration and may 
be conducted remotely by a HHC.  All 
titration visits will be conducted in the 
clinic.  Subjects will either report to the 
clinic or interact with a HHC in the 
morning for their visits (after a minimum 
8-hour overnight fast except for water) to 
undergo Titration Period assessments. 
Note that telemedicine will be utilized at 
these visits for the Investigator to assess 
the subject’s status and tolerability of 
the study drug and to make a titration 
decision. Any other issues may also be 
discussed with the subject. 
Subjects should bring into the clinic, or 
provide to the HHC, any remaining study 
drug with them.   
Changes conduct of Visits 
6 to 10 
60 
 
62 
 
 
63 
 
64 
 
65 
6.3.1 Visits 6 to 
10 
6.3.2 Visit 
11/Last Titration 
Visit 
6.4.1 Visits 12 to 
23 
6.4.2 Visit 24/ 
Early Termination 
6.5.1 Visit 25 
 Assess for liver dysfunction (liver 
chemistry tests, symptoms, signs)  
 Assess clinically for liver dysfunction 
(liver chemistry tests, symptoms, signs 
[if a clinic visit]) in accordance with the 
checklist  and instructions in Appendix 
4 (Section Error! Reference source 
not found.). 
Removes the liver 
chemistry tests from 
assessment of liver 
dysfunction (assessed 
separately) and adds the 
use of a new checklist. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           24 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
60 
6.3.1 Visits 6 to 
10 
 Follow the flowchart in Error! 
Reference source not found. […]. 
o Based on the decision made from 
the flowchart, contact the IRT to 
receive the kit assignment for the 
next period of time 
o Dispense study drug and instruct 
subject how many capsules to 
take based on the dose level guide 
in Error! Reference source not 
found. 
 Follow the flowchart in Error! 
Reference source not found. […]. For 
remote visits, the HHC will call the 
Investigator to receive direction on this 
decision. The Investigator may want to 
utilize telemedicine to interact with the 
subject. 
o Based on the decision made from 
the flowchart, contact the IRT to 
receive the kit assignment for the 
next period of time 
o Dispense study drug and instruct 
subject how many capsules to take 
based on the dose level guide in 
Error! Reference source not 
found. 
o For remote visits, the site will contact 
the IRT sufficiently in advance of the 
scheduled visit day to obtain kit 
assignment and to allow sufficient 
time for drug to be shipped to arrive 
at subject’s home prior to the visit 
date. 
Updates procedures for 
titration decisions  
60 
6.3.1 Visits 6 to 
10 
 At each visit, remind the subject […] 
urine specimen on the morning of 
their next visit, which they will bring 
with them. 
 At each visit, remind the subject […] 
urine specimen on the morning of their 
next visit, which they will bring with 
them (if a clinic visit) or provide to the 
HHC if a remote visit is conducted. 
Explains procedure to 
collect urine specimen for 
remote visits 
62 
6.3.2 Visit 
11/Last Titration 
Visit 
The procedures specified for Visit 11 
[…] enter the Maintenance Period. 
Subjects will report to the clinic in the 
morning to undergo the assessments 
for the last visit of the Titration Period.  
The procedures specified for Visit 11 
[…] enter the Maintenance Period at 
that time.  The last titration visit may 
be in the office or conducted remotely 
by a HHC.  If conducted remotely, 
Explains the changes that 
ensue if Visit 11 is 
conducted remotely 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           25 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
Subjects should bring in any 
remaining study drug with them.   
telemedicine will be used for the 
Investigator to interact with the subject 
and confirm that the subject can 
continue into the Maintenance Period. 
Subjects will either report to the clinic 
in the morning or interact with the 
HHC, if a remote visit is conducted, to 
undergo the assessments for the last 
visit of the Titration Period.  Subjects 
should bring any remaining study drug 
into the clinic or provide to the HHC 
any remaining study drug with them.   
62 
6.3.2 Visit 
11/Last Titration 
Visit 
 Perform a brief physical exam 
 Perform a 12-lead ECG 
 Perform a brief physical exam 
 Perform a 12-lead ECG 
Removes the brief 
physical exam and ECG at 
Visit 11 and moves them 
to Visit 17 
63 
6.3.2 Visit 
11/Last Titration 
Visit 
-- 
o For remote visits, the site will contact 
the IRT sufficiently in advance of the 
scheduled visit day to obtain kit 
assignment and to allow sufficient time 
for study drug to be shipped to arrive 
at subject’s home prior to the visit 
date. 
Explains the changes that 
ensue if visits are 
conducted remotely 
63 
6.4 Maintenance 
Period 
The Maintenance Period will last 52 
weeks (Visit 12 to Visit 24).  If 
available and when necessary, the 
following visits may be done remotely: 
Visits 12, 13, 15, 16, 18, 19, 21, 22, 
and 23. 
The Maintenance Period will last 52 
weeks (Visit 12 to Visit 24).  If available 
and when necessary, the following visits 
may be done remotely: Visits 12, 13, 14 
(with telemedicine), 15, 16, 18, 19, 20 
(with telemedicine), 21, 22, and 23. Note 
that telemedicine may be added to any 
other visit if the Investigator judges that 
additional interaction or information is 
needed to assess the subject’s status. 
Adds remote visits 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           26 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
63 
6.4.1 Visits 12 to 
23 
Subjects should bring in any 
remaining study drug with them. 
Subjects should bring any remaining 
study drug into the clinic or provide to 
the HHC. any remaining study drug with 
them. 
Explains the changes that 
ensue if visits are 
conducted remotely 
63 
6.4.1 Visits 12 to 
23 
 Check AEs and SAEs and inquire 
about tolerability of the study drug 
 Assess for liver dysfunction (liver 
chemistry tests, symptoms, signs). 
 Review study drug compliance/ 
reconciliation  
 Collect and review concomitant 
medication information and update 
the CRF 
 
 Review lab results from prior visit 
o For subjects exhibiting an increase 
in ALT or AST during the 
Maintenance Period (>3 x ULN) or 
total bilirubin (>2 x ULN), follow the 
instructions in Section Error! 
Reference source not found.. 
 Check AEs and SAEs and inquire 
about tolerability of the study drug 
 Assess clinically for liver dysfunction 
(liver chemistry tests, symptoms, 
signs [if a clinic visit]) as directed by 
the checklist in Appendix 4 (Section 
Error! Reference source not 
found.) 
 Review study drug compliance/ 
reconciliation  
 Collect and review concomitant 
medication information and update 
the eCRF 
 Perform a brief physical exam (Visit 
17) 
 Perform a 12-lead ECG  (Visit 17) 
 
Details changes to 
procedures for Visits 12 to 
23 including moving the 
brief physical exam and 
12-lead ECG to Visit 17 
64 
6.4.2 Visit 
24/Early 
Termination 
 Check AEs and SAEs 
 Assess for liver dysfunction (liver 
chemistry tests, symptoms, signs). A 
 Review lab results from prior visit 
o For subjects exhibiting an increase 
in ALT or AST during the 
Maintenance Period (>3 x ULN) or 
Details new procedures 
and changes to 
procedures for Visit 24 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           27 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
checklist will be provided is the visit 
is conducted remotely. 
total bilirubin (>2 x ULN), follow the 
instructions in Section Error! 
Reference source not found.. 
 Check AEs and SAEs 
 Assess clinically for liver dysfunction 
(liver chemistry tests, symptoms, 
signs) as directed by the checklist in 
Appendix 4 (Section Error! 
Reference source not found.). 
65 
6.5 Follow-up 
Period 
Visits 25 and 26 may be done 
remotely 
Visits 25 and 26 may be done remotely 
by a HHC (with telemedicine if 
necessary). 
Allows for telemedicine 
65 
6.5.1 Visit 25 
-- 
 Review lab results from prior visit 
o For subjects exhibiting an increase 
in ALT or AST (>3 x ULN) or total 
bilirubin (>2 x ULN) at the prior 
visit, follow the instructions in 
Section Error! Reference source 
not found.. 
 Assess clinically for liver dysfunction 
(symptoms, signs [if a clinic visit]) as 
directed by the checklist in Appendix 
4 (Section Error! Reference source 
not found.). 
Details new procedures 
for Visit 25 
66 
6.5.3 Visit 27 
(End of Study 
Visit) 
Visit 27 is the last visit in this study 
and will occur 28±3 days after the last 
dose of study drug (Visit 24).   
Visit 27 is the last visit in this study and 
will occur 28±3 days after the last dose 
of study drug (Visit 24).  The visit will be 
conducted in the clinic.  
Adds that this visit is in-
clinic 
67 
7.2.1 Specific 
Gravity and Urine 
Osmolality 
They will bring that specimen to their 
clinic visit where specific gravity will 
be measured by dipstick using an 
automated device in the clinic.   
They will either bring that specimen to 
their clinic visit or provide to a HHC if a 
remote visit is conducted, where specific 
gravity will be measured by dipstick 
using an automated device in the clinic.   
Updates procedures for 
specific gravity 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           28 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
69 
7.3.4 Vital Sign 
Measurements 
Subjects will remain at rest in a seated 
position for… 
Subjects will remain at rest in a seated 
position for… 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. 
Allows for positions other 
than seated for vital signs 
under certain 
circumstances. 
69 
7.3.4 Vital Sign 
Measurements 
…Any confirmed, clinically significant 
vital sign measurements must be 
recorded as an AE.   
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.   
Specifies when CS vital 
signs should be recorded 
as AEs 
70 
7.3.5 12-Lead 
ECGs 
All CS findings will be reported as 
AEs. 
All CS findings will be reported as 
Medical History during the Screening 
and Baseline Periods and as AEs after 
the start of study drug. 
Specifies when CS ECGs 
should be recorded as 
AEs 
73 
7.3.7.2 Changes 
in Study Drug 
Dosing if Liver 
Chemistry Test 
Abnormalities 
Occur… 
- 
Liver chemistry test increases of a 
lesser extent should be discussed with 
the medical monitor.  They may be 
related to the underlying variability of 
such tests in ADPKD patients.  
Generally, dosing should continue, but 
the frequency of laboratory testing 
should increase, particularly during the 
Maintenance Period.  Slowing of titration 
may also be considered if the 
abnormalities occur during the Titration 
Period. 
Additional instructions for 
handling liver chemistry 
test increases that are 
below the threshold of >3 
x ULN for transaminases 
or >2 x ULN for total 
bilirubin. 
74 
7.3.8.2 Eliciting 
and Documenting 
AEs and SAEs 
Other changes in health or new 
symptoms occurring during the 
Other changes in health or new 
symptoms occurring during the 
Adds the Baseline Period 
to record AEs and SAEs 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           29 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
screening period will be recorded as 
medical history. 
sScreening or Baseline pPeriods will be 
recorded as medical history. 
75 
7.3.8.3 Reporting 
AEs, SAEs, and 
AEs of Special 
Interest 
Any medical condition that is present 
at the time the subject is screened, 
i.e., medical history, but does not 
deteriorate should not be reported as 
an AE.   
Any medical condition that is present at 
the time the subject is screened or 
during baseline, i.e., medical history, but 
does not deteriorate should not be 
reported as an AE.   
Adds the Baseline Period 
to statement 
77 
7.3.8.8 
Pregnancy 
Pregnancy is not regarded as an AE 
unless there is a medical/surgical 
complication.  Any pregnancy that 
occurs during study participation must 
be reported as an AESI using a 
clinical study pregnancy reporting 
form.  To ensure subject safety, each 
pregnancy must be reported through 
this mechanism to ICON PVSS within 
24 hours of learning of its occurrence. 
Pregnancy is not regarded as an AE 
unless there is a medical/surgical 
complication.  Any pregnancy of a 
subject or the partner of a subject that 
occurs during study participation must 
be reported as an AESI using a clinical 
study pregnancy reporting form.  To 
ensure subject safety, each pregnancy 
must be reported through this 
mechanism to ICON PVSS within 24 
hours of learning of its occurrence. 
Adds that pregnancies in 
partners of subjects will be 
followed like pregnancies 
in subjects. 
78 
7.3.10 HERC 
- 
The HERC will also assess the 
relationship to tolvaptan of prior 
instances of liver dysfunction and liver 
chemistry test abnormalities that 
occurred while enrolled subjects were 
previously receiving tolvaptan. 
Additional assessment by 
HERC 
80 
8.4.1 Primary 
Hepatic Safety 
Endpoint 
Descriptive statistics (n, percentage, 
95% confidence interval) will be used 
to summarize the proportion of 
subjects who develop ALT levels >3 x 
ULN that were assessed by the 
Investigator in consultation with the 
medical monitor and sponsor and 
adjudicated by the independent HERC 
to be related to lixivaptan and resulted 
Descriptive statistics (n, percentage, 
95% confidence interval) will be used to 
summarize the proportion of subjects 
who develop ALT levels >3 x ULN that 
were assessed by the Investigator in 
consultation with the medical monitor 
and sponsor and adjudicated by the 
independent HERC to be at least 
probably related to lixivaptan and 
Updates primary endpoint 
to match other instances 
in the protocol. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           30 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
in discontinuation of the study drug 
during the Titration and Maintenance 
Periods. 
resulted in discontinuation of the study 
drug during the Titration and or 
Maintenance Periods. 
80-
81 
8.4.2 Secondary 
Hepatic Safety 
Endpoints 
Similarly, descriptive statistics (n, 
percentage, 95% confidence interval) 
will be utilized to present the 2 
secondary endpoints: 
 
 
 
 
 
 
The proportion of subjects who 
develop ALT levels >5 x ULN that 
were assessed by the Investigator 
in consultation with the medical 
monitor and sponsor and 
adjudicated by the independent 
HERC to be related to lixivaptan 
and resulted in discontinuation of 
the study drug during the Titration 
and Maintenance Periods; and  
The proportion of subjects who 
develop ALT levels >3 x ULN that 
were assessed by the Investigator 
in consultation with the medical 
monitor and sponsor and 
adjudicated by the independent 
HERC to be related to lixivaptan 
and resulted in lixivaptan dose 
reduction during the Titration and 
Maintenance Periods 
Similarly, descriptive statistics (n, 
percentage, 95% confidence interval) 
will be utilized to present the 2 
secondary endpoints: 
The proportion of subjects who 
develop ALT levels >5 x ULN that 
were assessed by the Investigator in 
consultation with the medical monitor 
and sponsor and adjudicated by the 
independent HERC to be at least 
probably related to lixivaptan and 
resulted in discontinuation of the study 
drug during the Titration and or 
Maintenance Periods; and  
The proportion of subjects who 
develop ALT levels >3 x ULN that 
were assessed by the Investigator in 
consultation with the medical monitor 
and sponsor and adjudicated by the 
independent HERC to be at least 
possibly related to lixivaptan and 
resulted in lixivaptan dose reduction 
during the Titration and or 
Maintenance Periods 
Updates the secondary 
endpoints to match other 
instances in the protocol. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA‐ADPKD‐303: The ALERT Study  
                                                                           Clinical Study Protocol Version 3 dated September 2, 2020 
Confidential                       
 
 
 
 
 
           31 
Page Section 
Version 2 dated June 18, 2020 
Version 3 
Explanation 
85 
9.3 Subject 
Information and 
Consent 
A written informed consent […] shall 
be obtained from each subject before 
entering the study or performing any 
unusual or non-routine procedure […].  
Informed consent templates may […] 
A Wwritten informed consents […] shall 
be obtained from each subject before 
entering the study, upon re-screening, 
and when or performing any unusual or 
non-routine procedure […].  An 
Iinformed consent templates may […] 
Adds the need to have a 
new ICF for re-screening 
89 
11.1.1 Monitoring 
of the Study 
In doing so, the Monitor will visit the 
Investigator and study site at periodic 
intervals, in addition to maintaining 
necessary telephone and letter 
contact.   
In doing so, the Monitor 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.   
Changes the study 
monitoring procedures 
due to remote visits 
95 
13.4 Appendix 3: 
Additional 
Potential Hepatic 
Testing… 
-- 
 
Clinical chemistry: 
o Glutamate dehydrogenase 
(GLDH) 
 
Addition of newly 
described liver chemistry 
test 
96-
97 
13.4 Appendix 4: 
Liver Dysfunction 
Checklist 
-- 
Adds Appendix 4 
Adds Liver Dysfunction 
Checklist, a form to be 
completed for both remote 
and clinic visits with 
associated instructions.  
 

SAP_001.pdf: 
Study Title: An Open-Label Study of Lixivaptan in Subjects With Autosomal Dominant 
Polycystic Kidney Disease Who Previously Experienced Abnormal Liver Chemistry Test 
Results While Receiving Tolvaptan: The ALERT Study 
 
ClinicalTrials.gov ID: NCT04152837 
 
 
 
Statistical Analysis Plan Version 2.0, dated 06-Sep-2022 
 
Note: a summary of changes implemented from Version 1.0 (dated 10-Dec-2020) is provided in 
the Revision History.   


 
Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 1 of 42
 
Protocol Title: 
An Open-label Study of Lixivaptan in Subjects with Autosomal 
Dominant Polycystic Kidney Disease Who Previously Experienced 
Abnormal Liver Chemistry Test Results While Receiving Tolvaptan: 
The ALERT Study 
Protocol Number: 
PA-ADPKD-303 
Protocol Version, Date 
4.0 / 17NOV2021 
ICON ID:  
5016/0003 
Document Version, Date: 
 
Final Version 2.0, 06Sep2022 
Prepared by: 
ICON Clinical Research Services 
 
On behalf of: 
Palladio Biosciences, Inc., 
5 Walnut Grove Drive,  
Suite 120, 
Horsham, PA 19044 
 
Confidentiality statement: 
▪ 
The information provided in this document is strictly confidential.  
▪ 
The recipients of the SAP must not disclose the confidential information contained 
within this document or any related information to other persons without the permission 
of the sponsor. 
▪ 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
DocUUID : 32136f7c-3683-49fd-b477-f395f9955d92


 
Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 2 of 42
 
SIGNATURE PAGE 
Prepared at ICON Clinical Research by:  
 
 
 
 
 
 
 
    David Raj, Senior Statistician II 
 
Date 
Reviewed at ICON Clinical Research by:  
 
 
 
 
 
 
 
 
 
 
  Gloria Crispino, Director of Biostatistics  
          (StatisticaMedica Ltd.) 
 
Date 
 
 
 
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ea17d882-1f03-487b-bd6f-fff7db59e073
Gloria Crispino
06 Sep 2022 09:43:05 PDT (-07:00)
REASON: I approve this document
a05dfa7f-b536-4636-ad10-1bb0fd2ce580
David Raj
06 Sep 2022 11:20:41 PDT (-07:00)
REASON: I approve this document as author.


 
Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 3 of 42
 
Reviewed at Palladio Biosciences, Inc. by: 
 
 
 
 
 
 
 
 
       Genzhou Liu, Head of Biometrics and Data Management  
 
 Date 
   
 
Approved at Palladio Biosciences, Inc. by: 
 
 
 
 
 
 
 
 
 
 
 
        Neil H. Shusterman, MD FACP, Chief Medical Officer 
 
Date 
 
 
 
 
       Genzhou Liu, Head of Biometrics and Data Management 
 
Date  
 
 
 
DocUUID : 32136f7c-3683-49fd-b477-f395f9955d92
b23914c8-cfaf-496f-8d18-9a094689fd8a
Genzhou Liu
06 Sep 2022 09:46:56 PDT (-07:00)
REASON: I have reviewed this document and have no comments that require addressing.
b23914c8-cfaf-496f-8d18-9a094689fd8a
Genzhou Liu
06 Sep 2022 09:46:57 PDT (-07:00)
REASON: I approve this document
40af71ac-d834-444d-981a-9ead798865a8
Neil Shusterman
06 Sep 2022 10:38:46 PDT (-07:00)
REASON: I approve this document


Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 4 of 42
REVISION HISTORY 
Version/Date 
Version 
name 
Section 
Changes implemented 
Version 1.0/10Dec2020 Final 
V1.0 
NA 
NA 
Version 2.0/06Sep2022 V2.0 
1.0 
9.0 
11.4 
Signature Page 
- Text added denoting early
termination of study
- Text added to describe the changes
to planned analyses and actual
outputs
- Added list of tables, listings and
Figures to be actually produced due
to the early termination of the study
- Signature page is updated
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Final Analysis 
Statistical Analysis Plan (SAP) 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 5 of 42
TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................2 
REVISION HISTORY ................................................................................................................4 
TABLE OF CONTENTS ............................................................................................................5 
LIST OF TABLES AND FIGURES ...........................................................................................8 
LIST OF ABBREVIATIONS .....................................................................................................9 
1 INTRODUCTION ..............................................................................................................11 
2 STUDY OBJECTIVES .......................................................................................................11 
Primary Objective ......................................................................................................11 
Secondary Objectives .................................................................................................11 
Exploratory Objectives...............................................................................................11 
3 STUDY DESIGN ................................................................................................................12 
General Study Design ................................................................................................12 
Randomization and Blinding .....................................................................................14 
Study Treatments and Assessments ...........................................................................14 
3.3.1 Study Duration ................................................................................................14 
3.3.2 Study Drug and Administration ......................................................................14 
4 STUDY ENDPOINTS ........................................................................................................21 
Primary Endpoint .......................................................................................................21 
Secondary Endpoints ..................................................................................................21 
4.2.1 Safety Endpoints .............................................................................................21 
4.2.2 Efficacy Endpoint............................................................................................21 
Exploratory Endpoints ...............................................................................................21 
5 SAMPLE SIZE AND POWER ...........................................................................................21 
6 ANALYSIS POPULATIONS .............................................................................................22 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 6 of 42
 
 Enrolled Population ....................................................................................................22 
 Safety Population .......................................................................................................22 
 Efficacy Population ....................................................................................................22 
 Pharmacokinetic (PK) Population ..............................................................................22 
 Pharmacodynamic (PD) Population ...........................................................................22 
 Protocol deviations/violations and exclusions from analysis sets .............................22 
7 Statistical Considerations and analysis ...............................................................................23 
 Derived General Variables .........................................................................................23 
 Handling of Missing Data ..........................................................................................24 
7.2.1 Handling of Missing or Partial Dates ..............................................................24 
7.2.2 Handling of Missing Efficacy or Safety Data .................................................25 
8 STATISTICAL METHODS ...............................................................................................25 
 General Statistical Conventions .................................................................................25 
 Subject Disposition ....................................................................................................26 
 Protocol Deviations ....................................................................................................27 
 Demographics and Baseline Characteristics ..............................................................27 
8.4.1 Medical History ...............................................................................................28 
8.4.2 Prior and Concomitant Medications................................................................28 
8.4.3 Concomitant Procedures .................................................................................28 
 Treatment Exposure and Compliance ........................................................................28 
8.5.1 Study Treatment Exposure ..............................................................................28 
8.5.2 Treatment Compliance ....................................................................................29 
8.5.3 Drug Tolerability and Modifications ..............................................................29 
 Safety Analyses ..........................................................................................................29 
8.6.1 Analysis of Primary Safety Endpoint ..............................................................29 
8.6.2 Analysis of Secondary Safety Endpoint ..........................................................30 
8.6.3 Analysis of Additional Hepatic Safety Endpoints ..........................................30 
8.6.4 Analysis of Additional Potential Hepatic Safety Endpoints ...........................30 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 7 of 42
 
8.6.5 Adverse Event (AE) ........................................................................................31 
8.6.6 Clinical Laboratory Evaluations .....................................................................32 
8.6.7 Vital Signs .......................................................................................................35 
8.6.8 Physical Examinations ....................................................................................35 
8.6.9 Electrocardiograms (ECG) ..............................................................................35 
8.6.10 Pregnancy Test ................................................................................................36 
 Efficacy Analyses.......................................................................................................36 
8.7.1 Analysis of Efficacy Endpoints .......................................................................36 
8.7.2 Exploratory Analysis .......................................................................................37 
 Interim Analysis .........................................................................................................38 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL ..........................38 
10 REFERENCES ....................................................................................................................38 
11 APPENDICES ....................................................................................................................39 
 Appendix I: Chronic Kidney Disease Classification Criteria ....................................39 
 Appendix II: DILI Network Causality Criteria, modified .........................................40 
 Appendix III: Additional Potential Hepatic Testing if Liver Chemistry Abnormalities 
Occur 41 
 
 
 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 8 of 42
 
LIST OF TABLES AND FIGURES 
 
Table 1: Dosing Levels during the Lixivaptan Titration Period .............................................. 15 
Table 2: Dosing Diagram in the Lixivaptan Titration Period .................................................. 16 
Table 3: Schedule of Procedures .............................................................................................. 18 
Table 4: Clinical Laboratory Evaluations ................................................................................ 33 
Table 5: Potentially Clinically Important Criteria (PCS): Laboratory ..................................... 34 
Table 6: Potentially Clinically Important Criteria: Vital Signs ............................................... 35 
 
Figure 1: Study Schematic ....................................................................................................... 12 
Figure 2: Titration Flowchart ................................................................................................... 17 
 
 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 9 of 42
 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
ADPKD 
Autosomal Dominant Polycystic Kidney Disease 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphate 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice per day 
BLQ 
Below limit of quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DILI 
Drug Induced Liver Injury 
DILIN 
Drug Induced Liver Injury Network 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
eGFR 
estimated Glomerular Filtration Rate 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatic C Antibody 
HERC 
Hepatic Events Review Committee 
HPF 
High Power Field 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 10 of 42
 
Abbreviation or 
special term 
Explanation 
IRT 
Interactive Response Technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
TBL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TE-AESI 
Treatment Emergent – Adverse Event of Special Interest 
TFLs 
Tables, Figures and Listings 
Uosm 
Urine Osmolality 
ULN 
Upper Limit of Normal 
ULQ 
Upper Limit of Quantification 
WHODrug 
World Health Organisation Drug Dictionary 
WOCBP 
Women of childbearing potential 
 
 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 11 of 42
 
1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol PA-ADPKD-303 
Version 3.0 “An Open-label Study of Lixivaptan in Subjects with Autosomal Dominant 
Polycystic Kidney Disease Who Previously Experienced Abnormal Liver Chemistry Test 
Results While Receiving Tolvaptan: The ALERT Study” dated 02Sep2020 for final analysis. 
The table of contents and templates for the Tables, Figures and Listings (TFLs) will be produced 
in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report 
(CSR). 
The preparation of this SAP is based on International Conference on Harmonization (ICH) E9 
and E3 guidelines. 
All data analyses and generation of TFLs will be performed using SAS version 9.4® or higher. 
NOTE: Please see Section 9 for an explanation of the impact of early termination of this study 
on the actual output produced. 
2 
STUDY OBJECTIVES 
 
Primary Objective 
The primary objective of this study is to assess the effect of lixivaptan on hepatic safety in 
subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD) who experienced 
abnormal liver chemistry test results on tolvaptan that resulted in permanent discontinuation of 
tolvaptan. 
 
Secondary Objectives 
The key secondary objectives of this study are: 
1) To characterize the non-hepatic safety and tolerability of lixivaptan in subjects with 
ADPKD who previously experienced abnormal liver chemistry test results while treated 
with tolvaptan.  
2) To assess renal function (efficacy) in ADPKD subjects while on lixivaptan using change 
in estimated glomerular filtration rate (eGFR). 
 
Exploratory Objectives 
1) To evaluate the relationship between abnormal liver chemistry test results and 
dose/exposure of lixivaptan as data permit.  
2) To assess potential genetic risk factors for hepatic abnormalities (if and when feasible). 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 12 of 42
 
3 
STUDY DESIGN 
 
General Study Design 
This is a Phase 3, open-label, repeat dose study designed to assess hepatic safety, non-hepatic 
safety, and efficacy of lixivaptan in subjects who previously experienced abnormal liver 
chemistry test results while treated with tolvaptan that resulted in permanent discontinuation of 
tolvaptan for that reason.  Up to 50 subjects will be enrolled and treated.  Evaluations will 
include frequent testing of liver chemistry tests (every week during the Baseline and Titration 
Periods, every 4 weeks during the Maintenance Period, and at the final Follow-up Visit), 
physical examinations, vital signs, safety labs (non-hepatic serum chemistry, hematology, and 
urinalysis), eGFR, urine osmolality determinations, and trough serum concentrations of 
lixivaptan. A deoxyribonucleic acid (DNA) sample to assess genetic variants associated with 
hepatic abnormalities (if and when feasible) will be obtained under a separate bio banking 
informed consent at Visit 5 or later in the study.  After meeting study entry criteria during a 1-
3-week Screening Period that can extend up to 8 weeks (in subjects who need adjustment of 
antihypertensive medications), subjects will enter a 3-week no-study-drug Baseline Period to 
obtain baseline serum creatinine measurements (for eGFR determinations) and repeat liver 
chemistry tests to assess baseline variability, followed by a 3-6 week Titration Period during 
which lixivaptan administered twice daily will be titrated to a dose that is tolerated and results 
in a reduced trough urine specific gravity (or until the maximum dose level is reached) as 
described below. The minimum dose to enter the Maintenance Period is Level 2 (100 mg twice 
per day (BID)). Treatment will continue for up to 52 weeks (12 months) after which study drug 
will be stopped, and final safety and efficacy assessments obtained during the Follow-up Period 
of 4 weeks. The maximum study duration will be 73 weeks (16.8 months). The study schematic 
is depicted in Figure 1. 
Figure 1: Study Schematic 
 
Screening Period (Visits 1, 2):  
After obtaining Informed consent, screening assessments will be performed at Visit 1 to 
determine subject eligibility. Subjects whose anti-hypertensive medications in the absence of 
diuretics are known and documented to have been stable (unchanged) for at least 3 weeks prior 
to Visit 1 may proceed to Visit 2 in 1 week to confirm eligibility. Subjects for whom the stability 
of anti-hypertensive medications in the absence of diuretics is unknown or not documented 
must be observed for 3 weeks during the Screening Period to ensure stable dosing of anti-
Screening 
Period 
 Baseline 
Period 
   1-8 weeks       3 weeks        3-6 weeks 
  
             
         
              52 weeks 
       
                   
  4 weeks 
Titration Period 
Maintenance                   Period 
Follow-
up Period 
V1                        V2   V3         V5 V6                  V11 V12                                                                                                                                                           V24  V25      V27 
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Final Analysis 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
Page 13 of 42
 
hypertensive medications then will be scheduled for Visit 2.. For those subjects who need to be 
discontinued from diuretic therapy and/or have their anti-hypertensive therapy optimized, the 
Screening Period may be extended up to a total of 8 weeks prior to Visit 2.   
Subjects who meet all the inclusion criteria and none of the exclusion criteria and achieve 
stability of background anti-hypertensive medications in the absence of diuretics will return to 
the clinic for end-of-screening assessments at Visit 2, including body weight, vital signs, and a 
Complete Chemistry Panel (only if blood pressure medications were adjusted) at Visit 2 (which 
may be conducted remotely by a home healthcare clinician [HHC] with telemedicine to 
determine final eligibility). Eligible subjects will then enter the Baseline Period immediately at 
the completion of Visit 2. Subjects who fail inclusion/exclusion criteria because of temporary 
or correctable reasons may be re-screened up to 2 times after obtaining new informed consents 
with the approval of the medical monitor and sponsor.  
Baseline Period (Visits 3 – 5): Following completion of all screening assessments and 
establishment of background medication stability, subjects will enter the 3-week no-study-drug 
Baseline Period during which time liver chemistry tests and serum creatinine (for eGFR 
calculation) will be assessed weekly to obtain baseline measurements and assess individual 
variability.  Baseline trough spot urine specific gravity (as a point-of-care surrogate for urine 
osmolality) and Uosm will be determined only at Visit 5. Visits 3 and 4 may be conducted 
remotely by a HHC.  At the successful completion of the Baseline Period (Visit 5), subjects 
will be dispensed study drug and begin treatment.  This completes the Baseline Period and 
subjects will enter the Titration Period.  
Titration Period (Visits 6 – 11): During a period of 3-6 weeks, the lixivaptan dose will be 
increased weekly according to the titration schedule to achieve a level that results in both a 
tolerable dose and reduced first morning (trough) spot urine specific gravity (as a point-of-care 
surrogate for urine osmolality) or until the maximum dose level (Level 4 [200 mg BID]) is 
reached.  Dosing will be started at Level 1 (50 mg BID), but the minimum dose to enter the 
Lixivaptan Maintenance Period is Level 2 (100 mg BID).  In most circumstances, dose 
tolerability will be confirmed during an additional week of dosing before the subject advances 
to the Maintenance Period.  At the 2 highest dose levels (Level 3 and Level 4) where aquaretic 
effects may be problematic in certain subjects, there will be an opportunity to reduce the 
evening (PM) dose (Level 3a [150 mg AM/100 mg PM] and Level 4a [200 mg AM/150 mg 
PM]).  Liver chemistry tests will be assessed weekly during the Titration Period. Urine specific 
gravity and Uosm will be measured at all titration visits that occur except Visit 11.  All titration 
visits may be conducted remotely by a HHC with telemedicine. 
Maintenance Period (Visits 12-24): Subjects will continue to receive lixivaptan at the dose 
achieved at the end of the Titration Period for up to 52 weeks (12 months).  The investigator 
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Final Analysis 
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Statistical Analysis Plan 
Protocol Number: PA-ADPKD-303 
 Version: Final 1.0, Date: 01 Dec 2020 
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will have the ability to lower the dose if necessary, to improve tolerability. Assessments, 
including liver chemistry tests, will be performed every 4 weeks during this period.  Visits 12, 
13, 14, 15, 16, 18, 19, 20, 21, 22, and 23 may be conducted remotely by a HHC.  If conducted 
remotely, Visits 14 and 20 will include telemedicine and the other visits may include 
telemedicine if deemed necessary by the Investigator.  
Follow-up Period (Visits 25 -27): After the last dose of lixivaptan is given, the subjects will 
enter the Follow-up Period which will last 4 weeks.  Three assessments of serum creatinine to 
determine eGFR will be obtained starting as early as the 8th day after the final dose of study 
medication and continuing through the 28th day of the Follow-up Period.  Visits 25 and 26 may 
be conducted remotely by a HHC (using telemedicine if deemed necessary by the Investigator).  
Other routine safety assessments will be performed at the last visit (Visit 27).  
Study assessments including clinical laboratory tests, spot urine collections, physical 
examination findings, vital signs, ECGs, trough PK sampling, and monitoring of AEs will be 
performed at the timepoints presented in the Schedule of Procedures (Table 3).  Serious AEs 
(SAEs) will be recorded from the time the subject signs the Informed Consent Form (ICF) until 
exit from the study.  All other AEs will be recorded from the start of the Titration Period until 
exit from the study.   
 
Randomization and Blinding 
The study will not be randomized and will be an open-label study. 
 
Study Treatments and Assessments 
3.3.1 Study Duration  
The total study duration will be up to approximately 73 weeks (16.8 months).  Note that the 
study may be interrupted at any time if safety issues compromise the safety of the subjects.   
3.3.2 Study Drug and Administration 
The investigational product, lixivaptan capsule, is formulated as a white hard gelatin capsule 
with a clear band (without markings) containing 50 mg of lixivaptan. 
The study drug (lixivaptan capsule) is intended to be taken orally, i.e., to be swallowed whole 
with water. The capsule should NOT be opened.   
During all treatment periods, study drug will be administered BID, with the PM dose 
administered approximately 10 hours after the AM dose. During the Lixivaptan Titration 
Period, 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 
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(PM) dose by 50 mg (from 150 mg to 100 mg and from 200 mg to 150 mg) if aquaretic effects 
are limiting subjects’ tolerability at either the 150 mg BID or 200 mg BID dose levels, 
respectively.  Titration will stop when a tolerable dose level is reached that achieves the goal 
of lowering trough (first AM) fasting spot urine specific gravity to ≤1.005 (as a point-of-care 
surrogate for Urine Osmolality (Uosm)) or the highest dose (Level 4 or 4a) is achieved 
(regardless of trough urine osmolality).  Subjects tolerating the drug at Level 2, 3, and 3a, but 
not achieving the urine specific gravity goal may be allowed to continue in the study after 
consultation with the medical monitor and sponsor. 
Table 1: Dosing Levels during the Lixivaptan Titration Period 
Dose Level 
AM Dose 
PM Dose* 
1† 
50 mg (1 capsule) 
50 mg (1 capsule) 
2 
100 mg (2 capsules) 
100 mg (2 capsules) 
3 
150 mg (3 capsules) 
150 mg (3 capsules) 
3a‡ 
150 mg (3 capsules) 
100 mg (2 capsules) 
4 
200 mg (4 capsules) 
200 mg (4 capsules) 
4a# 
200 mg (4 capsules) 
150 mg (3 capsules) 
*PM dose to be administered approximately 10 hours after the AM dose. 
†Dose Level 1 is only for initiation of treatment. 
‡Subjects having difficulty with aquaretic effects at Dose Level 3 can drop back to 150 mg in the AM 
and 100 mg in the PM (Dose Level 3a: 150/100 mg). 
#Subjects having difficulty with aquaretic effects at 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 and reduced trough urine specific gravity (or tolerability and maximum dose) 
are achieved, subjects will stay on that dose for 1 additional week to confirm tolerability (except 
when the dose is reduced to Level 3a or Level 4a after 2 weeks of dosing at Level 3 or Level 4, 
respectively, when a single final week at the lower dose level is sufficient; see Table 2).  The 
most common dosing scenarios that can be advanced to the Maintenance Period are shown in 
Table 2.  With concurrence of the medical monitor and the sponsor, some subjects may be 
allowed to enter the Maintenance Period at a lower dose (but not less than 100 mg BID) if 
tolerability is an issue after trying a higher dose (regardless of specific gravity result at the lower 
dose): 
Follow the flowchart in Figure 2 to determine whether to increase the dose, decrease the dose, 
advance the subject to Visit 11 procedures to initiate the Maintenance Period, or discontinue 
the subject. 
 
 
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Table 2: Dosing Diagram in the Lixivaptan Titration Period 
Dose Level 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
2 
50 mg 
BID 
100 mg 
BID 
100 mg 
BID 
 
 
 
3 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
150 mg 
BID 
 
 
3a 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
150/100 mg 
(AM/PM) 
150/100 mg 
(AM/PM) 
 
3a [*] 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
150 mg 
BID 
150/100 mg 
(AM/PM) 
4 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
200 mg 
BID 
200 mg 
BID 
 
4a 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
200 mg 
BID 
200/150 mg 
(AM/PM) 
200/150 mg 
(AM/PM) 
4a [**] 
50 mg 
BID 
100 mg 
BID 
150 mg 
BID 
200 mg 
BID 
200 mg 
BID 
200/150 mg 
(AM/PM) 
[*] when 2nd week of Level 3 (150 mg BID) is not tolerated 
[**] when 2nd week of Level 4 (200 mg BID) is not tolerated 
Subjects who tolerate their optimized dose will then enter the Maintenance Period during which 
time they will continue at the lixivaptan dose level achieved at the end of the Titration Period.  
During the Maintenance Period, the dose may be adjusted downward at the Investigator’s 
discretion if needed to manage non-hepatic side effects and may also be increased back to the 
dose achieved at the end of the Titration Period.  The Investigator may instruct the subject to 
hold the study drug for up to 7 days, if necessary, to manage acute intercurrent illness, 
tolerability issues, surgical procedures or life situations, e.g., airplane travel, etc.  Additionally, 
subjects who have a longer interruption due to illness, including COVID-19, or other reasons 
may be able to re-start study drug when medically stable after discussion with the medical 
monitor and sponsor.  Temporary or permanent study drug discontinuation for management of 
abnormal liver chemistry test results is allowed. 
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in Table 3.  
 
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Figure 2: Titration Flowchart  
 
 
 
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Table 3: Schedule of Procedures 
Assessment 
Screening 
 (1-8 weeks) 
 
Baseline 
(Weekly ± 3 
days) 
(3 weeks) 
Titration Period 
(Weekly ± 3 days) 
(Up to 6 weeks) 
 
Maintenance Period 
(every 28 days ± 3 days) 
for 52 weeks 
Follow-up 
Period 
 (4 weeks after 
last doseb) 
Visit Number 
V1  
V2a
 
V3, 4, 5 
V6 
V7 
V8 
V9 
V10 
V11 
V12-V23 
V24 
V25, 26, 27 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history/Prior meds 
X 
X 
 
 
 
 
 
 
 
 
 
 
Review 
eligibility 
(Inclusion/Exclusion) 
X 
X 
V5 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
V5 
 
 
 
 
 
 
V17 
X 
V27 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
V27 
Physical examinationd 
X 
 
 
 
 
 
 
 
 
V17 
X 
V27 
Body weight/heighte 
X 
X 
V5 
X 
X 
X 
X 
X 
X 
 
X 
 
Pregnancy test (WOCBP)f 
X 
 
V5 
 
 
 
 
 
X 
V14,17,20 
X 
V27 
Chemistry/Serology samplesg 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Chemistry Panel 
X 
(X) 
V5 
 
 
 
 
 
X 
V14,17,20 
X 
V27 
Liver Chemistry Panel 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
V27 
Serum Creatinine 
 
 
V3, 4 
 
 
 
 
 
 
 
 
V25, 26 
HBsAg, Anti-HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
 
V5 
 
 
 
 
 
X 
V17 
X 
V27 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
V27 
Urine 
specific 
gravity/ 
osmolalityi 
 
 
V5 
X 
X 
X 
X 
X 
 
 
X 
V27 
Trough PK samplej 
 
 
V5 
 
 
 
 
 
X 
(X) 
(X) 
 
DNA samplek 
 
 
V5 
 
Dosing review/Tolerability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug dispensation 
 
 
V5 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug reconciliation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
IRT entry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsl 
<--------------------------------------------------------------------------------------------------------------------------------------------------------------> 
Assess for liver dysfunction 
 
<--------------------------------------------------------------------------------------------> 
V25 
Concomitant medications 
<-------------------------------------------------------------------------------------------------------------------------------------------------------------> 
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NOTES:  
• 
V24 also serves as the Early Termination (ET) visit.  
• 
Remote visits (if available) may occur at V2 (with telemedicine), V3, V4, V6 – V11 (each with telemedicine), V12, V13, and V14 (with telemedicine), V15, V16, V18, V19, and 
V20 (with telemedicine), V21, V22, V23, V25 and V26. Any remote visit may have a telemedicine component added if needed.  With permission from the medical monitor and 
sponsor, other visits may be done remotely on a case-by-case extraordinary basis. 
a V2 should be scheduled as follows: 1 week after V1 for subjects whose anti-hypertensive medications in the absence of diuretics are documented to have been stable for 
at least 3 weeks prior to V1; 3 weeks after V1 in subjects whose stability of anti-hypertensive medications in the absence of diuretics is unknown or not documented.  
However, in subjects who have an adjustment to anti-hypertensive medications or discontinuation of diuretics, V2 should be scheduled once the regimen is stable for 3 
weeks, but no longer than 8 weeks after V1. 
b During the Follow-up Period, 3 visits should be scheduled over 4 weeks. Visit 25 cannot occur earlier than the 8th day (+3) after the last dose of study drug (V24). Visit 
26 will occur 7-14 ±3 days after V25. Visit 27 is the last visit in this study and will occur 28±3 days after the last dose of study drug (V24). 
c Vital signs after the subject has been sitting for 5 minutes include heart rate, blood pressure, respiratory rate, and temperature at V1. At all subsequent visits include 
sitting heart rate and sitting blood pressure.  
d A full physical examination will be performed at V1 and V24/ET. A brief physical examination will be performed at V17 and V27. Additional physical examinations 
will be performed only for assessment of signs or symptoms reported by the subject that might require further evaluation. 
e Height will only be measured at V1. 
f Serum pregnancy test for WOCBP will be obtained at V1. Subsequently, urine pregnancy tests will be performed at V5, V11/Last Titration, V14, V17, V20, V24/ET 
and V27. All positive urine results will be confirmed by a serum pregnancy test. 
g  Chemistry blood samples and calculations: 
 
• Complete Chemistry Panel will be obtained at V1, V5, V11/Last Titration, V14, V17, V20, V24/ET, V27. If a subject required adjustment of blood pressure 
medications during Screening, then a repeat Complete Chemistry Panel will be performed at V2. 
 
• Liver Chemistry Panel will be obtained at V1, V3-V24/ET, and V27. If a subject requires adjustment of blood pressure medications during Screening, then a repeat 
Liver Chemistry Panel will be performed at V2. 
 
• Serum creatinine will be obtained at V3, V4, V25 and V26.  
 
• eGFR will be calculated and reported whenever serum creatinine is obtained either as part of the Complete Chemistry Panel or when serum creatinine alone is measured.  
 
• Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (Anti-HCV) will be obtained at V1 only. 
h Hematology blood samples will be obtained at V1, V5, V11/Last Titration, V17, V24/ET, and V27. 
i First morning, fasting urine specific gravity and osmolality (AM trough) will be obtained at V5, at every visit during the Lixivaptan Titration Period (except V11/Last 
Titration) and at V24 and V27.  Dispense container and review instructions (including not to take study drug on the morning of the next visit) with subject at V4-V9, 
V23, and V26. 
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j Trough (7-10 AM prior to AM dose) plasma specimens for measurement of lixivaptan will be obtained at V5, at the final visit during the Titration Period (V11/Last 
Titration), and during the Maintenance Period if ALT levels >3 x ULN and/or total bilirubin >2 x ULN occur.  
k Utilizing a separate informed consent, all subjects will be asked to provide a DNA sample at the end of the Baseline Period (V5) to assess genetic variants associated 
with hepatic abnormalities (if and when feasible). 
l 
Serious adverse events (SAEs) will be collected throughout the study beginning with signing of informed consent.  All non-serious adverse events will be collected 
beginning at the start of the Titration Period. Adverse Events of Special Interest (AESI) include hepatic events and pregnancy and will be reported on special forms using 
the SAE pathway of reporting.
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4 
STUDY ENDPOINTS 
 
Primary Endpoint 
The primary endpoint is to assess the proportion of subjects who develop alanine 
aminotransferase (ALT) levels >3 x Upper Limit of Normal (ULN) during the Titration or 
Maintenance Periods that were assessed by the independent Hepatic Events Review Committee 
(HERC) to be at least probably related to lixivaptan and resulted in discontinuation of the study 
drug. 
 
Secondary Endpoints 
4.2.1 Safety Endpoints  
• Proportion of subjects who develop ALT levels >5 x ULN during the Titration or 
Maintenance Periods that were assessed by the independent HERC to be at least probably 
related to lixivaptan and resulted in discontinuation of the study drug. 
• Proportion of subjects who develop ALT levels >3 x ULN during the Titration or 
Maintenance Periods that were assessed by the HERC to be at least probably related to 
lixivaptan and resulted in dose reduction of the study drug. 
• The safety and tolerability of lixivaptan assessed through evaluation of AEs, clinical 
laboratory findings (clinical chemistry including additional analyses of liver chemistry 
tests, hematology and urinalysis), vital signs, and 12-lead ECG. 
4.2.2 Efficacy Endpoint 
• Change in eGFR from baseline (mean of 3 eGFR determinations obtained during 
Screening and Baseline Periods) to final assessment (mean of 3 eGFR determinations 
obtained during the Follow-up Period). 
 
Exploratory Endpoints 
• Correlation of abnormal liver chemistry test results to plasma levels of lixivaptan. 
• Assessment of genetic variants (if and when feasible) to understand potential genetic risk 
factors for hepatic abnormalities. 
5 
SAMPLE SIZE AND POWER 
Up to 50 subjects will be enrolled.  This is based on a similar study conducted with ambrisentan 
in subjects who had previous liver chemistry test abnormalities on other endothelin receptor 
antagonists for the treatment of pulmonary arterial hypertension. 
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6 
ANALYSIS POPULATIONS 
 
Enrolled Population  
The Enrolled Population is defined as all who meet inclusion/exclusion criteria during screening 
period and complete Visit 3. All general summaries, except safety and efficacy analyses are 
based on the Enrolled population, unless specified otherwise.  
 
Safety Population  
The Safety Population is a subset of the Enrolled Population defined as those enrolled subjects 
who received at least 1 dose of lixivaptan.  This population will be utilized for all safety analyses.  
 
Efficacy Population 
The Efficacy Population is a subset of the Safety Population defined as those subjects who have 
at least 1 eGFR determination during the Baseline Period and have at least 1 eGFR determination 
during the Follow-up Period. This population will be used for efficacy analyses.  
 
Pharmacokinetic (PK) Population 
The Pharmacokinetic (PK) Population is a subset of the Safety Population defined as those 
subjects who had at least 1 on-therapy evaluable PK measurement.  
 
Pharmacodynamic (PD) Population 
The Pharmacodynamic (PD) Population is a subset of the Enrolled Population defined as those 
subjects who have at least 1 set of urine specific gravity and urine osmolality measurements 
from the same specimen.  
 
Protocol deviations/violations and exclusions from analysis sets 
A protocol deviation is defined as an unintended or unanticipated departure from the procedures 
or processes approved by the Sponsor and the Institutional Review Board (IRB) and agreed to 
by the Investigator. A major deviation occurs when there is not adherence to the protocol by the 
subject or Investigator that results in a significant, additional risk to the subject.   
Major deviations can include the following but not limited to: 
• Not adhering to inclusion or exclusion criteria 
• Enrollment of the subject without prior Sponsor approval 
• Not adhering to Food and Drug Administration (FDA) regulations or ICH Good Clinical 
Practice (GCP) guidelines 
• Subjects not ≥ 80% compliant with the prescribed study drug doses during the study  
Protocol deviations will be identified and reviewed by the project team prior to database lock. 
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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
 
Derived General Variables 
The below table (Table 4) provide the list of derived variables for demographic and baseline 
characteristics, various duration derivations, drug compliance, baseline derivations and other 
important derivations applicable for this study. 
Table 4: Derived Variables 
Variables 
Formula 
Demographic characteristics 
Age at informed 
consent (in years) 
Age = year of informed consent – year of birth   
BMI (kg/m2) 
weight (kg)/[height (m)]^2 
Derivation of Duration 
Study Duration 
(Days) 
(Date of Last Visit – Date of informed consent) + 1 
Study day at any visit 
Date of interest – date of first dose of study drug. One day is 
added if this difference is ≥ 0 
Adverse event 
duration (in days) 
Event end date - Event onset date + 1. 
Duration of Exposure 
Duration of Exposure 
(days) in Titration 
Period 
(Date of last administration of study drug – Date of first 
administration of study drug) +1, during the 6 week titration period 
Duration of Exposure 
(days) in 
Maintenance Period 
(Date of last administration of study drug – Date of first 
administration of study drug) +1, during the 52 week maintenance 
period 
Treatment Compliance 
Treatment 
Compliance  
(Total No. of capsules dispensed – Total No. of capsules 
returned)*50/total assigned dose*100 
where, total assigned dose will be derived by sum of (AM+PM 
dose)*duration of this dose level for all different dosing levels 
eGFR Baseline and Final Assessment Derivation (Appendix I) 
Baseline eGFR 
Mean of 3 eGFR assessments (Visit 3, Visit 4 & Visit 5) obtained 
during the baseline period 
Final Assessment 
eGFR 
Mean of 3 eGFR assessments (Visit 25, Visit 26 & Visit 27) 
obtained during the follow-up period 
Baseline Derivations 
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Baseline  
Latest non-missing measurement prior to first dose of study drug 
administration  
Change from baseline Test Value at Post baseline value – Baseline Value 
Geometric Coefficient of Variation (CV%) for Pharmacokinetic data 
Geometric CV% 
CV (%) =100×√exp(σ̂2) −1, where σ̂2 denotes the variance of 
the natural log-transformed values. 
 
Handling of Missing Data 
7.2.1 Handling of Missing or Partial Dates 
7.2.1.1 Imputation rules for missing or partial AE start date: 
If only Day of AE start date is missing:  
If the AE start year and month are the same as that for the first dose date (date of titration visit 
6), then: 
• If the full (or  partial) AE end date is NOT before the first dose date (date of titration 
visit 6) or AE end date is missing, then impute the AE start day as the day of first dose 
date (titration visit 6); otherwise, impute the AE start day as 1. 
• Otherwise, impute the AE start day as 1. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year (year of titration visit 6), then: 
• If the full (or partial) AE end date is NOT before the first dose date (date of titration visit 
6) or AE end date is missing, then impute the AE start Month and Day as the Month and 
Day of first dose date (date of titration visit 6); otherwise, impute the AE start Month as 
January and the Day as 1. 
• Otherwise, impute the AE start MONTH as January and the DAY as 1. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with no 
imputation. Also compare the full (or partial) AE end date to the first dose date (date of titration 
visit 6). If the AE end date is before the first dose date (date of titration visit 6) then the AE 
should be considered as a pre-treatment AE. Otherwise, the AE will be considered as TEAE. 
Compare the imputed AE start date with the treatment-emergent period to determine whether 
the AE is pre-treatment AE, TEAE (Treatment Emergent Adverse Event) or post-treatment AE. 
7.2.1.2 Imputation rules for missing or partial medication start/stop dates: 
Missing or partial medication start date: 
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• If only DAY is missing, use the first day of the month.  
• If DAY and Month are both missing, use the first day of the year.  
• If DAY, Month and Year are all missing, use a date before the first dose date (date of 
titration visit 6). 
Missing or partial medication stop date: 
• If only DAY is missing, use the last day of the month. 
• If DAY and Month are both missing, use the last day of the year. 
If DAY, Month and year are all missing, assign ‘continuing’ status to stop date 
7.2.2 Handling of Missing Efficacy or Safety Data 
If any values of baseline or follow-up eGFR values are missing (i.e. for instance if only two 
measurements are available then the mean of two measurements will be considered and if in 
case more than two values are missing the last available measurement will be considered), the 
remaining available values will be used to determine the baseline or follow-up eGFR. 
Unscheduled visit values will not be considered for eGFR calculation. 
No imputation will be done for any of the safety/PK/PD data. 
8 
STATISTICAL METHODS 
 
General Statistical Conventions 
All statistical procedures will be completed using SAS Grid version 9.4 or higher.  
Unscheduled visit results will be included in date/time chronological order, within subject 
listings only. Unscheduled visit shall not be summarized in tables. 
Categorical variables will be summarized using number (n) and percentage in each category 
including missing category if any.  All percentages will be rounded to one digit after decimal 
point. The number and percentage will be presented in the form XX (XX.X %), where the 
percentage is in the parentheses. If the percentage of a category is “100”, then display it as “100” 
(do not add decimal after 100). 95% confidence intervals will be presented along with frequency 
counts and percentages for primary and secondary safety endpoints. 
Continuous variables will be summarized using number of subjects (n), number of missing 
subjects, mean, median, standard deviation (SD), minimum, and maximum for continuous 
variables. All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal places than 
the measured value. The minimum and maximum will be displayed to the same number of 
decimal places as the original data. For pharmacokinetic data, geometric mean (with one decimal 
than the measured value) and geometric CV % (with 1 decimal place) will be presented 
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additionally.  
All general summaries will be presented by Overall, having all the subjects, unless otherwise 
specified. For safety assessments, the summaries will be presented by titration and maintenance 
combined, follow-up and overall, unless otherwise specified. 
All subject data will be presented in individual subject data listings. All listings will be sorted 
for presentation in order of dose level if applicable, subject number (including site ID), date/time 
and visit. The dose level as well as subject’s sex, age and race will be stated on each listing. In 
general, no imputed dates or values will be presented in listings unless specified. 
 
Subject Disposition 
The following categories will be summarized only for “Overall” Column. The summary is based 
on all subjects. 
• No. of subjects screened  
• No. of subjects who screen failed 
• No. of subjects who re-screened 
• No. of subjects who complete visit 3 during baseline period (Enrolled Population) 
• No. of baseline failure subjects 
• No. of subjects who completed the baseline period 
The following categories will be summarized overall. The summary is based on Enrolled 
population. 
• No. of subjects who completed study 
• No. of subjects who discontinued from study 
• Primary reason for study discontinuation 
• No. of subjects who completed treatment 
• No. of subjects who discontinued from treatment 
• Primary reason for treatment discontinuation 
• No. of subjects who entered titration period 
• No. of subjects who completed treatment during titration period  
• No. of subjects who discontinued treatment during titration period  
• No. of subjects who entered maintenance period 
• No. of subjects who completed treatment during maintenance period 
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• No. of subjects who discontinued treatment during maintenance period 
In addition, number of subjects in the safety population who completed or discontinued during 
titration and maintenance period will be summarized by last dose level assigned during the 
specified period. 
A listing of subject disposition will be provided for all subjects, with the extent of their 
participation in the study and the reason for discontinuation from study or treatment.  
Additionally, a listing of inclusion/exclusion criteria will be presented for all subjects. 
 
Protocol Deviations 
A summary of subjects excluded from safety population, efficacy population, pharmacokinetic 
and pharmacodynamic populations will be presented by enrolled population. 
A summary of major (key) protocol deviations will be presented for Enrolled population. All 
protocol deviations will be listed.  
 
Demographics and Baseline Characteristics 
Subject characteristics and demographics will be summarized for the Enrolled population. The 
summary will include descriptive statistics such as the number of subjects (n), mean, SD, median, 
minimum (min), and maximum (max) for continuous measures and frequency counts and 
percentages for categorical measures. No formal statistical comparisons will be made among 
dose levels. 
The following demographics will be summarized: Age (years), Height (cm), Weight (kg), Body 
Mass Index (BMI) (kg/m2), Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), 
Sex, Child bearing potential for female population, Race (Primary, Secondary and subcategory) 
and Ethnicity. 
Baseline disease characteristics include: 
• Baseline eGFR 
• Baseline AST or ALT levels  
• Baseline Total Bilirubin levels  
• History of ADPKD 
Above summary of demographics and baseline characteristics will be repeated for safety and 
efficacy populations if any subject in the Enrolled population was excluded from these two 
populations. 
A listing including demographic and baseline characteristics will be presented separately by 
subject for all subjects. 
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8.4.1 Medical History 
A summary of medical history by medical history code (as per the case report form (CRF)) will 
be presented by system organ class (SOC) and preferred term (PT) using Medical Dictionary 
for Regulatory Affairs® (MedDRA) Version 23.0 or higher will be presented for the safety 
population.  
A by subject listing including medical history will be presented for all subjects. 
8.4.2 Prior and Concomitant Medications 
Subject’s CRF captured all medications within 1 month prior to study drug administration. 
However, additional medications specified in Exclusion Criteria 7, 8, and 9 in protocol Section 
4.1.2 will also be recorded within the prior 3 months.   
Prior medications are defined as medications where dosing ended prior to the first dose of study 
drug administration (exclusive).  Concomitant medications are defined as medications that were 
taken between the first dose (inclusive) and last dose of study drug (inclusive). This also includes 
medications started prior and still ongoing at the start of the study drug. Details for imputing 
missing or partial start and/or stop dates of medication are described in section 7.2.1. 
Separate summaries showing the number and percentage of subjects who took prior or 
concomitant medications will be presented by Anatomical Therapeutic Chemical (ATC) coding 
scheme of the World Health Organisation Drug Dictionary (WHO Drug) Global B3 March 2019 
version or later on Level 2 term and preferred term for the Safety population.  
A listing of prior/concomitant medications will be presented for all subjects. Prohibited 
medications/therapies if any will be highlighted by marking asterisk symbol (*) in the ATC 
column of the table and listing.  
8.4.3 Concomitant Procedures 
The Concomitant Procedures during the study will be coded using MedDRA Version 23.0 or 
higher.  A by-subject listing including details of concomitant procedures will be presented for 
all subjects. 
 
Treatment Exposure and Compliance 
8.5.1 Study Treatment Exposure 
Total dose and duration of exposure for study drug (section 7.1) for titration period (period of 6 
weeks) and maintenance period (period of 52 weeks), will be summarized using descriptive 
statistics by titration and maintenance period based on safety population.  
A by subject listing of exposure will be presented based for the safety population.  
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8.5.2 Treatment Compliance 
Treatment Compliance will be derived using the formula below: 
(𝑇𝑜𝑡𝑎𝑙 𝑁𝑜.  𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑇𝑜𝑡𝑎𝑙 𝑁𝑜. 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑) × 50
𝑇𝑜𝑡𝑎𝑙 𝑎𝑠𝑠𝑖𝑔𝑛𝑒𝑑 𝑑𝑜𝑠𝑒
× 100 
Where total assigned dose (in mg) will be derived by sum of (AM+PM dose) × duration of this 
dose level for all different dosing levels.  
Study drug compliance will be summarized using standard summary statistics based on safety 
population. Study drug compliance will also be summarized in “<80%”, 80% – 120%” and 
“>120%” using frequency tables. 
A complete listing of drug accountability will be presented based for the safety population. 
8.5.3 Drug Tolerability and Modifications 
Summary of subjects with intolerable doses and dose modifications will be presented using 
frequency and percentages for each visit based on safety population.  
A complete listing of drug tolerability/modification by visits will be presented based for the 
safety population. 
 
Safety Analyses 
Safety assessments will be conducted throughout the entire study period. Analyses will be 
performed using the safety population, unless otherwise specified. All safety data will be 
summarized by period. No formal statistical hypothesis testing will be conducted.  
The safety evaluations will include primary hepatic and secondary hepatic safety analysis. 
Analyses of adverse events, clinical laboratory tests (clinical chemistry/serology, hematology, 
urinalysis, other tests, additional liver testing & other testing), vital signs, physical examination, 
12-lead electrocardiogram (ECG) and serum/urine pregnancy results will also be presented. The 
safety analyses involving changes from baseline to a specific time point in safety variables (e.g., 
laboratory parameters, vital signs, and ECG) will only include subjects from the safety 
population who have data available for both the baseline and the time point under consideration 
unless otherwise specified. 
8.6.1 Analysis of Primary Safety Endpoint 
Descriptive statistics (n and percentage) along with exact binomial 95% Confidence Interval 
(CI)) will be presented to summarize the proportion of subjects who develop ALT levels >3 x 
ULN that were assessed by the independent HERC to be related to lixivaptan and resulted in 
discontinuation of the study drug during the Titration and Maintenance Periods.  
The above summary will be presented additionally based on the investigator decision alone as 
documented in the CRF. 
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8.6.2 Analysis of Secondary Safety Endpoint 
Similarly, descriptive statistics (n and percentage) along with exact binomial 95% CI will be 
presented to summarize the following 2 secondary endpoints:  
• The proportion of subjects who develop ALT levels >5 x ULN that were assessed by the 
independent HERC to be related to lixivaptan and resulted in discontinuation of the study 
drug during the Titration and Maintenance Periods. 
• The proportion of subjects who develop ALT levels >3 x ULN that were assessed by the 
independent HERC to be related to lixivaptan and resulted in dose reduction of the study 
drug during the Titration and Maintenance Periods. 
The above summaries will be presented additionally based on the investigator decision alone as 
documented in the CRF. 
8.6.3 Analysis of Additional Hepatic Safety Endpoints 
The proportion of subjects along with the exact binomial 95% CI who develop the following 
abnormalities during the Titration and Maintenance Periods will be tabulated and presented 
descriptively: 
• >3 x, 5 x, >10 x, and 20 x ULN elevations for ALT  
• >3 x, 5 x, 10 x, and 20 x ULN elevations for Aspartate aminotransferase (AST) 
• >3 x, 5 x, 10 x, and 20 x ULN elevations for either ALT or AST 
• ALT or AST levels >2 x their baseline 
• Any elevation of total bilirubin (TBL) >2 x ULN 
• Any elevation of alkaline phosphatase (ALP) >2 x ULN 
• Elevation of aminotransferase (>3 x ULN) accompanied by elevated bilirubin (>2 x 
ULN) will be evaluated using Drug-Induced Serious Hepatotoxicity (eDISH) plots  
• Elevation of aminotransferase in temporal association with nausea, vomiting, anorexia, 
abdominal pain, or fatigue will be explored graphically using swimmer plots. 
• Possible liver-related deaths and liver-related treatment discontinuations. 
The liver dysfunction occurring during the titration and maintenance period judged using the 
Drug Induced Liver Injury Network (DILIN) (Appendix II) probability criteria independently 
by investigator and HERC will be listed separately. 
8.6.4 Analysis of Additional Potential Hepatic Safety Endpoints 
The summary of additional hepatic safety assessments will be presented based on potential 
hepatic testing (Appendix III) based on liver chemistry abnormalities. The assessments will be 
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presented tabulated using descriptive statistics or frequency and percentages based on the data 
type. These data will further be listed separately based on all subjects. 
8.6.5 Adverse Event (AE) 
All AE verbatim descriptions will be coded using the MedDRA, version 23.0 or higher.   
A 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. For this study, 
pregnancies and liver events are considered to be AESIs (Adverse Events of Special Interest).  
All AEs will be summarized by period (titration and maintenance period, follow-up period, and 
overall). 
If a subject experiences multiple AEs under the same preferred term (system organ class), then 
the subject will be counted only once for that preferred term (system organ class). If a subject 
experiences the same AE more than once with different severity, then the event with the 
maximum severity will be tabulated in “by maximum severity” tables. In addition, AEs with a 
missing intensity will be presented in the summary table as an intensity category of “Missing.”  
If a subject, experiences the same AE more than once with different relationship, then the event 
with the strongest relationship will be tabulated in “by strongest relationship” tables. TEAEs 
with a missing relationship to study medication will be regarded as “Possible” to study 
medication. Adverse events with a relationship to study drug considered possibly, probably, or 
definitely related will be considered related.    
An overview table will also be presented with the number and percentage of subjects as well as 
number of events for the following categories: 
• At least one AE 
• At least one TEAE 
• At least one Serious TEAE 
• Related TEAE 
• Related Serious TEAE 
• Any TE-AESI 
• TEAEs by maximum severity 
• TEAEs by strongest relationship to the study drug  
• TEAEs leading to dose modifications (i.e. dose reduced or dose interrupted) 
• TEAEs leading to study drug withdrawal 
• TEAEs leading to death.  
All TEAEs will be summarized as below: 
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• TEAEs by SOC and PT 
• Serious TEAEs by SOC and PT  
• Related TEAEs by SOC and PT 
• TE-AESI by SOC and PT 
• TEAEs leading to deaths by SOC and PT 
• TEAEs leading to drug modification by SOC and PT 
• TEAEs leading to study drug withdrawal by SOC and PT 
• TEAEs by SOC, PT, and severity 
• TEAEs by SOC, PT, and maximum severity  
• TEAEs by SOC, PT, and relationship  
• TEAEs by SOC, PT, and strongest relationship  
• TEAEs by PT 
• Serious TEAEs by PT 
• Related TEAEs by PT 
Adverse events will be presented in data listings including dose level, subject number, start/end 
dates/times of event, MedDRA system organ class, preferred term, duration of the event, 
seriousness, severity, action taken, relationship to study drug and outcome. 
The following by subject listings will be provided for all subjects: 
• AEs  
• Serious AEs 
• TE-AESIs 
• AEs leading to Deaths  
• AEs leading to dose modification (including interruption, reduction and discontinuation) 
8.6.6 Clinical Laboratory Evaluations 
Laboratory safety assessments include complete chemistry, hematology, liver chemistry, 
urinalysis and other tests. Additionally, assessment also includes serum creatinine, HBsAg and 
Anti-HCV. 
The specific clinical laboratory evaluations and additional live chemistry testing are as below in 
Table 4. 
 
 
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Table 4: Clinical Laboratory Evaluations 
Chemistry  
Hematology 
Urinalysis 
Albumin 
Hematocrit 
pH 
Blood urea nitrogen (urea) 
Hemoglobin 
Specific gravity 
Calcium 
Red blood cell count 
Protein 
Chloride 
Quantitative platelet count 
Glucose 
CO2 
WBC count with differential 
(total and %)  
only if WBC count is 
abnormal: 
   Neutrophils 
   Lymphocytes 
   Monocytes 
   Eosinophils 
   Basophils 
Ketones 
Creatinine 
Bilirubin 
Glucose 
Blood 
Phosphorous 
Urobilinogen 
Potassium 
Leukocytes 
Protein 
Nitrite 
Sodium 
Microscopic examination 
(if positive for blood, 
protein, nitrite, or 
leukocytes) 
Uric acid 
Liver Chemistry Panel 
Other Tests 
 
Alanine aminotransferase 
Urine specific gravity (local to 
guide titration) 
 
Alkaline phosphatase 
Urine osmolality 
 
Aspartate aminotransferase 
Urine or serum pregnancy test 
(female subjects) 
 
Bilirubin Total and Direct 
Specimen for potential DNA 
analysis 
 
Glutamate dehydrogenase 
(GLDH) 
 
 
Abbreviations: CO2 = carbon dioxide; WBC = white blood cell. 
All laboratory data will be summarized in International System of Units (SI). Quantitative 
laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), 
or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the 
purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in 
the listings.  
Descriptive statistics of absolute value and change from baseline (mean, SD, median, min, and 
max) for clinical laboratory data will be presented for each scheduled time point. For all 
continuous clinical laboratory variables, a shift table comparing the baseline value (normal, low, 
and high) to last observation on treatment will be presented.  
For categorical data, the laboratory results will be summarized using frequency and proportion 
at each scheduled time point. 
For urinalysis, a shift table comparing the baseline value to the maximum value will be presented 
(using number of subjects with results of negative, trace, or positive). 
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Shift table from baseline to worst post-baseline value according to abnormality assessed by 
investigators (normal, Clinically Significant (CS) and Not Clinically Significant (NCS)) will be 
presented for all applicable laboratory evaluations. 
Potentially clinically significant results of clinical laboratory evaluations identified using 
prospectively defined criteria (Table 5) will also be summarized descriptively. 
Table 5: 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 
Hematocrit: Decrease from baseline of ≥ 10% (absolute change) 
Urinalysis 
Glucose: ≥2+ 
RBC/HPF: >10 
Protein: >2+ 
Ketones: > 2 + 
Leukocytes: >10 
Abbreviations: RBC=Red Blood Cell; HPF=high power field. 
Individual data listings of clinical laboratory results will be presented for each subject.  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.  
Abnormal laboratory results will be listed separately by all subjects. 
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8.6.7 Vital Signs 
Vital sign assessments are performed in order to characterize basic body function. Absolute and 
changes from baseline in vital signs at each scheduled time point will be summarized using 
descriptive statistics (n, mean, SD, median, minimum, and maximum). The parameters collected 
are the following: systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate 
(beats/min), respiratory rate (breaths/min), body temperature (°C), weight (kg) and BMI (kg/m2). 
Vital signs summary will be based on safety population. 
Potentially clinically significant results of vital signs (Table 6) identified using prospectively 
defined criteria will also be summarized descriptively. 
Table 6: Potentially Clinically Important Criteria: 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% 
Vital sign assessments will be presented subject in a data listing for all subjects.  
8.6.8 Physical Examinations 
A complete physical examination will be performed during Screening Visit 1, Visit 17 and the 
final Maintenance/Early Termination Visit (Visit 24) and Follow-up period (Visit 27). Brief 
physical examination will subsequently be measured at the time points specified in study 
schedule of procedures (Table 3).  
Complete physical examinations will include 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 incidence of abnormality in physical examination will be tabulated separately for each visit 
based on the safety population. 
Abnormal physical examination will be presented for each subject in a data listing for all 
subjects.  
8.6.9 Electrocardiograms (ECG) 
Observed values and changes from baseline for continuous ECG parameters including heart rate, 
ventricular rate, PR interval, QRS duration, QT interval (uncorrected), RR interval and QT 
interval corrected for heart rate according to Fridericia’s formula (QTcF) interval will be 
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summarized over each scheduled time point in terms of absolute values using descriptive 
statistics (n, mean, SD, median, minimum, and maximum).   
Overall evaluation of ECG will be summarized using frequency counts and percentage of 
subjects 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: 
Subjects with the highest QTcF post-baseline value  
• <450 msec 
• 450-480 msec 
• ≥480 msec 
Subjects 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 dose levels and subjects for all subjects. Additionally, a listing will 
be provided for Investigator-identified ECG abnormalities.   
8.6.10 Pregnancy Test 
Serum pregnancy test for Women of childbearing potential (WOCP) will be obtained at V1. 
Subsequently, urine pregnancy tests will be performed at V5, V11/Last Titration, V14, V17, 
V20, V24/ET and V27. All positive urine results will be confirmed by a serum pregnancy test. 
Results of serum pregnancy test will be presented for each subject by dose level in a data listing 
for all female subjects. 
 
Efficacy Analyses 
The efficacy analyses will be based on the efficacy population. 
8.7.1 Analysis of Efficacy Endpoints 
8.7.1.1 Change from Baseline in eGFR 
eGFR will be calculated and reported whenever serum creatinine (Appendix I) is obtained either 
as part of the Complete Chemistry Panel or when serum creatinine alone is measured. 
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Descriptive statistics will be presented for baseline (mean of 3 determinations obtained during 
the baseline period) and final assessment (eGFR determination obtained during the follow-up 
period). Change from baseline to final assessment will also be summarized using descriptive 
statistics. 
A listing of serum creatinine including eGFR data by subject will be presented for all subjects. 
No formal statistical analysis is planned for evaluation of efficacy endpoint.  
8.7.2 Exploratory Analysis 
8.7.2.1 Relationship of Liver Chemistry Test Abnormalities to Drug Levels 
Descriptive statistics (mean, SD, CV %, median, geometric mean, geometric CV %, min and 
max,) will be presented for plasma lixivaptan trough concentrations at each scheduled time point 
for PK population.  
Any possible relationships between liver chemistry test abnormalities and trough levels of 
lixivaptan on PK population collected during the study will be explored if sufficient data exist. 
A boxplot at scheduled trough collection timepoints by liver chemistry abnormality on trough 
levels of plasma lixivaptan concentration will be generated. A scatterplot with regression line 
will be presented with X-axis as plasma trough concentration and Y-axis with liver function test 
(ALT, ALP, TBL and ALP, respectively). The individual abnormal liver function test values 
will be labeled or highlighted. In addition, an individual plot will be generated for trough level 
(Y-axis) and time after dosing (X-axis) with liver function test as second Y-axis (in x ULN for 
ALT, AST, TBL, or ALP).  
The following liver chemistry test abnormality will be assessed: 
• >3 x, 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 
• ALT or AST levels >2 x their baseline 
• TBL >2 x ULN 
• ALP >2 x ULN 
8.7.2.2 Assessment of Genetic Variants 
A descriptive summary for safety population including frequency and percentages will be 
presented by different genetic variants by associated hepatic abnormalities if in the event that 
specific genetic variants confirming increased or decreased risk to hepatic abnormalities in 
subjects with drug induced liver injury (DILI) become known during the time of the study.  
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8.7.2.3 Pharmacodynamic (PD) Assessments 
A descriptive summary based on PD population will be presented for urine specific gravity and 
urine osmolality for all protocol schedule visits. Number and percentages will be presented for 
urine specific gravity ≤ 1.005 and urine osmolality ≤ 250 for all the applicable visits in titration, 
maintenance and follow-up period. The Relationship between urine specific gravity and urine 
osmolality (Uosm) in the titration and maintenance period will be explored using Pearson's 
correlation coefficient for PD population. Scatter plots will be presented to show the strength of 
the correlation between urine specific gravity and Uosm with X-axis as urine specific gravity 
and Y-axis as Uosm. 
 
Interim Analysis 
There will be no interim analysis during this study. 
9 
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL 
This study has been early terminated by the Sponsor. Due to only 6 participants being enrolled 
into treatment maintenance period in the study and most of them being prematurely terminated 
from 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. 
Please see Appendix IV for the TLFs to be produced. 
 
10 REFERENCES 
1. ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- 
adopted December 1995). 
2. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted 
March 1998). 
3. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J; 
DILIN Study Group. 2009. Drug-Induced Liver Injury Network (DILIN) prospective 
study: rationale, design and conduct. Drug Saf. 32(1):55-68. 
 
 
 
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11 APPENDICES 
 Appendix I: Chronic Kidney Disease Classification Criteria 
This study uses the 2009 CKD-EPI creatinine equation (Levey A, which is recommended by the 
KDIGO Clinical Practice Guidelines for Management of Chronic Kidney Disease. 
The CKD-EPI equation is: 
𝑒𝐺𝐹𝑅= 141 ×  𝑚𝑖𝑛(𝑆𝑐𝑟
κ , 1)
α
× max (𝑆𝑐𝑟
κ , 1)
−1.209
× 0.993Age × 1.018 (if female)
× 1.159 (if black),   
where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and 
-0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of 
Scr or 1. 
 
 
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 Appendix II: DILI Network Causality Criteria, modified 
Causality assessment scoring in the Drug-Induced Liver Injury Network (DILIN) prospective 
study, modified (Fontana RJ et al) 
Causality score 
Likelihood 
(%) 
Description 
1 = definite 
>95 
Liver injury is typical for drug or herbal product 
(‘signature’ or pattern of injury, timing of onset, 
recovery). 
The evidence for causality is “beyond a reasonable doubt”. 
2 = highly likely 
75-95 
The evidence for causality is ‘clear and convincing’ but 
not definite. 
3 = probable 
50-74 
The causality is supported by ‘the preponderance of 
evidence’ as implicating the drug but the evidence cannot 
be considered definite or highly likely. 
4 = possible 
25-49 
The causality is not supported by ‘the preponderance of 
evidence’; however, one cannot definitely exclude the 
possibility. 
5 = unlikely 
6-24 
The evidence for causality is ‘highly unlikely’ based upon 
the available information. 
6 = unrelated 
0-5 
An alternate cause was clearly established. 
7 = insufficient data 
Not 
applicable 
Key elements of the drug exposure history, initial 
presentation, alternative diagnoses and/or diagnostic 
evaluation prevent one from determining a causality score. 
 
 
 
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 Appendix III: Additional Potential Hepatic Testing if Liver Chemistry 
Abnormalities Occur 
The medical monitor may request the following additional testing if liver chemistry test 
abnormalities occur: 
• Hematology/coagulation:  
o CBC with Diff  
o International normalized ratio (INR) 
• Clinical chemistry 
o Glutamate dehydrogenase (GLDH) 
• Viral hepatitis serology:  
o Hepatitis A immunoglobulin M (IgM) antibody  
o Hepatitis B surface antigen  
o Hepatitis B core antibody  
o Hepatitis C RNA  
o Hepatitis E IgM antibody (hepatitis E RNA, if available) 
o Epstein-Barr viral capsid antigen IgM antibody 
o Cytomegalovirus IgM antibody 
•  Autoimmune serology:  
o Total serum immunoglobulin G  
o Anti-nuclear antibody  
o Anti-smooth muscle antibody 
• Ultrasound of the liver and gallbladder 
 
 
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 Appendix IV: List of Tables, Listings, and Figures 
List of Tables, Listings, Figures 
Listing 16.2.1.1 Subject Disposition All Subjects 
Listing 16.2.2 Protocol Deviations All Subjects 
Listing 16.2.4.1 Demographic Characteristics All Subjects 
Listing 16.2.4.2.1 Baseline Characteristics - eGFR All Subjects 
Listing 16.2.4.2.2 Baseline Characteristics - ALT, AST and Total Bilirubin All Subjects 
Listing 16.2.4.3 Medical History All Subjects 
Listing 16.2.4.4 Concomitant Procedures All Subjects 
Listing 16.2.4.5 Medical History of Autosomal Dominant Polycystic Kidney Disease (ADPKD) All Subjects 
Listing 16.2.4.6 Prior and Concomitant Medications All Subjects 
Listing 16.2.5.1 Drug Accountability Safety Population 
Listing 16.2.5.2 Drug Tolerability/Modification Safety Population 
Listing 16.2.6.1 Listing of Serum Creatinine and estimated Glomerular Filtration Rate (eGFR) All Subjects 
Listing 16.2.7.1.1 Liver Dysfunction Details All Subjects 
Listing 16.2.7.1.2 Potential Hepatic Events All Subjects 
Listing 16.2.7.2 Criteria for Primary and Secondary Hepatic Safety Endpoints  All Subjects 
Listing 16.2.7.3 Adverse Events All Subjects 
Listing 16.2.8.1.1   Laboratory Test Results - Hematology  All Subjects 
Listing 16.2.8.1.2.1 Laboratory Test Results - Chemistry  All Subjects 
Listing 16.2.8.1.3   Laboratory Test Results - Liver Chemistry  All Subjects 
Listing 16.2.8.1.4 Laboratory Test Results - Urinalysis All Subjects 
Listing 16.2.8.1.6 Additional Potential Hepatic Testing  All Subjects 
Listing 16.2.9.1 Vital Signs Results  All Subjects 
Listing 16.2.10 .1  Electrocardiogram (ECG) Results  All Subjects 
Listing 16.2.12 Pregnancy Results  All Female Subject 
Table 14.1.1.1 Summary of Subject Disposition All Subjects 
Table 14.1.1.4 Summary of Protocol Deviation Enrolled Population 
Table 14.1.2.1.1 Summary of Demographic Characteristics Enrolled Population 
Table 14.1.2.2.1 Summary of Baseline Disease Characteristics Enrolled Population 
Table 14.1.5.1 Summary of Study Drug Exposure Safety Population 
Table 14.3.1.1.1 Overall Summary of Treatment Emergent Adverse Events (TEAEs) Safety Population 
Table 14.3.1.2.1 Summary of TEAEs by System Organ Class and Preferred Term Safety Population 
Table 14.3.1.2.2.1 Summary of Serious TEAEs by System Organ Class and Preferred Term  Safety Population 
Table 14.3.1.2.2.2 Summary of Non-serious TEAEs by System Organ Class and Preferred Term  Safety Population 
Table 14.3.1.2.4 Summary of Adverse Event of Special Interest by System Organ Class and Preferred Term  
Safety Population 
Table 14.3.2.1 Summary of Liver Chemistry Abnormalities Defined as Primary and Secondary Hepatic Safety 
Endpoints Safety Population 
Table 14.3.5.4 Summary of Post-Baseline QTcF Safety Population 
 
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