Conditions: Autosomal Dominant Polycystic Kidney Disease
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
This is a Phase 2, open-label, parallel-group, multiple dose study designed to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of lixivaptan in Autosomal Dominant Polycystic Kidney Disease subjects with chronic kidney disease (CKD) in stages CKD1, CKD2 or CKD3.

Detailed description:
Therapeutic interventions aimed at counterbalancing the effect of vasopressin and/or normalizing intracellular levels of cAMP may be effective in delaying disease progression in autosomal dominant polycystic kidney disease (ADPKD).

The primary objectives of this study in subjects with ADPKD are:

* To characterize the safety and tolerability of lixivaptan following multiple doses in ADPKD subjects with relatively preserved kidney function (chronic kidney disease CKD1 and CKD2) and moderately impaired renal function (CKD3).

The secondary objectives of this study are:

* To characterize the PK profile of lixivaptan and its major metabolites following multiple doses of lixivaptan in ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately impaired renal function (CKD3).
* To characterize the pharmacodynamic effect of lixivaptan on urine output, urine osmolality, total kidney volume, serum vasopressin, and serum creatinine following multiple doses of lixivaptan in ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately impaired renal function (CKD3).

Arms:
arm 1: Oral high dose lixivaptan in participants with CKD1 or CKD2 arm 2: Oral low dose lixivaptan in participants with CKD1 or CKD2 arm 3: Oral high dose lixivaptan in participants with CKD3 arm 4: Oral low dose lixivaptan in participants with CKD3

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

Protocol document:
Prot_000.pdf: 
Study Title: A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of Lixivaptan in Subjects With Autosomal 
Dominant Polycystic Kidney Disease 
ClinicalTrials.gov ID: NCT03487913 
Clinical Study Protocol Version 5.0, dated March 21, 2019 
Summary of Changes in the Conduct of the Study (from Section 9.8.1 of the Clinical Study 
Report, dated September 22, 2020 
Clinical Study Protocol Version 5.0, dated March 21, 2019, Summary of Changes 
Clinical Study Protocol Version 4.0, dated January 9, 2019, Summary of Changes 


 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of Lixivaptan in Subjects with 
Autosomal Dominant Polycystic Kidney Disease 
 
Protocol Number: PA-102 
IND Number: 136,419 
 
Sponsor: 
Palladio Biosciences, Inc. 
12 Penns Trail 
Unit A 
Newtown, PA 18940 
Sponsor Contact: 
Elaine Richardson 
Vice President, Clinical Operations 
Palladio Biosciences, Inc. 
12 Penns Trail, Unit A 
Newtown, PA 18940 
ERichardson@palladiobio.com 
  
Medical Monitor: 
Andrew Lowy, MD, FRACP 
Medical Director, IQVIA 
Direct: (984) 201-6550 (including urgent medical issues) 
Mobile: (310) 431-7666 
Fax: +1 (520) 829-9405 
Email: Andrew.Lowy@quintiles.com  
 
IQVIA 24/7 Medical Emergency Contact Center (MECC): 
(973) 659-6677;  
(512) 652-0191 (back-up) 
 
Version of Protocol:  
5   
Date of Protocol:  
March 21, 2019  


 
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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.  The study will be conducted according to 
the International Council for Harmonisation (ICH) harmonized tripartite guideline E6 (R1): 
Good Clinical Practice (GCP). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Approval - Sponsor Signature 
Protocol Title 
A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of Lixivaptan in Subjects 
with Autosomal Dominant Polycystic Kidney Disease 
Protocol Number PA-102 
Protocol Version 
5 
Protocol Date 
March 21, 2019 
 
Protocol accepted and approved by: 
Neil H. Shusterman, M.D. 
Chief Medical Officer 
Palladio Biosciences, Inc. 
12 Penns Trail, Unit A 
Newtown, PA 18940  
 
 
 
 
 
 
 
 
 
 
 
March 21, 2019 
Signature 
 
Date 
 


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Declaration of Investigator 
I have read and understood all sections of the protocol titled “A Phase 2, Open-Label, 
Multi-Center Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of 
Lixivaptan in Subjects with Autosomal Dominant Polycystic Kidney Disease” and the 
accompanying current version of the Investigator Brochure (IB). 
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 (R1): GCP, 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) 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 ...........................................................................................................5 
LIST OF TABLES .....................................................................................................................8 
PROTOCOL SYNOPSIS ...........................................................................................................9 
LIST OF ABBREVIATIONS ..................................................................................................12 
1 
INTRODUCTION ............................................................................................................15 
1.1 
Background .............................................................................................................15 
1.2 
Overview of ADPKD ..............................................................................................15 
1.3 
Overview of Available Therapies for ADPKD .......................................................16 
1.4 
Rationale for Lixivaptan Therapy for ADPKD .......................................................16 
1.5 
Summary of Nonclinical Studies ............................................................................18 
1.6 
Summary of Clinical Studies ..................................................................................18 
1.7 
Study Rationale .......................................................................................................19 
1.8 
Dose Rationale ........................................................................................................19 
2 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................20 
2.1 
Study Objectives .....................................................................................................20 
2.1.1 
Primary Objectives ..................................................................................20 
2.1.2 
Secondary Objectives ..............................................................................20 
2.2 
Study Endpoints ......................................................................................................20 
2.2.1 
Primary Endpoints ...................................................................................20 
2.2.2 
Secondary Endpoints ...............................................................................21 
3 
INVESTIGATIONAL PLAN ...........................................................................................22 
3.1 
Study Design ...........................................................................................................22 
3.1.1 
Rationale of Study Design .......................................................................23 
4 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA .........................................25 
4.1 
Selection of Study Population .................................................................................25 
4.1.1 
Inclusion Criteria .....................................................................................25 
4.1.2 
Exclusion Criteria ....................................................................................27 
4.2 
Withdrawal of Subjects from the Study ..................................................................29 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................29 
4.2.2 
Handling of Withdrawals .........................................................................30 
4.2.3 
Replacements ...........................................................................................31 


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5 
STUDY TREATMENTS ..................................................................................................32 
5.1 
Method of Assigning Subjects to Treatment Groups ..............................................32 
5.2 
Blinding and Randomization ..................................................................................32 
5.3 
Treatments Administered ........................................................................................32 
5.4 
Identity of Investigational Product..........................................................................33 
5.5 
Management of Clinical Supplies ...........................................................................33 
5.5.1 
Study Drug Packaging and Storage .........................................................33 
5.5.2 
Test Article Accountability ......................................................................34 
5.6 
Overdose Management ...........................................................................................34 
5.6.1 
Treatment of Overdose ............................................................................34 
5.7 
Treatment Compliance ............................................................................................34 
5.7.1 
Study Dosing Diary .................................................................................34 
5.8 
Prior and Concomitant Therapy ..............................................................................35 
5.8.1 
Permitted Therapy ....................................................................................35 
5.8.2 
Prohibited Therapy ..................................................................................36 
5.9 
Diet, Fluid, and Activity Control ............................................................................37 
6 
STUDY ASSESSMENTS AND PROCEDURES ............................................................39 
6.1 
Safety and Tolerability Assessments .......................................................................39 
6.1.1 
Body Height, Weight, and BMI ...............................................................39 
6.1.2 
Physical Examinations and Medical History ...........................................39 
6.1.3 
Vital Sign Measurements .........................................................................39 
6.1.4 
12-Lead Electrocardiograms ....................................................................40 
6.1.5 
Clinical Laboratory Tests .........................................................................40 
6.1.6 
MRI Assessment ......................................................................................41 
6.1.7 
Urine Osmolality and Specific Gravity ...................................................42 
6.1.8 
Questionnaire for Tolerability ..................................................................42 
6.1.9 
Adverse Events ........................................................................................43 
6.2 
Laboratory Analyses ...............................................................................................46 
6.3 
Pregnancy ................................................................................................................46 
7 
STATISTICAL AND ANALYTICAL PLAN ...................................................................47 
7.1 
Pharmacokinetic Parameters ...................................................................................47 
7.2 
Pharmacodynamic Parameters ................................................................................48 
7.3 
Safety Variables ......................................................................................................48 
7.4 
Sample Size Calculations ........................................................................................49 


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7.5 
Analysis Sets ...........................................................................................................49 
7.6 
Description of Subgroups to be Analyzed ..............................................................49 
7.7 
Statistical Analysis Methodology ...........................................................................50 
7.7.1 
Pharmacokinetic Analysis ........................................................................50 
7.7.2 
Pharmacodynamic Analyses ....................................................................50 
7.7.3 
Safety Analyses ........................................................................................51 
7.7.4 
Other Analyses .........................................................................................52 
7.8 
Data Quality Assurance...........................................................................................52 
7.8.1 
Data Management ....................................................................................53 
8 
ETHICS ............................................................................................................................54 
8.1 
Institutional Review Board .....................................................................................54 
8.2 
Ethical Conduct of the Study ..................................................................................54 
8.3 
Subject Information and Consent............................................................................54 
9 
INVESTIGATOR’S OBLIGATIONS ..............................................................................55 
9.1 
Confidentiality ........................................................................................................55 
9.2 
Financial Disclosure and Obligations .....................................................................55 
9.3 
Investigator Documentation ....................................................................................55 
9.4 
Study Conduct .........................................................................................................56 
9.5 
Adherence to Protocol.............................................................................................56 
9.6 
Adverse Events and Study Report Requirements ...................................................56 
9.7 
Investigator’s Final Report .....................................................................................56 
9.8 
Records Retention ...................................................................................................56 
9.9 
Publications .............................................................................................................57 
10 STUDY MANAGEMENT ...............................................................................................58 
10.1 Monitoring ..............................................................................................................58 
10.1.1 
Monitoring of the Study ...........................................................................58 
10.1.2 
Inspection of Records ..............................................................................58 
10.2 Management of Protocol Amendments and Deviations..........................................58 
10.2.1 
Modification of the Protocol ....................................................................58 
10.2.2 
Protocol Deviations..................................................................................58 
10.3 Study Termination ...................................................................................................59 
10.4 Final Report ............................................................................................................59 
11 REFERENCE LIST ..........................................................................................................60 


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12 APPENDICES ..................................................................................................................62 
12.1 Appendix 1: Chronic Kidney Disease Classification Criteria ................................62 
12.2 Appendix 2: Schedule of Assessments ...................................................................62 
12.3 Appendix 3: Assessment Windows .........................................................................66 
 
LIST OF TABLES 
Table 3-1 
Chronic Kidney Disease Classification Summary .......................................... 23 
Table 5-1 
Study Cohorts and Lixivaptan Dose Levels.................................................... 32 
Table 5-2 
Investigational Product ................................................................................... 33 
Table 6-1 
Clinical Laboratory Parameters ...................................................................... 41 
Table 6-2 
Guideline for Assessment of Adverse Event Causality ................................... 45 
Table 7-1 
Probability of Not Observing an Adverse Event for Various True Incidence 
Rates ................................................................................................................ 49 
Table 12-1 
Schedule of Assessments ................................................................................ 63 
Table 12-2 
Assessment Windows...................................................................................... 66 
 


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PROTOCOL SYNOPSIS 
Protocol Number: 
PA-102 
Protocol Title: 
A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of Lixivaptan in Subjects with Autosomal 
Dominant Polycystic Kidney Disease 
Sponsor: 
Palladio Biosciences 
12 Penns Trail 
Unit A 
Newtown, PA 18940 
Study Phase: 
Phase 2 
Study Sites: 
Approximately 15 sites 
Indication: 
Autosomal Dominant Polycystic Kidney Disease 
Rationale: 
Therapeutic interventions aimed at counterbalancing the effect of vasopressin may 
be effective in delaying disease progression in autosomal dominant polycystic 
kidney disease (ADPKD). 
Objectives: 
The primary objectives of this study are: 
• To characterize the safety and tolerability of lixivaptan following multiple 
doses in ADPKD subjects with relatively preserved kidney function (chronic 
kidney disease CKD1 and CKD2) and moderately impaired renal function 
(CKD3). 
• To characterize the PK profile of lixivaptan and its major metabolites (WAY-
141624, WAY-138451, and WAY-138758) following multiple doses of 
lixivaptan in ADPKD subjects with relatively preserved kidney function 
(CKD1 and CKD2) and moderately impaired renal function (CKD3). 
The secondary objectives of this study are: 
• To characterize the effect of lixivaptan on urine osmolality over a 24-hour 
period following multiple doses of lixivaptan in ADPKD subjects. 
• To characterize the time course of the hemodynamic effect of lixivaptan on 
urine output, total kidney volume, liver volume, circulating vasopressin, and 
serum creatinine in ADPKD subjects. 
Subject Population: 
The subjects will be male or female, between 18 and 65 years of age (inclusive) at 
the time of Screening, with a body mass index (BMI) between 18 and 35 kg/m2 
(inclusive) at the time of Screening.  The subjects will have an estimated glomerular 
filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 (Cohort 1 and 3), or eGFR ≥ 30 to < 60 
mL/min/1.73 m2 (Cohort 2 and 4), with eGFR calculated by the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation.  Subjects will have been 
diagnosed with ADPKD based on modified Ravine criteria. 
Study Design: 
This is a Phase 2, open-label, parallel-group, multiple dose study designed to 
evaluate the PK, PD, safety, and tolerability of multiple BID doses of 50 and 200 mg 
lixivaptan in ADPKD subjects with chronic kidney disease in stages CKD1, CKD2 
or CKD3.   


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Estimated Study 
Duration: 
Screening Duration: 42 days (Day -44 through Day -3)  
Confinement Period: Subjects will be confined from Check in (Day -2 or Day-1) 
until Day 2 in the morning. Subjects will be confined from Day 6 in the afternoon 
through Day 8 in the morning. 
Outpatient: Subjects will return to the clinical research unit (CRU) on an outpatient 
basis on Day 4 in the morning and Day 6 in the morning for a trough PK assessment. 
End of Study Visit: Subjects will return on Day 35 (±2) for end of study assessment. 
Total Study Duration: Up to 80 days 
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. 
Enrolled subjects will be assigned according to CKD classification to take one of 2 
lixivaptan oral dose regimens for 7 days as shown below.  Each dose regimen 
includes morning (AM) and evening (PM) oral administration of lixivaptan.  
Cohort 
CKD stage 
Dose 
N 
1 
CKD1 or CKD2 
200 mg BID 
8 subjects 
2 
CKD3 
200 mg BID 
8 subjects 
3 
CKD1 or CKD2 
50 mg BID 
8 subjects 
4 
CKD3 
50 mg BID 
8 subjects 
 
Doses of lixivaptan will be administered both at the CRU and at home.   
Study Assessments: 
Pharmacokinetic: The following PK parameters will be calculated using 
noncompartmental methods, whenever possible, based on lixivaptan and lixivaptan 
metabolite concentrations:  the maximum observed plasma drug concentration 
(Cmax), the time to reach maximum plasma concentration (tmax), the area under the 
concentration-time curve (AUC) from time 0 until the last quantifiable concentration 
(AUC0-t), AUC from time 0 until 14 hours postdose (AUC0-14), AUC extrapolated to 
infinity (AUC0-inf), the apparent terminal elimination rate constant (λz), the terminal 
elimination phase half-life (t1/2), total body clearance (CL/F), and the volume of 
distribution (Vz/F). 
Pharmacodynamic: The pharmacodynamic (PD) analysis will include assessments 
of urine osmolality and urine output, total kidney volume, liver volume, plasma 
copeptin and serum creatinine. 
Safety: The safety analysis will include clinical laboratory findings (hematology, 
clinical chemistry, and urinalysis), 12-lead electrocardiograms (ECGs), vital signs, 
physical examination findings, assessments of adverse events (AE) and the 
questionnaire of tolerability. 
Sample Size: 
Approximately 32 subjects (8 subjects in CKD1/2 and 8 subjects in CKD3 per dose 
level). 


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Statistical Methods: 
Pharmacokinetic: Lixivaptan and lixivaptan metabolite (WAY-141624, WAY-
138451, and WAY-138758) plasma concentrations will be tabulated and 
summarized using descriptive statistics (including sample size, arithmetic and 
geometric mean, standard deviation [SD], coefficient of variation [CV%], median, 
minimum, and maximum) for each Cohort.  The PK parameters for lixivaptan and 
lixivaptan metabolites will be summarized for each Cohort. 
Plasma concentration data for lixivaptan and lixivaptan metabolites will also be 
displayed graphically on linear and semi-logarithmic scales.  The following plots 
will be presented for the concentration-time data: 
• Individual subject plasma concentration profile versus time, stratified by 
Cohort. 
• Arithmetic-mean concentration (±SD) versus time, stratified by Cohort. 
Pharmacodynamic: The change from baseline in urine osmolality, serum 
creatinine, plasma copeptin, total kidney volume (TKV) and liver volume (LV) after 
multiple doses of lixivaptan will be summarized by renal function group (CDK1/2 
and CDK3), and at each scheduled time point using descriptive statistics (n, mean, 
SD, median, minimum, and maximum). 
Safety: Safety assessments, including clinical laboratory findings (hematology, 
clinical chemistry, and urinalysis), 12-lead electrocardiograms (ECGs), vital signs, 
physical examination findings, assessments of adverse events (AEs) and the 
questionnaire of tolerability will be analyzed descriptively. 
Date of Protocol: 
March 21, 2019 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-inf 
area under the concentration-time curve extrapolated to infinity 
AUC0-t 
area under the concentration-time curve from time 0 until the last 
quantifiable concentration 
BID 
twice per day 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
BUN 
blood urea nitrogen 
cAMP 
cyclic adenosine 3’,5’-monophosphate 
CDER 
Center for Drug Evaluation and Research 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CL/F 
total body clearance 
Cmax 
maximum observed plasma drug concentration  
CRU 
Clinical Research Unit 
CS 
clinically significant 
CT 
computerized tomography 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 


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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
I/E 
inclusion/exclusion 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LV 
liver volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
n 
number of non-missing observations 
N 
number of subjects 
NCS 
not clinically significant 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PKD 
polycystic kidney disease 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
REMS 
Risk Evaluation and Mitigation Strategy 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
Scr 
serum creatinine 
SD 
standard deviation 
SOC 
system organ class 
Sosm 
serum osmolality 
t1/2 
terminal elimination phase half-life 
TEAE 
treatment-emergent adverse event 
TKV 
total kidney volume 
tmax 
time to reach maximum plasma concentration 
ULN 
upper limit of normal 
Uosm 
urine osmolality  
US 
United States 
Vz/F 
volume of distribution 


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Abbreviation 
Definition 
Λz 
apparent terminal elimination rate constant 


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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.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).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 (HF) and syndrome of inappropriate anti-diuretic 
hormone secretion (SIADH).   
Additional background information for lixivaptan can be found in the Investigator’s 
Brochure. 
1.2 Overview of ADPKD 
Definition 
Autosomal dominant polycystic kidney disease (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 proteins PC1 (polycystin 1) and PC2 (polycystin 2), 
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.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 accompanied 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.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 function is normal.  However, in some cases the 
increased liver volume may lead to hepatomegaly as a result of the continuous cyst 
enlargement.5 This may cause symptoms of extrinsic compression, such as abdominal pain, 
early satiety, and obstruction of the hepatic veins or bile duct; and liver cyst infections cause 


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fever, right upper abdominal pain, and possible elevated CA19.9 and alkaline phosphatase 
(ALP) levels.  
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.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 response of vasopressin to sodium challenge as compared to 
normal individuals.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 
In April 2018, the vasopressin V2 receptor antagonist tolvaptan (JYNARQUE®) was 
approved in the 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 
(REMS).  
The European Medicines Agency (EMA) granted a positive opinion for the vasopressin V2 
receptor antagonist 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 (CHMP) recommended additional monitoring of the 
risk of liver damage with tolvaptan.  Similar approvals were granted in Japan, Canada, and 
Australia/New Zealand.  The US Food and Drug Administration (FDA) did not grant 
approval to tolvaptan for the treatment of ADPKD primarily due to concerns regarding liver 
safety. 
1.4 Rationale for Lixivaptan Therapy for ADPKD 
Given that elevated renal cAMP plays a pivotal role in the complex phenotypical 
manifestation of ADPKD,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,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 mozavaptan9  and 
tolvaptan10, 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 serum vasopressin concentration, are associated with 
faster disease progression.11 


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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 largest placebo-controlled Phase 3 study ever conducted in ADPKD.  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.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.14  Because complete vasopressin suppression is ensured if urinary 
osmolality is lowered to < 300 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.14 
More recently, the results of REPRISE, a second pivotal Phase 3 study with tolvaptan for the 
treatment of ADPKD, were published.15  This trial randomized 1370 patients with later stage 
ADPKD, which was defined as having a baseline estimated 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 an animal model of 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 the PCK rat model of PKD 
The PCK rat, an orthologous model of human polycystic kidney disease (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 human 
disease.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.  
Additional background information on the effect of lixivaptan in the PCK rat can be found in 
the Investigator Brochure (IB). 
Lixivaptan causes sustained suppression of urine osmolality to levels that are associated 
with therapeutic efficacy in ADPKD 


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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 and various patient populations 
(patients with hypervolemic and euvolemic hyponatremia and patients with ESRD) 
demonstrated that treatment with lixivaptan readily suppressed 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.14   
Additional background information on the effect of lixivaptan on urine osmolality can be 
found in the Investigator Brochure (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 increased urinary volume 
output about 3 to 4 times more than furosemide or hydrochlorothiazide at comparable doses 
and decreased 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 genetically crossed to produce offspring 
with no circulating serum vasopressin, and that harbor a renal cyst inducing PKD mutation, 
do not develop cysts.8  In addition, the V2 vasopressin receptor antagonists mozavaptan and 
tolvaptan can normalize renal cAMP and correct disease manifestations in rodent models of 
ADPKD.9,10  Similarly, the vasopressin V2 receptor antagonist lixivaptan reduces renal cAMP 
levels in a rodent model 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 Investigator Brochure. 
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 


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studies.  Lixivaptan was generally safe and well-tolerated in this patient population.  The 
most common adverse events (AE) were headaches, dizziness, thirst, orthostatic hypotension, 
and tachycardia events.   
Additional information regarding the clinical evaluation of lixivaptan can be found in the IB. 
Even though lixivaptan was never tested in ADPKD patients, proof of concept for the 
potential utility of lixivaptan for the treatment of ADPKD is provided by the vasopressin V2 
receptor antagonist tolvaptan.  Results from the TEMPO 3:4 Phase 3 trial led to approval in 
Europe for the use of tolvaptan to slow the progression of cyst development and renal 
insufficiency of ADPKD in adults with CKD stage 1 to 3.  The TEMPO 3:4 trial showed that 
tolvaptan slowed the progression of kidney enlargement and delayed the worsening of kidney 
function.12  The study also established suppression of urine osmolality to < 300 mOsm/kg as 
a predictive pharmacodynamic marker of clinical efficacy for a vasopressin V2 antagonist for 
the treatment of ADPKD.  More recently, the REPRISE Phase 3 study with tolvaptan 
demonstrated that the efficacy of vasopressin V2 receptor antagonism is maintained in 
patients with later stage ADPKD.15   
1.7 Study Rationale 
This study is being conducted to directly characterize the pharmacokinetic (PK), safety, and 
pharmacodynamic (PD) profiles of lixivaptan following administration of twice per day 
(BID) oral doses of 50 and 200 mg for 7 days in subjects with both autosomal dominant 
polycystic kidney disease (ADPKD) and chronic kidney disease (CKD) stage 1 (CKD1), 
stage 2 (CKD2) or stage 3 (CKD3).  These proposed PK, safety, and PD assessments will be 
used to guide appropriate lixivaptan dosing recommendations for subjects with ADPKD and 
mild or moderate CKD. 
1.8 Dose Rationale 
The human equivalent exposure range of lixivaptan proposed by this study has been shown to 
be safe and tolerated in nonclinical animal studies and previous clinical studies conducted in 
healthy subjects and in subjects with hyponatremia of various etiologies.   
As noted above, the selected doses are based on expected effect on urine osmolality. These 
doses were considered appropriate for the PK/PD evaluation of lixivaptan in subjects with 
ADPKD and mild or moderate CKD. 


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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 characterize the safety and tolerability of lixivaptan following multiple doses in 
ADPKD subjects with relatively preserved kidney function (CKD1 and CKD2) and 
moderately impaired renal function (CKD3); and 
• To characterize the PK profile of lixivaptan and its major metabolites (WAY-141624, 
WAY-138451, and WAY-138758) following multiple doses of lixivaptan in ADPKD 
subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately 
impaired renal function (CKD3). 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
• To characterize the effect of lixivaptan on urine osmolality over a 24-hour period 
following multiple doses of lixivaptan in ADPKD subjects; and 
• To characterize the time course of the pharmacodynamic effect of lixivaptan on urine 
output, total kidney volume, liver volume, plasma copeptin and serum creatinine in 
ADPKD subjects.  
2.2 Study Endpoints 
2.2.1 Primary Endpoints 
• The following PK parameters will be calculated using noncompartmental methods, 
whenever possible, based on the plasma concentrations of lixivaptan and its major 
metabolites (WAY-141624, WAY-138451, and WAY-138758), for lixivaptan and each 
metabolite:  maximum observed plasma drug concentration (Cmax), time to reach 
maximum plasma concentration (tmax), area under the plasma concentration-time 
curve (AUC) from time 0 until the last quantifiable concentration (AUC0-t), AUC 
extrapolated to infinity (AUC0-inf), terminal elimination phase half-life (t1/2), apparent 
terminal elimination rate constant (λz), total body clearance (CL/F; lixivaptan only), 
and volume of distribution (Vz/F; lixivaptan only). 
• The safety and tolerability of lixivaptan will be assessed through evaluation of 
physical examination findings, vital signs, 12-lead electrocardiograms (ECG), clinical 
laboratory findings (clinical chemistry, hematology and urinalysis), assessments of 
adverse events (AE) and a questionnaire assessing aquaretic tolerability (symptom 
burden of nocturia, urgency, frequency). 


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2.2.2 Secondary Endpoints 
The effect of lixivaptan on urine osmolality by lixivaptan will be determined through 
evaluation of: 
• Spot urine osmolality and 24h urine output. 
The pharmacodynamic effects of lixivaptan will be determined through evaluation of: 
• Serum creatinine, blood urea nitrogen (BUN), and estimated glomerular filtration rate 
(eGFR); 
• Total kidney volume (TKV) and liver volume (LV) measured by abdominal magnetic 
resonance imaging (MRI); and 
• Plasma copeptin, as a marker for circulating vasopressin. 


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3 INVESTIGATIONAL PLAN 
3.1 Study Design 
This is a Phase 2, open-label, parallel-group, multiple dose study designed to evaluate the 
PK, PD, safety, and tolerability of multiple BID doses of 50 and 200 mg lixivaptan in 
ADPKD subjects with chronic kidney disease in stages CKD1, CKD2 or CKD3.  The study 
will be conducted at multiple Clinical Research Units (CRUs) in the United States (US). 
For all subjects, this study includes a Screening period of 42 days (Day -44 through Day -3), 
i.e. up to 44 days prior to dosing on Day 1.  Subjects will be confined to the CRU on two 
separate occasions, with a total period of confinement of up to 7 days and 5 nights.  The first 
confinement period will last up to 4 days (up to 3 nights).  Subjects will be admitted to the 
CRU in the afternoon of Day -2 or, depending on travel arrangements, in the morning of Day 
-1, and will be domiciled until discharge from the CRU in the morning of Day 2.  The second 
confinement period will last 3 days (2 nights).  Subjects will return to the CRU to be 
admitted in the afternoon of Day 6 and will be discharged from the CRU in the morning of 
Day 8.  Alternatively, subjects may be offered the option to remain admitted to the CRU for 
the entire duration of the dosing period, i.e. from the initial admission on Day -2 (or Day -1 
where applicable) until discharge on Day 8.   
Except for the AM and PM doses on Days 1, 6, and 7, and the AM doses on Days 2, 4 and 6, 
all other doses will be self-administered by the subject.  Subjects will be required to record 
self-administered doses in a Study Dosing Diary (Section 5.7.1). 
Enrolled subjects will be assigned according to CKD classification to take one of 2 dose 
regimens (Table 5-1) for 7 days.  Each dose regimen includes morning (AM) and evening 
(PM) oral administration of lixivaptan.  Doses will be administered with approximately 10 
hours separation between the AM and PM doses as follows.  When subjects are confined to 
the CRU, the PM dose will be administered 10 ± 0.25 hours after the AM dose.  When 
lixivaptan is self-administered, the PM dose will be administered 10 ± 1.0 hours after the AM 
dose.  Subjects will maintain adequate hydration throughout the study by adhering to a 
predetermined daily fluid intake regimen (Section 5.9).  
To be enrolled, subjects must meet the following diagnostic criteria for ADPKD (modified 
Pei-Ravine criteria): 
• For subjects with family history of ADPKD, a minimum of 3 cysts per kidney by 
sonography or 5 cysts by computerized tomography (CT) or magnetic resonance 
imaging (MRI); or 
• For subjects without family history of ADPKD, a minimum of 10 cysts per kidney by 
any radiologic method and exclusion of other cystic kidney diseases. 
Subjects may be enrolled if they meet the modified Pei-Ravine criteria, have a confirmed 
CKD Classification of CKD1, CKD2 or CKD3 (Table 3-1 and see Appendix 1), and meet the 
other inclusion/exclusion (I/E) criteria (Section 4.1).   


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Table 3-1 
Chronic Kidney Disease Classification Summary 
CKD Classification 
Cohorts 
N 
eGFR* 
 
 
 
 
CKD1 or CKD2** 
1 and 3 
16 (8 per cohort) 
eGFR ≥ 60 mL/min/1.73 m2 
 
 
 
 
CKD3 
2 and 4 
16 (8 per cohort) 
eGFR ≥ 30 to < 60 mL/min/1.73 m2 
 
 
 
 
Abbreviations: CKD = chronic kidney disease, eGFR = estimated glomerular filtration rate, 
N = number of subjects. 
*eGFR is calculated by the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(Appendix 1).  
**At least 2 subjects with CKD1 or CKD2 will be included in 8 subjects assigned to Cohorts 1 and 3. 
Subjects may be allowed to re-screen or have repeat testing after agreement between the 
investigator and medical monitor.  Lab tests that need to be repeated during Screening may 
be obtained through the services of an at-home nursing service provided by the Sponsor. 
Subjects who withdraw early from the study may be replaced at the discretion of the 
Investigator and of the Sponsor to ensure that approximately 32 subjects (8 subjects in 
CKD1/2 and 8 subjects in CKD3 per dose level, see Table 5-1) complete the study. 
Study assessments including PK blood sampling, urine collection, PD blood sampling, 
physical examination findings, vital signs, ECGs, clinical laboratory tests, and monitoring of 
AEs will be performed at the timepoints presented in Table 12-1.  Adverse events and serious 
AEs (SAE) that are related to study participation (e.g., protocol-mandated intervention) will 
be recorded from the time the subject signs the Informed Consent Form (ICF) until the start 
of lixivaptan dosing.  All other AEs and SAEs will be recorded from the start of lixivaptan 
dosing until exit from the study.  Assessment windows are presented in Table 12-2. 
3.1.1 Rationale of Study Design 
The I/E criteria in Section 4.1 were chosen to recruit an adequate number of subjects 
representative of the ADPKD population to achieve the study’s primary objectives as 
presented in Section 2.1.1.   
Based on existing clinical evidence with lixivaptan and the related vasopressin antagonist 
tolvaptan, the PK and PD properties of lixivaptan are not expected to differ in ADPKD 
subjects with CKD1 and CKD2 stages, therefore these subjects with relatively preserved 
kidney function will be combined into one study group.  This approach decreases the total 
number of subjects that need to be recruited without compromising the study objectives.  
Conversely, subjects with moderately impaired renal function (CKD3 stage) may show 
distinct PK and PD responses to lixivaptan and will be enrolled into a separate group. 
The PK profile of lixivaptan and its metabolites will be monitored for 3-5 half-lives after the 
last dose to define terminal PK parameters.  Therefore, PK blood draws are included up to 96 
hours, i.e. approximately 4 half-lives of the longest-lived metabolite of lixivaptan, after the 
last dose of lixivaptan (Day 7 PM).   


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Treatment with lixivaptan is associated with transient and reversible increases in serum 
creatinine and circulating vasopressin.  In addition, based on clinical evidence with the 
related vasopressin antagonist tolvaptan,12 lixivaptan may be associated with transient and 
reversible decreases in Total Kidney Volume (TKV).  In order to characterize the time course 
and magnitude of these pharmacodynamic effects of lixivaptan in ADPKD subjects, the study 
design includes measurements of serum creatinine, plasma copeptin as a marker for 
circulating vasopressin, and TKV at three time points: at baseline, after completion of the 
scheduled treatment period and 4 weeks after the last dose of lixivaptan.   
The sample size of 32 subjects in total, with 16 subjects per Cohort, is typical for this type of 
study and is considered adequate to meet the study objectives. 


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4 SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1 Selection of Study Population 
Approximately 32 subjects will be enrolled at approximately 15 sites (or more as necessary 
to recruit subjects) in the US.  Subjects will be assigned to study treatment only if they meet 
all of the inclusion criteria and none of the exclusion criteria. 
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. Capable of understanding the written informed consent, provides signed and 
witnessed written informed consent, and agrees to comply with protocol requirements 
and study-related procedures. 
2. Male or female, between 18 and 65 years of age (inclusive) at the time of Screening. 
3. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) at the time of 
Screening. 
4. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 (Cohort 1 and 3), 
or eGFR ≥ 30 to < 60 mL/min/1.73 m2 (Cohort 2 and 4), with eGFR calculated by the 
CKD-EPI equation (Section 12.1). 
5. Subject has been diagnosed with ADPKD by modified Ravine criteria: 
• For subjects with family history of ADPKD, a minimum of 3 cysts per kidney by 
sonography or 5 cysts by CT or MRI; or 
• For subjects without family history of ADPKD, a minimum of 10 cysts per 
kidney by any radiologic method and exclusion of other cystic kidney diseases.   
To verify the cyst count, medical records may be used in association with the 
Screening visit.  Alternatively, in the absence of sonography or radiography evidence 
from medical records, subjects may be included at the discretion of the Investigator 
until a modified Ravine diagnosis can be confirmed through the baseline MRI 
assessment (see section 6.1.6).   
6. Considered by the Investigator to be in good health relative to underlying CKD status 
and clinically stable with respect to underlying CKD, based on medical evaluation 
that includes medical and surgical history, as well as a complete physical examination 
including vital signs, ECG, and laboratory test results.  A single repeat assessment is 
permitted for any laboratory, ECG, or vital sign parameter required for enrollment. 
7. Female subjects must: 
• be non-pregnant and non-lactating; 


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• be either postmenopausal (defined as amenorrhea for ≥ 12 months and, if 
confirmation is necessary based on Investigator discretion, a confirmed follicle 
stimulating hormone [FSH] ≥ 40 mIU/mL), surgically sterile (defined as having 
undergone hysterectomy and/or bilateral oophorectomy), practice total 
abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence 
is not acceptable), or agree to use an appropriate method of birth control 
consistently throughout the study and continue to use this method for 30 days 
after study drug administration. 
Double barrier methods of non-hormonal contraception are permitted in this 
study.  Acceptable forms of contraception include the following: 
 intrauterine device, including Mirena® 
 female condom with spermicide (cream, spray, gel, suppository, contraceptive 
sponge, or polymer film) 
 diaphragm with spermicide (with or without a condom) 
 cervical cap with spermicide (with or without a condom) 
 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) 
 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 
Estrogen-based hormonal contraception is not permitted in this pharmacokinetic 
study due to the potential for interaction with lixivaptan.   
8. Male subjects who are sexually active with a partner of child-bearing potential must 
either be sterile (vasectomy with history of a negative sperm count following the 
procedure); practice total abstinence from sexual intercourse as the preferred lifestyle 
(periodic abstinence is not acceptable); use a male condom with any sexual activity; 
or agree to use a birth control method considered to be appropriate by the Investigator 
(such as hormonal contraception or one of the methods identified above for female 
subjects of childbearing potential) from the time of Screening until 90 days after 
study drug administration.  Male subjects must agree not to donate sperm for a period 
of 90 days after study drug administration. 
9. Patients who are smokers will be allowed to smoke ≤ 10 cigarettes per day during the 
study. 
10. Subjects must be willing to be confined to the CRU for the entire duration required by 
the protocol, able to comply with all study-related requirements and able to adhere to 
study restrictions and visit schedules. 


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4.1.2 Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not eligible for study enrollment. 
1. Subjects with known sensitivity or idiosyncratic reaction to any compound present in 
lixivaptan, its related compounds such as benzazepines (e.g., tolvaptan, conivaptan, 
benazepril, fenoldopam, or mirtazapine), or any compound listed as being present in 
the study formulation.  
2. Women who are pregnant or breast feeding. 
3. Subjects who have taken any investigational drug or used an investigational device 
within 30 days or 5 half-lives, whichever is longer, prior to Day 1. 
4. Subjects who have taken tolvaptan, conivaptan, somatostatin analogs (e.g. lanreotide, 
pasireotide, octreotide, etc.), mTOR kinase inhibitors (e.g. everolimus, sirolimus, etc.), 
or oral or intravenous antibiotics within 30 days or 5 half-lives, whichever is longer, 
prior to Day 1. 
5. Subjects will be allowed to take their chronic medications unless excluded by the 
protocol (Section 5.8.2) and provided that their chronic medication therapy meets the 
conditions outlined in Section 5.8.1, including remaining constant throughout the 
duration of the study.  
6. Subjects who have taken, or are expected to be taking, strong or moderate CYP3A4 or 
CYP2C8 inhibitors (e.g. aprepitant, boceprevir, clarithromycin, chloramphenicol (not 
eye drops), cimetidine, ciprofloxacin, clopidogrel, clotrimazole (if used orally), 
cobicistat and cobicistat-containing products, crizotinib, cyclosporine, danazol, 
deferasirox, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, 
gemfibrozil, HIV protease inhibitors, imatinib, isoniazid, itraconazole, josamycin, 
ketoconazole, nefazodone, posaconazole, quinupristin/dalfopristin, ritonavir and 
ritonavir-containing products, telaprevir, teriflunomide, tofisopam, troleandomycin, 
verapamil, voriconazole) within 14 days or 5 half-lives, whichever is longer, of 
dosing;  or weak CYP3A4 or CYP2C8 inhibitors (e.g.chlorzoxazone, cilostazol, 
fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, tacrolimus, 
ticagrelor, trimethoprim) within 7 days or 5 half-lives, whichever is longer, from 
dosing.  For weak CYP3A4 or CYP2C8 inhibitors, medications may be allowed in 
consultation with the Medical Monitor (MM). 
7. Subjects who have taken, or are expected to be taking, strong or moderate CYP3A4 or 
CYP2C8 inducers (e.g. barbiturates, bosentan, carbamazepine, efavirenz, 
enzalutamide, etravirine, modafinil, mitotane, nevirapine, oxcarbazepine, phenytoin, 
pioglitazone, rifabutin, rifampin, St. John’s wort) within 14 days or 5 half-lives, 
whichever is longer, of dosing; or weak CYP3A4 or CYP2C8 inducers (e.g. 
armodafinil, rufinamide) within 7 days or 5 half-lives, whichever is longer, from 
dosing.  For weak CYP3A4 or CYP2C8 inducers, medications may be allowed in 
consultation with the Medical Monitor (MM). 
8. Subject who have a transplanted kidney, or absence of a kidney. 


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9. Subjects with a history of clinically significant drug or alcohol abuse within the past 5 
years. 
10. Subjects with a history of testing positive for hepatitis B surface antigen (HBsAg), 
hepatitis C (HCV), or human immunodeficiency virus (HIV). 
11. Subjects who have consumed grapefruit or Seville oranges (or their juices, or foods 
containing their extract) from 7 days prior to the first dose of study medication and 
until after the final dose. 
12. Subjects with clinically significant incontinence, overactive bladder, or urinary 
retention (e.g., benign prostatic hyperplasia). 
13. Subjects with clinically significant nocturia/urgency at Screening outside of the 2 to 4 
times awakening per night expected for ADPKD patients. 
14. Subjects with clinically significant liver disease, or clinically significant liver function 
abnormalities or serology other than that expected for ADPKD with cystic liver 
disease at baseline. 
15. Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) or total bilirubin ≥ 
1.5 × upper limit of normal (ULN) at Screening.  Subjects with elevated bilirubin due 
to Gilbert’s Syndrome may be allowed at the discretion of the Investigator. 
16. Subjects with any history of significant bleeding or hemorrhagic tendencies. 
17. Subjects with contraindications to or interference with MRI assessments 
(ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, or large 
abdominal/back tattoos) will be excused from this procedure, but may participate in the 
study providing that all other eligibility criteria are met.  Investigator should seek MRI 
safety guidance from the local MRI facility.  
18. Subjects who have experienced an illness that is considered by the Investigator to be 
clinically significant within 2 weeks of study drug administration on Day 1. 
19. Subjects with a history of difficulty in donating blood, or who have donated or lost a 
significant volume (> 450 mL) of blood within 56 days, or plasma within 7 days, prior 
to Day -1. 
20. Subjects who are unable to swallow medication. 
21. Subjects who participated in strenuous exercise within 48 hours prior to Check-in 
(Day -1). 
22. Subjects with New York Heart Association Functional Class 3 or 4 heart failure.  
23. Exclusion criteria for Screening ECG (a single repeat is allowed for eligibility 
determination): 
• Sinus pauses > 3 seconds. 
• Any significant arrhythmia or conduction abnormality, which, in the opinion of 
the Investigators and Medical Monitor, could interfere with the safety for the 
individual subject. 


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• Non-sustained or sustained ventricular tachycardia, or ≥ 3 consecutive 
ventricular ectopic beats. 
24. Subjects with any clinically significant concomitant disease or condition other than 
ADPKD (including treatment for such conditions) that, in the opinion of the 
Investigator, could either interfere with the study drug or pose an unacceptable risk 
to the subject. 
25. Subjects with any other clinically significant abnormalities in laboratory test results 
at Screening that would, in the opinion of the Investigator, increase the subject's risk 
of participation, jeopardize complete participation in the study, or compromise 
interpretation of study data. 
26. Subjects who have experienced elevated AST or ALT (defined as ≥ 2.0 × ULN) while 
taking tolvaptan. 
27. Any other reason, e.g. serious mental disorders, that would render the subject 
unsuitable for study enrollment at the discretion of the Investigator. 
4.2 Withdrawal of Subjects from the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the End of Study assessment, which will be on Day 35 or the 
date of Early Termination (ET) for subjects who are withdrawn prior to the End of Study 
assessment. 
4.2.1 Reasons for Withdrawal/Discontinuation 
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.  Every effort should be made 
to keep subjects in the study and, in the case of voluntary withdrawal, to inquire as to the 
reason(s) for withdrawal.  The reasons for subjects not completing the study will be recorded. 
If a subject withdraws for any reason after having received study drug, the subject will be 
asked to complete ET procedures, which will be the same as those scheduled to be performed 
prior to discharge from the CRU on Day 8.  If a subject voluntarily withdraws before 
receiving the study drug, no additional safety assessments or testing will be required. 
A subject may be withdrawn from the study for any of the following reasons: 
1. Does not meet the protocol inclusion or exclusion criteria. 
2. Noncompliance with the protocol. 


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3. 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 or an intercurrent illness that justifies withdrawal.  Mild elevations in serum 
creatinine or serum sodium are known pharmacodynamic effects of vasopressin 
antagonists like lixivaptan and are transient and reversible.  Therefore, patients should 
not be withdrawn 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. 
4. Lost to follow-up. 
5. Other (e.g., pregnancy, development of contraindications of use of study drug). 
6. The subject withdraws consent, or the Investigator or Sponsor decide to discontinue 
the subject’s participation in the study. 
7. The Investigator will also withdraw a subject if the Sponsor terminates the study. 
Upon occurrence of a serious or intolerable AE, the Investigator will confer with the Sponsor.  
If a subject is discontinued because of an AE, the event will be followed until it is resolved or 
stable as determined by the Investigator.  Any subject may withdraw his or her consent at any 
time. 
Subject safety will be closely monitored throughout the study and the study will be 
conducted following GCP.  The entire study may be stopped at any time at the discretion of 
the Investigator in consultation with the Sponsor. 
4.2.2 Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time.  Subject 
participation in the study may be stopped at any time at the discretion of the Investigator or at 
the request of the Sponsor. 
Subjects who discontinue study treatment or active participation in the study will no longer 
receive study drug.  When a subject withdraws from the study, the reason(s) for withdrawal 
shall be recorded by the Investigator on the relevant page of the electronic case report form 
(eCRF).  Whenever possible, all subjects who discontinue study treatment or withdraw from 
the study prematurely will undergo all end-of-study assessments at the time of ET.  Subjects 
who fail to return for final assessments will be contacted by the site in an attempt to have 
them comply with the protocol.  Methods for follow up will consist of 2 documented phone 
calls followed by 1 registered letter. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or SAE.  In 
every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 


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4.2.3 Replacements 
If the Investigator withdraws a subject for a reason related to the study drug (in the opinion 
of the Investigator), then the subject is considered discontinued from the study.  Discontinued 
subjects will be replaced if deemed necessary by the Sponsor. 
If a subject does not complete the study for a reason that is unrelated to the study drug, the 
subject may be replaced if the Sponsor instructs the site to do so.  The decision regarding the 
replacement of subjects will be documented. 


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5 STUDY TREATMENTS 
5.1 Method of Assigning Subjects to Treatment Groups 
Each subject will be assigned a screening number.  Once enrolled into the study, subjects will 
be assigned a unique subject number starting with a 2 digit site number, followed by a unique 
2 digit subject number.     
Subjects who replace discontinuing subjects after the first study drug administration has 
taken place will be assigned their own unique subject number and same cohort assignment as 
the subject being replaced.  
5.2 Blinding and Randomization 
This is an open-label study and no blinding procedures will be used.  Following enrollment, 
subjects will be centrally assigned to one of 4 cohorts depending on CKD status (Table 5-1) 
and based on a predetermined algorithm.  The 200 mg BID dose cohorts will be enrolled 
first.  At least 2 males or females will be included in the 8 subjects (i.e., can be up to a 
25%/75% split of male/female or 75%/25% split of male/female) assigned to each cohort. 
Similarly, at least 2 subjects with CKD1 or CKD2 will be included in 8 subjects each 
assigned to Cohorts 1 and 3. 
5.3 Treatments Administered 
Subjects assigned to one of the 2 dose levels of lixivaptan (Table 5-1) will receive oral 
lixivaptan BID (AM and PM) from Day 1 through Day 7.  The PM dose will be administered 
approximately 10 hours after the AM dose. 
Table 5-1 
Study Cohorts and Lixivaptan Dose Levels 
Cohort 
CKD stage 
Dose* 
N 
 
1 
CKD1 or CKD2 
200 mg BID 
8 subjects 
Candidate 
maximum tolerated 
dose 
2 
CKD3 
200 mg BID 
8 subjects 
3 
CKD1 or CKD2 
50 mg BID 
8 subjects 
Candidate lowest 
effective dose 
4 
CKD3 
50 mg BID 
8 subjects 
*PM dose to be administered approximately 10 hours after the AM dose 
Prior to the morning doses on Days 1 and 7, subjects will fast overnight for ≥ 8 hours prior to 
study medication administration.  Water will be allowed ad libitum during the overnight 
fasting.  Liquids (other than water) are considered part of the ≥ 8 hour overnight fast. 
In the morning of Days 1 and 7, subjects will receive lixivaptan with room temperature water 
(approximately 240 mL [8 ounces]) and will remain fasted for 2 hours after dosing.  Water 


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will be allowed ad libitum during the 2 hours fasting, however subjects will be required to 
abstain from consuming other liquids until 2 hours after dosing.   
The evening doses on Days 1 and 7 will be administered in the CRU under fasting 
conditions, i.e. 2 hours before and 2 hours after meals.  Liquids (other than water) are 
considered part of the 2 hour fast. 
Study drug will be administered orally to subjects.  Administration of each dose of study drug 
while the subject is confined at the CRU will be supervised, verified, and documented 
according to the CRU’s standard operating procedures.  A mouth and hand check will be 
performed immediately after study drug administration. 
The actual date and time of each dose administration will be entered in the eCRF. 
When not confined to the CRU, subjects will self-administer lixivaptan with water 
(approximately 240 mL) and without fasting.  Subjects will continue to adhere to the 
recommended fluid intake regimen outlined in Section 5.9. 
5.4 Identity of Investigational Product 
The Sponsor will provide adequate supplies of lixivaptan for use during the study as shown 
in Table 5-2. 
Table 5-2 
Investigational Product 
 
Lixivaptan 
Strength 
50 mg 
Formulation 
Capsules 
Batch Number 
B17121A1 
Supplier/ 
manufacturer 
Palladio Biosciences 
12 Penns Trail, Unit A 
Newtown, PA 18940 
PMRS, Inc. 
202 Precision Road  
Horsham, PA 19044 
 
5.5 Management of Clinical Supplies 
5.5.1 Study Drug Packaging and Storage 
Lixivaptan 50 mg capsules are packaged in HDPE bottles with desiccant.  Each bottle 
contains thirty 50 mg capsules and is labeled with protocol number and necessary regulatory 
statements.  
All investigational drug supplies should be stored in a secure, locked area under the 
responsibility of the Investigator or other authorized individual.  Lixivaptan 50 mg capsules 
must be stored under refrigerated conditions between 2-8°C (36-46°F) in tightly closed 
containers and protected from extreme conditions of temperature, light and humidity. While 
subjects are confined to the CRU, doses of lixivaptan will be prepared and dispensed by the 
Investigator or a qualified designee.  When subjects are not confined to the CRU, they should 


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be instructed to store study drug in its original packaging under refrigerated conditions until 
ready to take. 
Unused study medication dispensed to and returned by a study subject should be stored under 
refrigerated conditions until returned to the Sponsor or designee or destroyed according to 
applicable regulations. 
5.5.2 Test Article 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 test article is dispensed 
and used by each subject in the study.  Reasons for departure from the expected dispensing 
regimen must also be recorded.  At the completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all unused study drugs will be reconciled and 
retained, returned to the Sponsor or designee, or destroyed according to applicable 
regulations. 
5.6 Overdose Management 
An overdose is any dose of study treatment 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. 
5.6.1 Treatment of Overdose 
In the event of suspected overdose, the appropriate supportive clinical care should be 
instituted at the discretion of the Investigator or as dictated by the subject’s clinical status. 
5.7 Treatment Compliance 
When subjects are confined at the CRU, each dose of study drug will be administered by the 
Investigator or qualified designee.  A hand and mouth check will be performed immediately 
after each study drug administration to verify that the study drug was swallowed.  The 
determination of plasma concentrations of lixivaptan during the analytical phase will provide 
further confirmation of treatment compliance. 
Subjects will maintain a diary of outpatient administration of lixivaptan as described below.   
5.7.1 Study Dosing Diary 
Subjects will maintain a Study Dosing Diary for the duration of the outpatient treatment 
period (Day 2 to Day 6) and during the week immediately following the last dose of 
lixivaptan (PM dose on Day 7).  Subjects will be asked to record in the Study Dosing Diary 
each self-administered dose of lixivaptan, including date and time of dose and number of 
capsules taken, any subject-reported AEs and any other medications taken, including over-
the-counter medications. 


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Subjects will be asked to bring the Study Dosing Diary together with their unused study 
product at each scheduled visit to the CRU. 
Information from the diary will be entered into the eCRF. 
5.8 Prior and Concomitant Therapy 
Use of all prior medications within 1 month prior to study drug administration will be 
recorded in the subject’s eCRF.  The minimum requirement is that drug name and the dates 
of administration are recorded.  This will include all prescription drugs, herbal products, 
vitamins, minerals, and 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 and the potential for masking symptoms of a more significant underlying event 
(Section 5.8.1).  The Investigator is responsible for ensuring that details regarding 
concomitant medication use are recorded in the eCRF.  For each concomitant medication 
administered after admission to the CRU on Day -2 or Day -1, as the case may be, the 
following details will be documented and recorded in the subject’s eCRF: name of 
medication, dose administered, date 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 OTC medications) without consulting the Investigator. 
5.8.1 Permitted Therapy 
Allowed medications include those typically prescribed to treat ADPKD, CKD and their 
complications, with the exception of tolvaptan.  These include angiotensin II receptor 
blockers (e.g., valsartan, candesartan, telmisartan, irbesartan) and angiotensin-converting 
enzyme inhibitors (e.g., enalapril, lisinopril).   
Acetaminophen, at doses ≤ 1 g per day, is permitted for use any time during the study in 
subjects who usually take acetaminophen to control episodic pain.  Higher daily doses of 
acetaminophen may be allowed on a case-by-case basis upon the Investigator’s discretion 
and only in consultation with the Medical Monitor.  The use of acetaminophen at any dose is 
not permitted in subjects who cannot recall taking acetaminophen at least once in the prior 12 
months.   
Non-sedating antihistamines (other than loratadine) and decongestants may be 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 5.8.2), on a case-by-case 
basis upon the Investigator’s discretion in consultation with the Medical Monitor.  All 
medications should be stable for 1 month prior to dosing, allowing for minor adjustments per 
the standard of care to treat medical conditions and avoiding, whenever possible, adjustments 
that will significantly impact serum creatinine levels.  The stability of certain drugs, such as 
insulin and warfarin, should be based on the standard of care rather than on a stable dose.   


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Lixivaptan has the potential to inhibit the metabolism of CYP3A4 and CYP2C8 substrates, 
including atorvastatin, simvastatin, and amlodipine. Therefore, care should be exercised 
when administering lixivaptan in combination with these substrates.  In order to minimize the 
potential for AEs due to drug-drug interactions, prior to enrollment in the study, the 
Investigator, in consultation with the Medical Monitor, should consider potential dose 
adjustments or alternative therapeutic options that are not CYP3A4 or CYP2C8 substrates 
(e.g. rosuvastatin to replace simvastatin or atorvastatin) or that have a high therapeutic index.  
If subjects are receiving simvastatin as background medication and it is not possible to 
replace simvastatin with rosuvastatin, the dose of simvastatin should be decreased to < 20 mg 
daily in subjects who are administered the 50 mg BID dose of lixivaptan and < 10 mg daily 
in subjects who are administered the 200 mg BID dose of lixivaptan.  If amlodipine is needed 
for clinical care, the dose should not exceed 5 mg daily. 
5.8.2 Prohibited Therapy 
Appropriate medications may need to be administered at the discretion of the Investigator as 
described in Section 5.8 and Section 5.8.1 if required for proper care of the patient.  
However, subjects must abstain from taking certain prescription and non-prescription drugs 
or supplements during the period prior to Day 1, and until after the final assessment on 
Day 35.   
The following medications are strictly prohibited for all subjects within 30 days prior to 
study drug administration on Day 1 (or 5 half-lives, whichever is longer) and until after the 
final assessments on Day 35: 
• Treatment with tolvaptan or conivaptan; 
• Treatment with any investigational drug or device; 
• Treatment with somatostatin analogs (e.g. lanreotide, pasireotide, octreotide, etc.); 
• Treatment with mTOR kinase inhibitors (e.g. everolimus, sirolimus, etc.); 
• Treatment with diuretics. 
Hormonal contraception is not permitted for female subjects of child-bearing potential. 
The following medications are strictly prohibited for all subjects within 14 days prior to 
study drug administration on Day 1 (or 5 half-lives, whichever is longer) and until after the 
final PK assessment: 
• Treatment with strong or moderate CYP3A4 or CYP2C8 inhibitors, including 
aprepitant, boceprevir, clarithromycin, chloramphenicol (not eye drops), cimetidine, 
ciprofloxacin, clopidogrel, clotrimazole (if used orally), cobicistat and cobicistat-
containing products, crizotinib, cyclosporine, danazol, deferasirox, diltiazem, 
dronedarone, erythromycin, fluconazole, fluvoxamine, gemfibrozil, HIV protease 
inhibitors, imatinib, isoniazid, itraconazole, josamycin, ketoconazole, nefazodone, 
posaconazole, quinupristin/dalfopristin, ritonavir and ritonavir-containing products, 
telaprevir, teriflunomide, tofisopam, troleandomycin, verapamil, voriconazole; 
• Treatment with strong or moderate CYP3A4 or CYP2C8 inducers, including 
barbiturates, bosentan, carbamazepine, efavirenz, enzalutamide, etravirine, modafinil, 


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mitotane, nevirapine, oxcarbazepine, phenytoin, pioglitazone, rifabutin, rifampin, St. 
John’s wort. 
The following medications are prohibited for all subjects within 7 days prior to study drug 
administration on Day 1 (or 5 half-lives, whichever is longer) and until after the final PK 
assessment: 
• Treatment with weak CYP3A4 or CYP2C8 inhibitors, including, chlorzoxazone, 
cilostazol, fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, 
tacrolimus, ticagrelor, trimethoprim.  For weak CYP3A4 or CYP2C8 inhibitors, 
medications may be allowed in consultation with the Medical Monitor; 
• Treatment with weak CYP3A4 or CYP2C8 inducers, including armodafinil and 
rufinamide.  For weak CYP3A4 or CYP2C8 inducers, medications may be allowed in 
consultation with the Medical Monitor. 
The use of CYP3A4 or CYP2C8 substrates is not prohibited, however care should be 
exercised when administering lixivaptan in combination with these substrates (Section 5.8.1) 
due to the potential for drug-drug interactions.  
5.9 Diet, Fluid, and Activity Control 
During confinement at the CRU, subjects will receive standardized meals (breakfast, lunch, 
dinner, and snack) at scheduled times that do not conflict with other study-related activities.  
Meals or snacks may be provided to subjects per the Investigator’s discretion.  Patients will 
be advised to maintain their normal diet upon discharge from the CRU. 
During Days -2 and -1 of CRU confinement, subjects should continue consuming their usual 
amount of fluids.  Due to the expected aquaretic effects of lixivaptan, subjects should be 
reminded to maintain adequate fluid intake and be mindful of their thirst status at each study 
visit starting with Day 1 of CRU confinement.  Subjects should be instructed to replenish 
fluids with each void and aim to drink 4-5 liters of fluid per day, or as needed to maintain 
adequate hydration, while taking lixivaptan.  Additionally, subjects will be instructed to drink 
1-2 glasses of fluid before bedtime, regardless of perceived thirst, and replenish fluids 
overnight with each episode of nocturia.  During CRU confinement, water consumption will 
be freely available to all subjects and daily fluid intake will be recorded.  Fluid intake will 
not be recorded outside of the CRU.  The Investigator will assess ongoing fluid needs (e.g., 
by monitoring daily body weight, urine output, laboratory testing, etc.) as necessary in order 
to maintain adequate hydration of the subject throughout the study.  Special care must be 
taken if subjects are at an increased risk of water loss, e.g. in case of vomiting or diarrhea.  
Patients will refrain from consumption of grapefruit or Seville oranges (or their juices) from 
7 days prior to the first dose of study medication until after the final PK assessment.  
Consumption of caffeinated beverages (coffee, tea, sodas, etc.) will be permitted during the 
study, however subjects must be advised to limit their consumption to two caffeinated drinks 
(12-16 fl. oz. each) per day.  Energy drinks with caffeine are prohibited. 
Patients will be advised not to consume alcohol from 72 hours before admission to the CRU 
on Day -1 or Day -2, as the case may be, until discharge from the CRU on Day 8, and for 72 
hours before the final end of study assessment. 


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Subjects will refrain from strenuous exercise from 48 hours prior to Check-in (Day -1) and 
during the study through the final end of study assessment. 
Patients who are smokers will be allowed to smoke ≤ 10 cigarettes per day during the study. 


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6 STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study procedures, all potential subjects will sign an ICF.  Subjects 
will have the opportunity to have any questions answered before signing the ICF.  The 
Investigator must address all questions raised by the subject. 
The study assessments to be performed at each visit and timepoint are specified in the study 
schedule of assessments (Table 12-1).  Assessment windows are presented in Table 12-2. 
6.1 Safety and Tolerability Assessments 
The safety and tolerability of lixivaptan will be assessed by evaluation of AEs, physical 
examinations, vital sign measurements, ECGs, clinical laboratory parameters (hematology, 
clinical chemistry including liver function tests, and urinalysis), and the questionnaire for 
tolerability.  Additional safety assessments may be performed as needed at the discretion of 
the Investigator.  Safety assessments will be performed at scheduled intervals from Day -2 
through the end of study assessment as presented in the study schedule of assessments  
(Table 12-1).  Assessment windows are presented in Table 12-2. 
6.1.1 Body Height, Weight, and BMI 
Body height (centimeters) and weight (kilograms) will be measured to the nearest tenth, and 
BMI will be calculated (BMI [kg/m2] = body weight [kg] / height2 [m2]).  Assessment 
windows are presented in Table 12-2. 
6.1.2 Physical Examinations and Medical History 
Complete physical examinations will include, at a minimum, 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.  A licensed physician or qualified designee will 
conduct the examinations. 
Brief physical examinations include, at a minimum, assessment of the following systems: 
skin, head, eyes, and throat, chest and heart auscultation, abdominal examination, neurologic 
condition (i.e., alert and oriented x3; not including cranial nerves), and edema and hydration 
assessment.  A licensed physician or qualified designee will conduct the examinations. 
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. 
Medical history and demographic data, including initials, sex, age, race, and ethnicity will be 
recorded at the timepoints specified in the study schedule of assessments (Table 12-1). 
6.1.3 Vital Sign Measurements 
Vital sign measurements will include systolic blood pressure, diastolic blood pressure, pulse 
rate, respiration rate, and body temperature and will be performed at the timepoints specified 


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in the study schedule of assessments (Table 12-1).  Assessment windows are presented in 
Table 12-2. 
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 
using an automated sphygmomanometer.  A confirmatory repeat vital sign measurement may 
be performed at the discretion of the Investigator.  If other procedures are scheduled at the 
same timepoint, vital signs will be obtained first, before an ECG and/or blood draw. 
6.1.4 12-Lead Electrocardiograms 
Electrocardiogram parameters of heart rate, ventricular rate, PR interval, QRS duration, QT 
interval (uncorrected), and QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF) will be performed at the timepoints specified in the study schedule of 
assessments (Table 12-1).  Assessment windows are presented in Table 12-2. 
Electrocardiograms will be obtained with the subject remaining in a supine or semi-
recumbent position following 5 minutes of rest.  All electrocardiograms throughout the study 
for a given subject should be measured in the same position, i.e. either all in a supine position 
or all in a semi-recumbent position.  If other procedures are scheduled at the same timepoint, 
the ECG should be obtained after vital sign measurements and/or before the scheduled blood 
draw.   
For all subjects, ECGs will be reviewed, signed, and dated by the Investigator or a qualified 
designee.  The ECGs will be classified as being one of three categories:  normal, abnormal 
but not clinically significant (NCS), or abnormal and CS.  All CS findings will be reported as 
AEs. 
6.1.5 Clinical Laboratory Tests 
Blood and urine specimens will be collected for the clinical laboratory (hematology, clinical 
chemistry, and urinalysis), pregnancy tests (all female subjects) and FSH tests (if necessary 
for postmenopausal female subjects) at the timepoints specified in the study schedule of 
assessments (Table 12-1).  A confirmatory assessment should be obtained as soon as possible 
for any clinically significant abnormal laboratory parameter.  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.   
Assessment windows are presented in Table 12-2.  Clinical laboratory parameters for analysis 
are presented in Table 6-1. 


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Table 6-1 
Clinical Laboratory Parameters 
Chemistry Panel 
Hematology 
Urinalysis 
Alanine aminotransferase* 
Hematocrit 
pH 
Albumin 
Hemoglobin 
Specific gravity 
Alkaline phosphatase* 
Red blood cell count 
Protein 
Aspartate aminotransferase* 
Quantitative platelet count 
Glucose 
Bilirubin Total and Direct* 
White blood cell count 
Ketones 
Blood urea nitrogen 
  with differential (total and %): 
Bilirubin 
Calcium 
  Neutrophils 
Blood 
Chloride 
  Lymphocytes 
Nitrite 
CO2 
  Monocytes 
Urobilinogen 
Creatinine 
  Eosinophils 
Leukocyte esterase 
Gamma-glutamyl transferase* 
  Basophils 
Microscopic examination (if  
Glucose 
 
  positive blood, nitrite,  
Phosphorous 
Other Tests 
  leukocyte esterase, or protein) 
Potassium 
Urine or serum pregnancy test  
Urea 
Protein 
  (female subjects) 
Creatinine 
Sodium 
FSH (if necessary for  
Sodium 
Urea 
  postmenopausal female subjects) 
 
Uric acid 
 
 
Abbreviations: CO2 = carbon dioxide; FSH = follicle-stimulating hormone. 
*Liver function testing 
6.1.6 MRI Assessment 
In order to investigate lixivaptan’s pharmacodynamic effect on kidney and liver volume, 
patients will undergo a standardized abdominal MRI assessment without use of intravenous 
contrast for the determination of combined renal volume of both kidneys (total kidney 
volume or TKV) and liver volume (LV) at 3 timepoints as specified in Table 12-1:  
1) at baseline (any time from Screening until CRU admission);   
2) immediately after completion of the 7-day treatment period (Day 8 or 9); and  
3) at the final End of Study assessment (Day 35 ± 2).   
Given the importance of performing the second MRI assessment within a short time interval 
after the last dose of study medication (PM dose on Day 7), it is recommended that all MRI 
assessments be scheduled for each subject at the time of the Screening visit.  Assessment 
windows are presented in Table 12-2.   
Occasionally, patients may be unable to continue into the study after completing their 
Screening visit and baseline MRI assessment (for example, due to changed personal 
circumstances or for not meeting laboratory inclusion criteria).  These patients may 
subsequently qualify for the study and be rescreened at a later time.  In this case, their prior 
baseline MRI assessment may be used instead of obtaining a new baseline MRI scan; 


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provided, however, that no more than 8 weeks have elapsed from the time of the initial MRI 
assessment until admission into the CRU.    
The MRI acquisition protocol will be detailed in the study imaging manual.  MRI images will 
be sent to a central reading facility for quality control and measurement of TKV and LV.  
Depending on technical feasibility, combined renal cyst volume (total cyst volume of both 
kidneys) and combined renal parenchyma volume (total parenchyma volume of both 
kidneys) may be determined for a subset of subjects at a later date. 
In the absence of sonography or radiography evidence at the time of the Screening visit, the 
baseline MRI assessment could be used to confirm a subject’s diagnosis of ADPKD 
according to modified Ravine criteria. 
Subjects with ferro-magnetic prostheses, aneurysm clips, severe claustrophobia or other 
contraindications or exclusions interfering with MRI measurements will be excused from this 
procedure, but may participate in the study providing that all other eligibility criteria are met.  
Investigator should seek MRI safety guidance from local MRI facility.  
6.1.7 Urine Osmolality and Specific Gravity 
Spot urine collections will be obtained at the timepoints specified in the study schedule of 
assessments (Table 12-1).  Subjects will be asked to completely empty their bladders 15 
minutes prior to each scheduled spot urine collection, after which each subject will have 30 
minutes to provide a spot urine specimen for the determination of urine osmolality and 
specific gravity.  The goal is to provide a spot urine sample within 30 minutes.  Subjects who 
will not be able provide a sample within the initial 30 minutes after voiding will be given an 
additional 30 minutes to do so and the different sampling time will be recorded.   
Spot urine samples will be used to construct the time course of urine osmolality and specific 
gravity upon dosing.  Urine osmolality measurements will be performed at the central 
laboratory, whereas the determination of urine specific gravity will be performed in the CRU 
in two manners: using dipsticks provided by the Sponsor and using existing CRU equipment, 
where available. 
6.1.8 Questionnaire for Tolerability 
A questionnaire will be provided in the study reference manual that will assess how well 
patients tolerate aquaresis-associated events due to the planned lixivaptan doses.  The 
questionnaire will be completed at 2 timepoints as specified in the study schedule of 
assessments (Table 12-1). 
6.1.8.1 Sample Collections 
Instructions regarding the collection, processing, and shipment of laboratory samples is 
detailed in a separate laboratory manual.  All samples will be given a unique identifier.  The 
exact clock time of dosing, as well as actual sample collection date and time will be entered 
on the eCRF. 


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Blood samples for the PK analysis of lixivaptan will be collected at the timepoints specified 
in the study schedule of assessments (Table 12-1).  Assessment windows are presented in 
Table 12-2. 
6.1.9 Adverse Events 
6.1.9.1 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 6.1.9.2 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. 
6.1.9.2 Eliciting and Documenting Adverse Events and Serious Adverse 
Events 
AEs and SAEs that are related to study participation (e.g., protocol-mandated intervention) 
will be recorded from the time the subject signs the ICF until the start of study treatment.  All 
other AEs and SAEs will be recorded from the start of study treatment until exit from the 
study.  Other changes in health or new symptoms occurring during the screening period will 
be recorded as medical history. 
At every study visit, subjects will be asked a standard nonleading question to elicit any 
medically related changes in their well-being.  They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject observations, AEs will be documented from any data collected that is 
deemed clinically significant by the Investigator (e.g., laboratory values, physical 
examination findings, vital signs, or ECG changes) or identified from review of other 
documents (e.g., subject diaries) that are relevant to subject safety. 


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6.1.9.3 Reporting Adverse Events 
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, time of onset, 
Investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome.  
Adverse events 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 that the subject is screened 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. 
Any abnormal 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, deemed 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. 
Any AE that meets SAE criteria (Section 6.1.9.1) must be reported to the Medical Monitor 
and Sponsor (or designee) immediately (i.e. within 24 hours) after the time site personnel 
first learn about the event.  Investigators should record all SAE details available, including 
investigator causality assessment, on an Adverse Event eCRF and submit the report via the 
EDC system within 24 hours of becoming aware of the event.  Notification of SAE entry will 
be generated and sent to Palladio Drug Safety and its designee by the EDC system. In the 
event the EDC system is unavailable, a completed SAE Report Form should be submitted to 
IQVIA drug safety via email at PHV_PA-102@quintiles.com or via fax at 1-866-599-1342. 
If questions arise regarding SAE report submission, please contact the IQVIA Lifecycle 
Safety SAE hotline for assistance at 1-866-599-1341.   
6.1.9.4 Assessment of Severity 
AEs should be graded as mild, moderate, severe, life-threatening, or death using the 
following definitions: 
• Mild (Grade 1): 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 (Grade 2): 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. 


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• Severe (Grade 3): Events interrupt the participant’s normal daily activities and 
generally require systemic drug therapy or other treatment; they are usually 
incapacitating. 
• Life-threatening (Grade 4): Events that place the participant at immediate risk of 
death or are disabling. 
• Death (Grade 5): Events that result in death. 
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.  Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
6.1.9.5 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 6-2. 
Table 6-2 
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). 


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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). 
6.1.9.6 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. 
6.2 Laboratory Analyses 
Any abnormal 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. 
6.3 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication.  Any pregnancy 
that occurs during study participation must be reported using a clinical study pregnancy 
reporting form.  To ensure subject safety, each pregnancy must be reported within 24 hours of 
learning of its occurrence to the Medical Monitor and to IQVIA Lifecycle Safety on the 
paper pregnancy reporting form to PHV_PA-102@quintiles.com.  
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 
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 the Medical Monitor and the 
Sponsor. 


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7 STATISTICAL AND ANALYTICAL PLAN 
The statistical and analytical plan for this study is summarized below.  Further details are 
provided separately in the Statistical Analysis Plan (SAP). 
7.1 Pharmacokinetic Parameters 
The following PK parameters will be calculated using noncompartmental methods, whenever 
possible, based on lixivaptan and lixivaptan metabolite (WAY-141624, WAY-138451, and 
WAY-138758) concentrations, and at the timepoints shown in Table 12-1: 
PK Day 1 (AM Dose) 
PK Parameter 
Definition 
Cmax 
maximum observed plasma drug concentration 
tmax 
time to reach maximum plasma concentration 
AUC0-t 
area under the concentration-time curve from time 0 until the last quantifiable 
concentration, calculated using the linear trapezoidal rule for increasing values, and 
the log trapezoidal rule for decreasing values 
AUC0-inf 
area under the concentration-time curve extrapolated to infinity, calculated as: 
AUC0-inf = AUC0-t + Ct/λz 
Λz 
apparent terminal elimination rate constant 
t1/2 
terminal elimination phase half-life, calculated as ln(2)/λz 
CL/F 
total body clearance, calculated as Dose/AUC0-inf (lixivaptan only) 
Vz/F 
volume of distribution, calculated as CL/F/λz (lixivaptan only) 
 
PK Day 1 (PM Dose) – Study Day 1 - 2 
PK Parameter 
Definition 
Cmax 
maximum observed plasma drug concentration 
tmax 
time to reach maximum plasma concentration 
AUC0-t 
area under the concentration-time curve from time 0 until the last quantifiable 
concentration, calculated using the linear trapezoidal rule for increasing values, and 
the log trapezoidal rule for decreasing values 
 


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Day 7 (AM Dose) 
PK Parameter 
Definition 
Cmax 
maximum observed plasma drug concentration 
tmax 
time to reach maximum plasma concentration 
AUC0-t 
area under the concentration-time curve from time 0 until the last quantifiable 
concentration, calculated using the linear trapezoidal rule for increasing values, and 
the log trapezoidal rule for decreasing values 
CL/F 
total body clearance, calculated as Dose/AUC0-last- (lixivaptan only) 
Vz/F 
volume of distribution, calculated as CL/F/λz (lixivaptan only) 
 
Day 7 (PM Dose) 
PK Parameter 
Definition 
Cmax 
maximum observed plasma drug concentration 
tmax 
time to reach maximum plasma concentration 
AUC0-14 
area under the concentration-time curve from time 0 until 14 hours postdose 
AUC0-t 
area under the concentration-time curve from time 0 until the last quantifiable 
concentration, calculated using the linear trapezoidal rule for increasing values, and 
the log trapezoidal rule for decreasing values 
Λz 
apparent terminal elimination rate constant 
t1/2 
terminal elimination phase half-life, calculated as ln(2)/λz 
 
Pharmacokinetic parameters will be calculated using validated software and using actual 
sampling times.  The calculation of PK summary statistics will be performed using validated 
software.   
Calculation of accumulation ratios (Day 7/Day 1), metabolite to parent ratios for each 
metabolite, an assessment of dose proportionality, or additional calculations may be made as 
appropriate to fully characterize available data.  Additional details regarding the PK 
parameter calculations are presented in the SAP. 
7.2 Pharmacodynamic Parameters 
The PD analysis will include assessments of urine osmolality and urine output, total kidney 
volume, liver volume, plasma copeptin, and serum creatinine in ADPKD subjects (see Table 
12-1).  Pharmacodynamic data will be listed and summarized as detailed in the SAP. 
7.3 Safety Variables 
The safety analysis will include clinical laboratory findings (hematology, clinical chemistry, 
and urinalysis), 12-lead ECGs, vital signs, physical examination findings, assessments of 
AEs and the questionnaire of tolerability.  Safety data will be listed and summarized as 
detailed in the SAP. 


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7.4 Sample Size Calculations 
Calculations were performed assuming a coefficient of variation (CV) of 0.30 and 0.41 for 
lixivaptan Cmax and AUC, respectively.  Assuming lognormal distribution, this implies that 
the variances for the logarithm of Cmax and AUC are 0.086 and 0.155, respectively.  Under 
these assumptions and a random sample of 8 observations, the probability is 0.90 that the 
point estimate of the population central value (observed geometric mean) for lixivaptan Cmax 
and AUC will be within (84.3%, 118.6%) and (79.5%, 125.7%) of the population central 
value (the median), respectively. 
From the perspective of tolerability assessment for multiple dose regimens, for the true 
population incidence rates of 0.10, 0.20, 0.30, 0.40 and 0.50 for a given AE, the probabilities 
that the AE would not be observed in a group of 8 subjects administered lixivaptan are given 
in Table 7-1. 
Table 7-1 Probability of Not Observing an Adverse Event for Various True Incidence 
Rates 
True Incidence Rate 
Probability of Not Observing an  
AE in Group of 8 Subjects 
0.1 
0.43 
0.2 
0.168 
0.3 
0.058 
0.4 
0.017 
0.5 
0.004 
Abbreviation: AE = adverse event. 
7.5 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Safety Analysis Set: The Safety Analysis Set will consist of all subjects who receive any 
study drug.  This analysis set will be used for the safety analyses and for summarization of 
baseline/demographic characteristics. 
Pharmacokinetic Analysis Set: The PK Analysis Set will consist of all subjects who undergo 
plasma PK sampling and have evaluable PK assay results.  This analysis set will be used for 
the PK analysis and for summarization of concentration/parameter data. 
Pharmacodynamic Analysis Set: The PD Analysis Set will consist of all subjects who receive 
study drug and have at least 1 postdose PD assessments of urine osmolality.  This analysis set 
will be used for the PD analysis and for summarization of PD biomarker data. 
7.6 Description of Subgroups to be Analyzed 
No subgroup analyses are planned. 


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7.7 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS® software Version 9.2 or higher.  All 
continuous variables will be summarized using the following descriptive statistics: number of 
non-missing observations (n), mean, standard deviation (SD), median, minimum, and 
maximum.  Categorical variables will be summarized using the following descriptive 
statistics: frequency counts and percentages.  All data will be listed in data listings.  Missing 
data will not be imputed but will be analyzed as missing. 
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. 
7.7.1 Pharmacokinetic Analysis 
The parameters describing the PK will be derived from plasma concentrations of lixivaptan 
and its metabolites and actual sample draw times using noncompartmental analysis.  For 
summary of plasma and urine concentrations, concentrations below the limit of quantification 
(BLQ) will be treated as zero for the calculation of all summary statistics except for the 
calculation of geometric mean and CV% of geometric mean, where they are treated as 
missing. 
Plasma concentration data for lixivaptan and its metabolites will also be displayed 
graphically on linear and semi-logarithmic scales.  The following plots will be presented for 
the concentration-time data: 
• Individual subject plasma concentration profile versus time, stratified by renal 
function group. 
• Arithmetic-mean concentration (±SD) versus time, stratified by renal function group. 
Additional details regarding the PK parameter calculations are presented in the SAP. 
7.7.2 Pharmacodynamic Analyses 
The change from baseline in urine osmolality, serum creatinine, plasma copeptin, TKV and 
LV after multiple doses of lixivaptan will be summarized by renal function group (CDK1/2 
and CDK3), and at each scheduled time point using descriptive statistics (n, mean, SD, 
median, minimum, and maximum). 
Except for the case of urine osmolality, the baseline value is the last value observed prior to 
first administration of study drug and any values after first administration of study drug are 
regarded as post-baseline values.  The change-from-baseline variables will be calculated as 
the post-baseline value minus the value at baseline. 
For urine osmolality assessments, the baseline value for each time point after first 
administration of study drug is the value observed at the corresponding time point on Day -1 
(or Day 1 for the AM predose assessment only).  Any values after first administration of 


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study drug are regarded as post-baseline values.  The change-from-baseline variables will be 
calculated as the post-baseline value minus the value at baseline.  The number of subjects 
who show suppressed urine osmolality, defined as spot urine osmolality < 300 mOsm/kg for 
24h, on Day 1 (AM predose) compared with Day 8 (AM predose) will be determined.   
7.7.3 Safety Analyses 
Clinical Laboratory Tests 
All laboratory data will be summarized by renal function group and at each scheduled 
timepoint using descriptive statistics (n, mean, SD, median, minimum, and maximum). 
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 
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 by renal function group.  
For categorical data, change-from-baseline will be summarized using frequency and 
proportion at each scheduled timepoint by renal function group. 
Individual data listings of laboratory results will be presented for each subject.  Values 
outside of the laboratory's reference range (i.e., those with low or high values) will be 
flagged in the laboratory listings. 
For all continuous 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 by renal function group (using number of subjects with results of negative, trace, or 
positive). 
ECGs 
A listing will be provided for Investigator-identified ECG abnormalities from safety ECGs.  
Overall evaluation of safety ECGs will be summarized by renal function group using 
frequency counts and percentage of subjects as normal or abnormal, and the relevance of the 
abnormality will be summarized by CS or NCS. 
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. 
Continuous ECG parameters including heart rate, ventricular rate, PR interval, QRS duration, 
QT interval (uncorrected), and QTcF interval will be summarized for renal function group 
and over each scheduled timepoint in terms of absolute values using descriptive statistics (n, 
mean, SD, median, minimum, and maximum). 


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Vital Signs 
Changes from baseline in vital signs at each scheduled timepoint will be summarized by 
renal function group for the Safety Analysis Set 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.  There will not be any imputation for missing 
values.  All vital sign data will be listed individually by each subject based on the Safety 
Analysis Set. 
Physical Examinations 
Changes in baseline in physical examination findings (Normal, Abnormal-NCS,  
Abnormal-CS) will be summarized using counts and percentages for renal function group 
and will also be listed individually for each scheduled timepoint. 
Adverse Events 
An overall summary of the number and percentage of subjects in each category will be 
presented, as will an overall summary of the number of events in each category.  The number 
and percentage of subjects reporting AEs in each category above will be summarized by renal 
function group according to the system organ class (SOC) and preferred term (PT) assigned 
to the event using MedDRA. 
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.  A summary of deaths (for all deaths, AE outcome, not AE term, is death) will be 
provided by number and percentage of subjects by renal function group. 
Questionnaire for Tolerability 
Tolerability data obtained from the questionnaire will be listed and summarized as detailed in 
the SAP. 
7.7.4 Other Analyses 
Listings will be provided for subject disposition, demographics, medical history, prior and 
concomitant medications, and summary tables will be prepared for disposition and 
demographics. 
7.8 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. 


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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. 
7.8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol.  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 Oracle Clinical 
Remote Data Capture program.  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 IQVIA standards 
and data cleaning procedures to ensure the integrity of the data, e.g. removing errors and 
inconsistencies in the data.  Adverse events and concomitant medication terms will be coded 
using the MedDRA and World Health Organization Drug Dictionaries, respectively. 
After database lock, each study site will receive all site-specific eCRF data for the study, 
including full discrepancy and audit history.  Additionally, a copy of all of the study site’s 
data from the study will be created and sent to the Sponsor for storage.  IQVIA 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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8 ETHICS 
8.1 Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB 
before participation of human subjects in research studies.  Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study subjects, and any 
other written information regarding this study to be provided to the subject or the subject’s 
legal guardian must be approved by the IRB.  Documentation of all IRB approvals and of the 
IRB compliance with ICH harmonized tripartite guideline E6 (R1): GCP will be maintained 
by the site and will be available for review by the Sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB 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.  The 
Investigator must promptly supply the Sponsor or its designee, the IRB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
8.2 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, ICH GCP, and all applicable regulations. 
8.3 Subject Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each subject before entering the study or performing 
any unusual or non-routine procedure that involves risk to the subject.  An informed consent 
template 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 consent 
should be reviewed by the Sponsor or its designee or both before IRB submission.  Once 
reviewed, the consent will be submitted by the Investigator to his or her IRB 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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9 INVESTIGATOR’S OBLIGATIONS 
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. 
9.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality.  All records will be kept in a secure 
storage area with limited access.  Clinical information will not be released without the 
written permission of the subject (or the subject’s legal guardian), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the FDA, or the IRB. 
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. 
9.2 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 IQVIA 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 IQVIA is financially responsible 
for further treatment of the subject’s disease. 
9.3 Investigator Documentation 
Before beginning the study, the Investigator will be asked to comply with ICH E6 (R1) 
Section 8.2 and Title 21 of the CFR by providing the following essential documents, 
including but not limited to: 
• IRB approval 
• 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 


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• 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-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 
9.4 Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of ICH 
E6 (R1).  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. 
9.5 Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6 (R1) and all applicable guidelines and regulations. 
9.6 Adverse Events and Study Report Requirements 
By participating in this study the Investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol.  In addition, the Investigator agrees to 
submit annual reports to the study site IRB as appropriate. 
9.7 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. 
9.8 Records Retention 
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. 


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9.9 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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10 STUDY MANAGEMENT 
10.1 Monitoring 
10.1.1 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, in addition to maintaining necessary telephone 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. 
10.1.2 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records.  
In the event of an audit, 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. 
The Investigator should promptly notify the Sponsor and IQVIA of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 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 for approval before subjects can be enrolled into an amended protocol, and before the 
changes can be implemented. 
10.2.2 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 approval.  As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 


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should be submitted to the IRB 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 1). 
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 should be notified of all protocol deviations in a timely manner. 
10.3 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. 
10.4 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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11 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. 


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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. 
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.  2017.  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 


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12 APPENDICES 
12.1 Appendix 1: Chronic Kidney Disease Classification Criteria 
This study uses the 2009 CKD-EPI creatinine equation,16 which is recommended by the 
KDIGO Clinical Practice Guidelines for Management of Chronic Kidney Disease. 
The CKD-EPI equation is: 
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 141 ×  𝑚𝑚𝑖𝑖𝑖𝑖൬𝑆𝑆𝑆𝑆𝑆𝑆
κ , 1൰
α
× max ൬𝑆𝑆𝑆𝑆𝑆𝑆
κ , 1൰
−1.209
× 0.993Age × 1.018 (if female) × 1.159 (if black),   
where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females 
and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr/κ or 1. 
 
 
12.2 Appendix 2: Schedule of Assessments 
 


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Table 12-1 
Schedule of Assessments 
Visit type: Screening17 Admit17 
In-
CRU 
In-
CRU 
Discharge 
after AM 
Assessments 
 
PK 
Visit 
in AM 
 
PK Visit  
in AM; 
Admit for 
PM dose 
In-
CRU 
Discharge 
after PK 
Collection and 
Assessments 
PK 
Collection18 
End of 
Study 
Visit 
Procedure: 
Study Day: 
-44 to -3 
or -2 
-2 or -1  
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9-11 
35 ±2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/Urine Pregnancy Test1,2 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
FSH3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height/Weight/BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Previous Medications1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications4 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Clinical Lab Evaluations5 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
Serum Creatinine6 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
Electrocardiogram7 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Vital Signs8 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Physical Examinations1,9 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse Events10 
X 
 
Daily Fluid Intake11 
 
 
X 
X 
X 
(AM only) 
 
 
 
 
X 
X 
(AM only) 
 
 
Administer Dose in-CRU12 
 
 
 
AM 
PM 
AM 
 
AM 
 
AM 
PM 
AM 
PM 
 
 
 
Self-Administer Dose12 
 
 
 
 
PM 
AM 
PM 
PM 
AM 
PM 
 
 
 
 
 
PK Blood Samples13 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Urine Osmolality14 
 
 
X 
X 
X 
 
 
 
 
X 
X 
 
 
Daily Urine Output15 
 
 
X 
X 
X 
(AM only) 
 
 
 
 
X 
X 
(AM only) 
 
 
Tolerability Questionnaire  
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Plasma Copeptin16 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
TKV and LV (by MRI) 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 


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Abbreviations: BMI= body mass index, CRU = clinical research unit, EOS = end of study, FSH = follicle-stimulating hormone, MRI = magnetic resonance 
imaging, PK = pharmacokinetic, Preg.  = pregnancy, TKV = total kidney volume, LV = liver volume.  
 
1 Assessments will be performed on Day -1 or Day -2 for subjects admitted to CRU on Day -2.  
2 Serum pregnancy test to be performed at Screening; Urine pregnancy test to be performed at Day -2 or Day -1 and at End of Study.  
3 Postmenopausal subjects with a urine pregnancy result outside the post-menopausal range or an indeterminate pregnancy test will undergo additional testing 
with FSH if necessary based on Investigator discretion to confirm postmenopausal status prior to study enrollment. 
4 Includes over the counter medications. 
5 Clinical labs: hematology, clinical chemistry (including liver function), and urinalysis at approximately the same time of day (in the morning and, on dosing 
days, before the lixivaptan dose).  The list of analytes is shown in Table 6-1. Lab tests that need to be repeated during Screening may be obtained through the 
services of an at-home nursing service provided by the Sponsor.   
6 Serum creatinine will be measured as part of the clinical laboratory assessment. 
7 12-lead ECG at Screening, Day 1 pre-dose, and prior to discharge from clinic on Day 8.  Electrocardiograms to be obtained following 5 minutes rest in supine 
or semi-recumbent position. The same position must be used throughout the study for a given subject. 
 
8 Vital signs will be measured following 5 minutes rest in a seated position.  Systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature 
will be measured at the following time points: prior to Day -1 procedures, prior to discharge from CRU on Day 8, and at the End of Study visit.  In addition, 
blood pressure and pulse rate will also be measured before each administration of study medication in the CRU.  
9 Complete physical examination at Screening, and prior to discharge on Day 8.  Brief physical examination on Day -2 or Day -1.  Symptom-directed physical 
examinations as needed. 
10 Adverse events and SAEs that are related to study participation (e.g., protocol-mandated intervention) will be recorded from the time the subject signs the 
informed consent form until exit from the study.  All other AEs and SAEs will be recorded from the first dose of lixivaptan until exit from the study. 
11 Record daily fluid intake on Day -1, Day 1 and Day 7.  On Day -1, measurement will begin 24 hours before the expected time of first study medication on Day 
1 AM.  On Day 1 and Day 7, measurements will begin immediately before the AM dose and will continue for 24 hours into the morning of Day 2 and Day 8, 
respectively.      
12 Subjects will take study medication in the AM and PM for 7 days.  Subjects will be asked to record each dose of the study product taken on an outpatient basis 
in the Study Dosing Diary.  Subjects will be asked to bring the Study Dosing Diary together with their unused study product at each visit to the CRU. 
13 PK blood collection timepoints: 
Day 1: 0, 1, 2, 4, 6, 9, 10, 11, 12, 14, and 16 hours post AM dose. The collections at 0 and 10 hours are immediately before the AM and PM doses, respectively; 
Day 2, 4 and 6: 0 hours (immediately before AM dose); 
Day 7: 0, 1, 2, 4, 6, 9, 10, 11, 12, 14, and 16 hours post AM dose. The collections at 0 and 10 hours are immediately before the AM and PM doses, respectively; 
Day 8: 0 hours (corresponding to 24 hours after AM dose on Day 7) and 10 hours (corresponding to 24 hours after PM dose on Day 7);  
Day 9: 48 hours after PM dose on Day 7;  
Day 11: 96 hours after PM dose on Day 7.  
14 Urine will be collected for determination of spot urine osmolality and urine specific gravity at the following timepoints: 
Day -1: 0 (start), 1, 2, 4, 6, 9, 10, 11, 12, and 14 hours. 


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Day 1: 0, 1, 2, 4, 6, 9, 10, 11, 12, and 14 hours post AM dose. The collections at 0 and 10 hours are immediately before the AM and PM doses, respectively; 
Day 2: 0 hours (immediately before AM dose on Day 2, corresponding to 24 hours after AM dose on Day 1). 
Day 7: 0, 1, 2, 4, 6, 9, 10, 11, 12, and 14 hours post AM dose. The collections at 0 and 10 hours are immediately before the AM and PM doses, respectively; 
Day 8: 0 hours (corresponding to 24 hours after AM dose on Day 7). 
Note: Subject may not be able to void at all timepoints - see Section 6.1.7.  For all voids, the volume (mL) and the date and time of void will be recorded.   
15 Record daily urine output on Day -1, Day 1 and Day 7.  On Day -1, measurement will begin 24 hours before the expected time of first study medication on 
Day 1 AM.  On Day 1 and Day 7, measurements will begin immediately before the AM dose and will continue for 24 hours into the morning of Day 2 and Day 
8, respectively.       
16 Blood samples for determination of plasma copeptin will be taken at approximately the same time of day (in the morning and, on dosing days, before the 
lixivaptan dose).  
17 Subjects will be admitted to the CRU in the evening of Day -2 or in the morning of Day -1.  For subjects admitted to the CRU on Day -2, the Screening period 
will be until Day -3.  For subjects admitted to the CRU on Day -1, the Screening period will be until Day -2.   
18 Three PK sampling points are contemplated after patients are discharged from the CRU on Day 8 (Day 8 PM, Day 9 PM, Day 11 PM).  Patients may return to 
the site for these PK sample collections.  Alternatively, if patients are not able to return to the CRU after discharge, they may utilize an at-home nursing service 
provided by the Sponsor.  If a patient does not return to the site for PK sample collection after discharge on Day 8, but has the blood drawn by an at-home 
nursing service, this will not be considered a protocol deviation. 
 
 


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12.3 Appendix 3: Assessment Windows 
Table 12-2 
Assessment Windows 
Procedure 
Dosing Day 
Window (units) 
Lixivaptan PM dose 
Day 1 – Day 7 
In CRU: 10 hr ± 15 minutes after AM dose 
Self-Administered: 10 hr ± 1 hr after AM dose 
 
 
 
 
Assessment Day 
 
PK Blood Samples 
Day 1, Day 2, Day 4, Day 
6, Day 7, Day 8, Day 9, 
Day 11 
- 60 minutes (predose Day 1) 
- 10 minutes (predose Day 7) 
± 3 min (≤4 hr) 
± 5 min (> 4 hr but ≤ 12 hr) 
± 10 min (> 12 hr but ≤ 24 hr) 
 
± 1 hr (> 24 hr but ≤ 48 hr) 
± 2 hr (> 48) 
Urine Osmolality and  
Urine Specific Gravity 
Day 1-2, Day 7-8 
Subjects will empty their bladders completely 15 
± 5 minutes prior to each scheduled collection, 
after which they will have 30 minutes to provide 
a spot urine sample.  Subjects who will not be 
able to provide a sample within 30 minutes will 
be given an additional 30 minutes to do so and 
the different sampling time will be recorded.   
Electrocardiogram 
Screening, Day 1, Day 8 
- 60 minutes (predose), ± 30 minutes (postdose) 
Vital Signs 
Screening, Day -1, Day 1, 
Day 2, Day 4, Day 6, Day 
7, Day 8, Day 35 
- 60 minutes (predose), ± 30 minutes (postdose) 
Clinical Laboratory 
Samples 
Screening, Day -1, Day 2, 
Day 7, Day 35 
- 60 minutes (predose Day 2 and Day 7) 
In the morning on Day -1 and Day 35 
Tolerability Questionnaire 
Day 2, Day 7 
Subjects will complete the questionnaire in the 
morning of Day 2, before discharge from the 
CRU, and in the morning of Day 7. 
TKV and LV (MRI) 
Baseline  
End of dosing 
End of study 
Baseline: between Screening and Day -1  
End of dosing: Day 7 or 8 or 9  
End of study: Day 35 ± 2  
Table abbreviations: hr = hours, PK= pharmacokinetic 
 


Summary of Changes in the Conduct of the Study (from Section 9.8.1 of the Clinical Study 
Report, dated September 22, 2020 
 
Changes in the Conduct of the Study 
There were 2 protocol versions that were not implemented or submitted to the IRB. Protocol 
versions 1 and 2 were marked final and dated 19 March 2018 but the version number 1.0 
remained unchanged in the footer of both versions. Refer to Note to File (dated 23 February 
2020) in Appendix 16.1.1 to distinguish between the 2 documents. 
Protocol version 3 (dated 24 April 2018) was the first protocol version submitted to the IRBs and 
amended. There were 2 subsequent protocol amendments, versions 4 and 5, that were 
implemented after the first subject was enrolled. Copies of the protocol and protocol 
amendments are provided in Appendix 16.1.1. Brief summaries of the changes are outlined 
below. 
Protocol version 4 (dated 09 January 2019) implemented the following changes: 
• Clinically relevant changes that affected the type or frequency of protocol procedures, or 
the addition of information to the protocol that influenced clinical decision making or 
consent: 
− Increased eligible age to 65 years for inclusion in the study; 
− Provided flexibility in screening procedures; 
− Allowed the use of the low progesterone-releasing intrauterine device Mirena; 
− Limited hormonal contraception exclusion to estrogen-containing contraceptives. 
Progesterone-only contraceptives were allowed. 
− Allowed inclusion of subjects with elevated bilirubin due to Gilbert’s Syndrome 
at the discretion of the investigator. 
− Allowed inclusion of subjects with contraindications to or interference with MRI 
assessments provided they met all other inclusion criteria. Clarified that no MRI 
tests would be conducted on these subjects. 
− Added exclusion of subjects who showed signs of liver toxicity on tolvaptan 
therapy. 
− Clarified batch number of investigational product. 
− Clarified fluid intake recommendations before the first dose of study drug and 
while taking study drug. 
− Allowed supine position for ECGs provided that the same position was 
maintained for the same subject throughout the study. 
− Clarified nature of pregnancy test at EOS visit. 
− Added Day 11 to the Assessment Window table. 
− Clarified the appropriate time window for time values that were on the extremes 
of each time interval. 
• Clarified text which included corrections of typos, text changes for consistency or other 
clarifications which did not affect clinical decision making or consent. These included 
deletion of mesylate, the counter-ion of fenoldopam from the exclusion criteria. 


• Administrative changes, including changes of names or roles of companies or personnel 
and/or contact information. These changes did not affect clinical decision making or 
consent. 
 
Protocol version 5 (dated 21 March 2019) implemented the following changes: 
• Clinically relevant changes that affected the type or frequency of protocol procedures, or 
the addition of information to the protocol that influenced clinical decision making or 
consent: 
− Extended screening duration from 4 weeks to 6 weeks. 
− Increased study duration by the addition of 14 days to Screening. 
− Updated information on the status of the vasopressin V2 receptor antagonist 
tolvaptan (JYNARQUE®) in the US. 
− Provided flexibility to stop enrollment of CKD1 subjects in Cohorts 1 and 3 if 
sufficient experience with CKD2 subjects had not occurred. 
− Provided the use of a home nursing service to draw blood if repeat lab tests were 
needed during Screening. 
− Deleted amlodipine from the exclusion criteria and prohibited therapy as it was a 
CYP3A4 substrate and not an inhibitor. 
− As inhibition of CYP3A4 by lixivaptan might reduce metabolism of amlodipine, a 
dosing limit was added. 
− Increased the allowable upper limit of liver function test (LFT) results at 
Screening to 1.5 × ULN based on the observation in the first 8 subjects treated 
with lixivaptan at 200 mg BID (highest dose) in this study that no significant LFT 
abnormalities had been detected. The highest values were 1.2 × ULN for 
transaminases with no increase in total bilirubin. 
− Clarified that if a subject did not come back for visits after Day 8, it was not a 
protocol deviation if the blood was drawn only by the at-home nursing service. 
• Clarified text which included corrections of typos, text changes for consistency or other 
clarifications. These changes did not affect clinical decision making or consent. 
• Administrative changes, including changes of names or roles of companies or personnel 
and/or contact information. These changes did not affect clinical decision making or 
consent. 


Palladio Biosciences 
    Summary of Changes 
Study PA-102  
   Clinical Study Protocol version 5 dated March 21, 2019 
Confidential 
  1 
Study PA-102 
Clinical Study Protocol version 5 dated March 21, 2019 
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.
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 4 dated January 9, 2019 
Version 5 
Explanation 
1 
Title page 
Version of Protocol: 4 
Version of Protocol: 5
Clarifies protocol version 
1 
Title page 
Date of protocol: January 9, 2019 
Date of protocol: March 21, 2019
Updates protocol date 
1 
Title page 
Sponsor Contact: 
Ruth Ann Subach, PharmD, BCPS 
Vice President, Clinical 
Development and Operations 
Design Space Inpharmatics, LLC 
Harleysville, PA 19438 
rsubach@dsipharmatics.com 
Sponsor Contact: 
Elaine Richardson 
Vice President, Clinical Operations 
Palladio Biosciences, Inc. 
12 Penns Trail, Unit A 
Newtown, PA 18940 
ERichardson@palladiobio.com 
Updates Sponsor Contact 
name and contact 
information.  
3 
Protocol approval – 
Sponsor signature 
Version of Protocol: 4 
Version of Protocol: 5
Updates protocol version 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 5 dated March 21, 2019 
Confidential                       
 
 
 
 
 
 
           2 
 
Page 
Section 
Version 4 dated January 9, 2019 
Version 5 
Explanation 
3 
Protocol approval – 
Sponsor signature 
Protocol date January 9, 2019 
Protocol date March 21, 2019 
Updates protocol date 
3 
Protocol approval – 
Sponsor signature 
Lorenzo Pellegrini, Ph.D. 
President & CEO 
Palladio Biosciences, Inc. 
12 Penns Trail, Unit A 
Newtown, PA 18940  
Neil H. Shusterman, M.D. 
Chief Medical Officer 
Palladio Biosciences, Inc. 
12 Penns Trail, Unit A 
Newtown, PA 18940 
Change of responsibility to 
Chief Medical Officer 
3 
Protocol approval – 
Sponsor signature 
Signature date January 9, 2019 
Signature date March 21, 2019 
Updates protocol date 
11 
Synopsis 
Date of protocol: January 9, 2019 
Date of protocol: March 21, 2019 
Updates protocol date 
All 
Footnote 
09-Jan-2019 
21-Mar-2019 
Updates protocol date 
All 
Footnote 
Version 4 
Version 5 
Updates protocol version 
 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 5 dated March 21, 2019 
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 
Section 
Version 4 dated January 9, 2019 
Version 5 
Explanation 
11 
Synopsis 
Pharmacokinetic: Lixivaptan and lixivaptan 
metabolite (WAY-141624, WAY-138451, and 
WAY-138758) plasma concentrations will be 
tabulated and summarized using descriptive 
statistics (including sample size, arithmetic 
and geometric mean, standard deviation [SD], 
coefficient of variation [CV%], median, 
minimum, and maximum) for each Cohort.  
The PK parameters for lixivaptan and 
lixivaptan metabolites will be will be 
summarized for each Cohort. 
 
Pharmacokinetic: Lixivaptan and lixivaptan 
metabolite (WAY-141624, WAY-138451, and 
WAY-138758) plasma concentrations will be 
tabulated and summarized using descriptive 
statistics (including sample size, arithmetic 
and geometric mean, standard deviation [SD], 
coefficient of variation [CV%], median, 
minimum, and maximum) for each Cohort.  
The PK parameters for lixivaptan and 
lixivaptan metabolites will be summarized for 
each Cohort. 
 
Deletion of 
duplicate words 
13 
List of 
Abbreviations 
 
REMS Risk Evaluation and Mitigation Strategy Adds new 
abbreviation 
35 
5.8.1 
Permitted 
Therapy 
Allowed medications include those typically 
prescribed to treat ADPKD, CKD and their 
complications, with the exception of tolvaptan.  
These include angiotensin II receptor blockers 
(valsartan, candesartan, telmisartan, 
irbesartan) and angiotensin-converting 
enzyme inhibitors (enalapril, lisinopril).   
Allowed medications include those typically 
prescribed to treat ADPKD, CKD and their 
complications, with the exception of tolvaptan.  
These include angiotensin II receptor blockers 
(e.g., valsartan, candesartan, telmisartan, 
irbesartan) and angiotensin-converting 
enzyme inhibitors (e.g., enalapril, lisinopril).   
Added “e.g.”, to 
show these are 
examples and 
not a complete 
list. 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 5 dated March 21, 2019 
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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 
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Version 5 
Comments 
10 
Synopsis 
Screening Duration: 28 days (Day -30 
through Day -3)  
Screening Duration: 42 days (Day -44 
through Day -3)  
Extends the duration of 
Screening from 4 weeks to 6 
weeks 
10 
Synopsis 
Total Study Duration: 66 days 
Total Study Duration: Up to 80 days 
Study duration is increased 
by the addition of 14 days to 
Screening. 
16 
1.3 Overview 
of Available 
Therapies for 
ADPKD 
As of the time of this document there 
are no drug therapies specifically 
approved in the US for the treatment of 
ADPKD. 
In April 2018, the vasopressin V2 
receptor antagonist tolvaptan 
(JYNARQUE®) was approved in the 
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 
(REMS).  
Updates information on the 
status of Jynarque in the 
United States. 
22 
3.1 Study 
Design 
For all subjects, this study includes a 
Screening period of 28 days (Day -30 
through Day -3), i.e. up to 30 days prior 
to dosing on Day 1.   
For all subjects, this study includes a 
Screening period of 42 days (Day -44 
through Day -3), i.e. up to 44 days prior 
to dosing on Day 1. 
Extends the duration of 
Screening from 4 weeks to 6 
weeks.  


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
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23 
3.1 Study 
Design, Table 
3-1, footnote 
Table 3-1 
Chronic Kidney Disease 
Classification Summary 
CKD 
Classification Cohorts 
N 
eGFR* 
 
 
 
 
CKD1 or 
CKD2** 
1 and 3 
16 (8 
per 
cohort) 
eGFR ≥ 60 
mL/min/1.73 
m2 
 
 
 
 
CKD3 
2 and 4 
16 (8 
per 
cohort) 
eGFR ≥ 30 
to < 60 
mL/min/1.73 
m2 
 
 
 
 
Abbreviations: CKD = chronic kidney disease, 
eGFR = estimated glomerular filtration rate, 
N = number of subjects. 
*eGFR is calculated by the 2009 Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation (Appendix 1).  
 
Table 3-2 
Chronic Kidney Disease 
Classification Summary 
CKD 
Classification Cohorts 
N 
eGFR* 
 
 
 
 
CKD1 or 
CKD2** 
1 and 3 
16 (8 
per 
cohort) 
eGFR ≥ 60 
mL/min/1.73 
m2 
 
 
 
 
CKD3 
2 and 4 
16 (8 
per 
cohort) 
eGFR ≥ 30 
to < 60 
mL/min/1.73 
m2 
 
 
 
 
Abbreviations: CKD = chronic kidney disease, 
eGFR = estimated glomerular filtration rate, 
N = number of subjects. 
*eGFR is calculated by the 2009 Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation (Appendix 1).  
**At least 2 subjects with CKD1 or CKD2 will 
be included in 8 subjects assigned to Cohorts 
1 and 3. 
Provides for flexibility to stop 
enrollment of CKD1 subjects 
in Cohorts 1 and 3 if sufficient 
experience with CKD2 
subjects has not occurred. 
23 
3.1 Study 
Design 
Subjects may be allowed to re-screen or 
have repeat testing after agreement 
between the investigator and medical 
monitor.   
Subjects may be allowed to re-screen or 
have repeat testing after agreement 
between the investigator and medical 
monitor.  Lab tests that need to be 
repeated during Screening may be 
obtained through the services of an 
at-home nursing service provided by 
the Sponsor. 
Provides for the use of a 
home nursing service to draw 
blood if repeat lab tests are 
needed during Screening. 
27 
4.1.2 = 
Exclusion 
criteria 
6.Subjects who have taken, or are 
expected to be taking, strong or 
moderate CYP3A4 or CYP2C8 inhibitors 
(e.g. aprepitant, boceprevir, 
clarithromycin, chloramphenicol (not eye 
6.Subjects who have taken, or are 
expected to be taking, strong or 
moderate CYP3A4 or CYP2C8 inhibitors 
(e.g. aprepitant, boceprevir, 
clarithromycin, chloramphenicol (not eye 
Amlodipine is a CYP3A4 
substrate and not an inhibitor.  
Thus, it has been deleted 
from this section. 


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    Summary of Changes 
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drops), cimetidine, ciprofloxacin, 
clopidogrel, clotrimazole (if used orally), 
cobicistat and cobicistat-containing 
products, crizotinib, cyclosporine, 
danazol, deferasirox, diltiazem, 
dronedarone, erythromycin, fluconazole, 
fluvoxamine, gemfibrozil, HIV protease 
inhibitors, imatinib, isoniazid, 
itraconazole, josamycin, ketoconazole, 
nefazodone, posaconazole, 
quinupristin/dalfopristin, ritonavir and 
ritonavir-containing products, telaprevir, 
teriflunomide, tofisopam, 
troleandomycin, verapamil, 
voriconazole) within 14 days or 5 half-
lives, whichever is longer, of dosing;  or 
weak CYP3A4 or CYP2C8 inhibitors 
(e.g., amlodipine, chlorzoxazone, 
cilostazol, fosaprepitant, istradefylline, 
ivacaftor, lomitapide, ranitidine, 
ranolazine, tacrolimus, ticagrelor, 
trimethoprim) within 7 days or 5 half-
lives, whichever is longer, from dosing.  
For weak CYP3A4 or CYP2C8 
inhibitors, medications may be allowed 
in consultation with the Medical Monitor 
(MM). 
drops), cimetidine, ciprofloxacin, 
clopidogrel, clotrimazole (if used orally), 
cobicistat and cobicistat-containing 
products, crizotinib, cyclosporine, 
danazol, deferasirox, diltiazem, 
dronedarone, erythromycin, fluconazole, 
fluvoxamine, gemfibrozil, HIV protease 
inhibitors, imatinib, isoniazid, 
itraconazole, josamycin, ketoconazole, 
nefazodone, posaconazole, 
quinupristin/dalfopristin, ritonavir and 
ritonavir-containing products, telaprevir, 
teriflunomide, tofisopam, 
troleandomycin, verapamil, 
voriconazole) within 14 days or 5 half-
lives, whichever is longer, of dosing;  or 
weak CYP3A4 or CYP2C8 inhibitors 
(e.g., amlodipine, chlorzoxazone, 
cilostazol, fosaprepitant, istradefylline, 
ivacaftor, lomitapide, ranitidine, 
ranolazine, tacrolimus, ticagrelor, 
trimethoprim) within 7 days or 5 half-
lives, whichever is longer, from dosing.  
For weak CYP3A4 or CYP2C8 
inhibitors, medications may be allowed 
in consultation with the Medical Monitor 
(MM). 
28 
4.1.2. – 
Exclusion 
criteria 
15.  Subjects with aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-
glutamyltransferase (GGT), alkaline 
phosphatase (ALP) or total bilirubin ≥ 
1.0 × upper limit of normal (ULN) at 
Screening.  Subjects with elevated 
15.  Subjects with aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-
glutamyltransferase (GGT), alkaline 
phosphatase (ALP) or total bilirubin > 
1.5 × upper limit of normal (ULN) at 
Screening.  Subjects with elevated 
Increases the allowable 
upper limit of liver function 
test (LFT) results at 
Screening to 1.5 × the upper 
limit of normal based on the 
observation in the first 8 
subjects treated with 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 5 dated March 21, 2019 
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Comments 
bilirubin due to Gilbert’s Syndrome may 
be allowed at the discretion of the 
Investigator. 
bilirubin due to Gilbert’s Syndrome may 
be allowed at the discretion of the 
Investigator. 
lixivaptan at 200 mg BID 
(highest dose) in this study 
that no significant LFT 
abnormalities have been 
detected. The highest values 
were 1.2 times the upper limit 
of normal for transaminases 
with no increase in total 
bilirubin. 
32 
5.2 Blinding 
and 
Randomization 
This is an open-label study and no 
blinding procedures will be used.  
Following enrollment, subjects will be 
centrally assigned to one of 4 cohorts 
depending on CKD status (Table 5 1) 
and based on a predetermined 
algorithm.  The 200 mg BID dose 
cohorts will be enrolled first.  At least 2 
males or females will be included in the 
8 subjects (i.e., can be up to a 25%/75% 
split of male/female or 75%/25% split of 
male/female) assigned to each cohort. 
This is an open-label study and no 
blinding procedures will be used.  
Following enrollment, subjects will be 
centrally assigned to one of 4 cohorts 
depending on CKD status (Table 5 1) 
and based on a predetermined 
algorithm.  The 200 mg BID dose 
cohorts will be enrolled first.  At least 2 
males or females will be included in the 
8 subjects (i.e., can be up to a 25%/75% 
split of male/female or 75%/25% split of 
male/female) assigned to each cohort. 
Similarly, at least 2 subjects with 
CKD1 or CKD2 will be included in 8 
subjects each assigned to Cohorts 1 
and 3. 
Provides for flexibility to stop 
enrollment of CKD1 subjects 
in Cohorts 1 and 3 if sufficient 
experience with CKD2 
subjects has not occurred. 
36 
5.8.1 – 
Permitted 
therapy 
Lixivaptan has the potential to inhibit the 
metabolism of CYP3A4 and CYP2C8 
substrates, including atorvastatin and 
simvastatin, therefore care should be 
exercised when administering lixivaptan 
in combination with these substrates.  In 
order to minimize the potential for AEs 
Lixivaptan has the potential to inhibit the 
metabolism of CYP3A4 and CYP2C8 
substrates, including atorvastatin, and 
simvastatin, and amlodipine. 
Therefore, care should be exercised 
when administering lixivaptan in 
combination with these substrates.  In 
Because inhibition of 
CYP3A4 by lixivaptan may 
reduce metabolism of 
amlodipine, a dosing limit has 
been added. 


Palladio Biosciences 
 
 
 
 
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due to drug-drug interactions, prior to 
enrollment in the study, the Investigator, 
in consultation with the Medical Monitor, 
should consider potential dose 
adjustments or alternative therapeutic 
options that are not CYP3A4 or 
CYP2C8 substrates (e.g. rosuvastatin to 
replace simvastatin or atorvastatin) or 
that have a high therapeutic index.  If 
subjects are receiving simvastatin as 
background medication and it is not 
possible to replace simvastatin with 
rosuvastatin, the dose of simvastatin 
should be decreased to < 20 mg daily in 
subjects who are administered the 50 
mg BID dose of lixivaptan and < 10 mg 
daily in subjects who are administered 
the 200 mg BID dose of lixivaptan. 
order to minimize the potential for AEs 
due to drug-drug interactions, prior to 
enrollment in the study, the Investigator, 
in consultation with the Medical Monitor, 
should consider potential dose 
adjustments or alternative therapeutic 
options that are not CYP3A4 or 
CYP2C8 substrates (e.g. rosuvastatin to 
replace simvastatin or atorvastatin) or 
that have a high therapeutic index.  If 
subjects are receiving simvastatin as 
background medication and it is not 
possible to replace simvastatin with 
rosuvastatin, the dose of simvastatin 
should be decreased to < 20 mg daily in 
subjects who are administered the 50 
mg BID dose of lixivaptan and < 10 mg 
daily in subjects who are administered 
the 200 mg BID dose of lixivaptan.  If 
amlodipine is needed for clinical 
care, the dose should not exceed 5 
mg daily. 
37 
5.8.2 
Prohibited 
Therapy 
• 
Treatment with weak CYP3A4 or 
CYP2C8 inhibitors, including 
amlodipine, chlorzoxazone, 
cilostazol, fosaprepitant, 
istradefylline, ivacaftor, lomitapide, 
ranitidine, ranolazine, tacrolimus, 
ticagrelor, trimethoprim.  For weak 
CYP3A4 or CYP2C8 inhibitors, 
medications may be allowed in 
consultation with the Medical 
Monitor; 
• 
Treatment with weak CYP3A4 or 
CYP2C8 inhibitors, including 
amlodipine, chlorzoxazone, 
cilostazol, fosaprepitant, 
istradefylline, ivacaftor, lomitapide, 
ranitidine, ranolazine, tacrolimus, 
ticagrelor, trimethoprim.  For weak 
CYP3A4 or CYP2C8 inhibitors, 
medications may be allowed in 
consultation with the Medical 
Monitor; 
Amlodipine is a CYP3A4 
substrate and not an inhibitor.  
Thus, it has been deleted 
from this section. 


Palladio Biosciences 
 
 
 
 
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                                                                                  Clinical Study Protocol version 5 dated March 21, 2019 
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63 
Table 21-1 
Schedule of 
Assessments 
Screening 
-30 to -3 or -2 
Screening 
-44 to -3 or -2 
Increased duration of 
Screening from 4 weeks to 6 
weeks 
64 
Footnote 5 to 
Table 12-1 - 
Schedule of 
Assessments 
5. Clinical labs: hematology, clinical 
chemistry (including liver function), and 
urinalysis at approximately the same 
time of day (in the morning and, on 
dosing days, before the lixivaptan dose).  
The list of analytes is shown in Table 
6-1.  . 
5. Clinical labs: hematology, clinical 
chemistry (including liver function), and 
urinalysis at approximately the same 
time of day (in the morning and, on 
dosing days, before the lixivaptan dose).  
The list of analytes is shown in Table 
6-1. Lab tests that need to be 
repeated during Screening may be 
obtained through the services of an 
at-home nursing service provided by 
the Sponsor.   
Provides for the use of a 
home nursing service to draw 
blood if repeat lab tests are 
needed during Screening. 
65 
Footnote 18 to 
Table 12-1 - 
Schedule of 
Assessments 
If a patient does not return to the site for 
PK sample collection after discharge on 
Day 8, this will not be considered a 
protocol deviation. 
If a patient does not return to the site for 
PK sample collection after discharge on 
Day 8, but has the blood drawn by an 
at-home nursing service, this will not 
be considered a protocol deviation. 
Indicates that if a subject 
does not come back for visits 
after Day 8, then it is not a 
protocol deviation only if the 
blood is drawn by the at-
home nursing service. 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 4 dated January 9, 2019 
Confidential                       
 
 
 
 
 
 
           1 
 
 
Study PA-102 
Clinical Study Protocol version 4 dated January 9, 2019 
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.   
 
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 April 24, 2018 
Version 4 
Explanation 
1 
Title page 
Version of Protocol: 3 
Version of Protocol: 4 
Clarifies protocol version 
1 
Title page 
Date of protocol: April 24, 2018 
Date of protocol: January 9, 2019 
Updates protocol date 
1 
Title page 
Medical Monitor: 
 
Hooman Hajian, MD, MPH 
Medical Director, IQVIA 
10188 Telesis Court, Suite 400 
San Diego, CA  92121 
Mobile: (425) 205 0946 
Medical Monitor: 
Andrew Lowy, MD, FRACP 
Medical Director, IQVIA 
Direct: (984) 201-6550 (including 
urgent medical issues) 
Mobile: (310)  431-7666 
Fax: +1 (520) 829-9405 
Email: Andrew.Lowy@quintiles.com 
 
IQVIA 24/7 Medical Emergency 
Contact Center (MECC): 
(973) 659-6677;  
(512) 652-0191 (back-up) 
Updates Medical Monitor 
name and contact 
information.  Adds contact 
information for Medical 
Emergency Contact Center.  


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Page 
Section 
Version 3 dated April 24, 2018 
Version 4 
Explanation 
All 
Footnote 
24-Apr-2018 
09-Jan-2019 
Updates protocol date 
All 
Footnote 
Version 3 
Version 4 
Clarifies protocol version 
3 
Protocol approval – 
Sponsor signature 
Version of Protocol: 3 
Version of Protocol: 4 
Clarifies protocol version 
3 
Protocol approval – 
Sponsor signature 
Protocol date April 24, 2018 
Protocol date January 9, 2019 
Updates protocol date 
3 
Protocol approval – 
Sponsor signature 
Signature date April 24, 2018 
Signature date January 9, 2019 
Updates protocol date 
4 
Declaration of 
investigator 
…the accompanying Investigator 
Brochure (IB), version 15, dated 
March 12, 2018. 
…the accompanying current version of 
the Investigator Brochure (IB). 
Updates version of 
Investigator Brochure by 
referring to the current 
version, which is 
documented in the trial 
master file. 
11 
Synopsis 
Date of protocol: April 24, 2018 
Date of protocol: January 9, 2019 
Updates protocol date 
28 
4.1.2. – Exclusion 
criteria 
 
 
Updated exclusion criteria 
numbering to reflect insertion 
of one additional exclusion 
criterion at position 26 in the 
list 
 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 4 dated January 9, 2019 
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Text Clarifications 
This section lists corrections of typos, text changes for consistency or other clarifications. These changes do not affect clinical decision 
making or consent. 
Page 
Section 
Version 3 dated April 24, 2018 
Version 4 
Explanation 
26 
4.1.2 – 
Exclusion 
criteria 
1. Subjects with known sensitivity or 
idiosyncratic reaction to any compound 
present in lixivaptan, its related compounds 
such as benzazepines (e.g., tolvaptan, 
conivaptan, benazepril, fenoldopam, 
mesylate, or mirtazapine), or any compound 
listed as being present in the study 
formulation. 
1. Subjects with known sensitivity or 
idiosyncratic reaction to any compound 
present in lixivaptan, its related compounds 
such as benzazepines (e.g., tolvaptan, 
conivaptan, benazepril, fenoldopam, or 
mirtazapine), or any compound listed as being 
present in the study formulation. 
Deletion of 
mesylate, the 
counter-ion of 
fenoldopam 
27 
4.1.2 – 
Exclusion 
criteria 
18. Subjects have experienced an illness that 
is considered by the Investigator to be 
clinically significant within 2 weeks of study 
drug administration on Day 1. 
19. Subjects who have experienced an illness 
that is considered by the Investigator to be 
clinically significant within 2 weeks of study 
drug administration on Day 1. 
 
39 
6.1.6 – MRI 
Assessment 
Given the importance of performing the 
second MRI assessment within a short time 
interval after the last dose of study medication 
(PM dose on Day 7), all MRI assessments will 
be scheduled for each subject in conjunction 
with the Screening visit.   
Given the importance of performing the 
second MRI assessment within a short time 
interval after the last dose of study medication 
(PM dose on Day 7), it is recommended that 
all MRI assessments be scheduled for each 
subject at the time of the Screening visit. 
 
61 
12 -
APPENDICES 
This study uses the 2009 CKD-EPI creatinine 
equation,16 which is recommended by the 
KDIGO Clinical Practice Guidelines for 
Management of Chronic Kidney Disease3. 
This study uses the 2009 CKD-EPI creatinine 
equation,16 which is recommended by the 
KDIGO Clinical Practice Guidelines for 
Management of Chronic Kidney Disease. 
Deletion of 
reference at end 
of sentence. 
 
 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
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                                                                                  Clinical Study Protocol version 4 dated January 9, 2019 
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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. 
 
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Version 4 
Comments 
9 
Synopsis 
The subjects will be male or 
female, between 18 and 60 years 
of age. 
The subjects will be male or 
female, between 18 and 65 years 
of age. 
Increases the eligible age for 
inclusion into the study to 65 
years. 
22 
3.1 - Study Design 
Subjects will be allowed to re-
screen for the study for up to two 
times. 
Subjects may be allowed to re-
screen or have repeat testing 
after agreement between the 
investigator and medical 
monitor. 
Introduces more flexibility in 
screening procedures. 
24 
4.1.1 – Inclusion 
Criteria 
2.  Male or female, between 18 
and 60 years of age (inclusive) at 
the time of Screening. 
2.  Male or female, between 18 
and 65 years of age (inclusive) at 
the time of Screening. 
Increases the eligible age for 
inclusion into the study to 65 
years.  
25 
4.1.1 – Inclusion 
Criteria 
Double barrier methods of non-
hormonal contraception are 
permitted in this study.  Acceptable 
forms of contraception include the 
following: 
• intrauterine device 
Double barrier methods of non-
hormonal contraception are 
permitted in this study.  Acceptable 
forms of contraception include the 
following: 
• 
intrauterine device, including 
Mirena® 
Clarifies that use of the low 
progesterone-releasing intrauterine 
device Mirena is allowed.  
25 
4.1.1 – Inclusion 
Criteria 
Hormonal contraception is not 
permitted in this pharmacokinetic 
study due to the potential for 
Estrogen-based hormonal 
contraception is not permitted in 
this pharmacokinetic study due to 
Limits hormonal contraception 
exclusion to estrogen-containing 
contraceptives.  Progesterone-only 


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Page 
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Version 3 dated April 24, 2018 
Version 4 
Comments 
interaction with lixivaptan.   
the potential for interaction with 
lixivaptan.   
contraceptives are allowed.    
27 
4.1.2. – Exclusion 
criteria 
15.  Subjects with aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-
glutamyltransferase (GGT), 
alkaline phosphatase (ALP) or total 
bilirubin ≥ 1.0 × upper limit of 
normal (ULN) at Screening.   
15.  Subjects with aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-
glutamyltransferase (GGT), 
alkaline phosphatase (ALP) or total 
bilirubin ≥ 1.0 × upper limit of 
normal (ULN) at Screening.  
Subjects with elevated bilirubin 
due to Gilbert’s Syndrome may 
be allowed at the discretion of 
the Investigator. 
Allows inclusion of subjects with 
elevated bilirubin due to Gilbert's 
Syndrome at the discretion of the 
Investigator. 
27 
4.1.2. – Exclusion 
criteria 
17. Subjects with contraindications 
to or interference with MRI 
assessments (ferromagnetic metal 
prostheses, aneurysm clips, 
severe claustrophobia, or large 
abdominal/back tattoos.  
Investigator should seek MRI 
safety guidance from local MRI 
facility). 
18. Subjects with contraindications 
to or interference with MRI 
assessments (ferromagnetic metal 
prostheses, aneurysm clips, 
severe claustrophobia, or large 
abdominal/back tattoos) will be 
excused from this procedure, 
but may participate in the study 
providing that all other eligibility 
criteria are met.  Investigator 
should seek MRI safety guidance 
from local MRI facility. 
Allows inclusion of subjects with 
contraindications to or interference 
with MRI assessments provided 
they meet all other inclusion 
criteria.  Clarifies that no MRI tests 
will be conducted on these 
subjects. 
28 
4.1.2. – Exclusion 
criteria 
 
26. Subjects who have 
experienced elevated AST or 
ALT (defined as ≥ 2.0 × ULN) 
while taking tolvaptan. 
Adds exclusion of subjects who 
have shown signs of liver toxicity 
on tolvaptan therapy. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 4 dated January 9, 2019 
Confidential                       
 
 
 
 
 
 
           6 
 
Page 
Section 
Version 3 dated April 24, 2018 
Version 4 
Comments 
32 
5.4 – Identity of 
Investigational 
Product 
Batch 17120A 
Batch 17121A1 
Clarifies batch number of 
investigational product. 
37 
5.9 - Diet, Fluid, 
and Activity Control 
Due to the expected aquaretic 
effects of lixivaptan, subjects 
should be reminded to maintain 
adequate fluid intake and be 
mindful of their thirst status at each 
study visit.  Subjects should be 
instructed to replenish fluids with 
each void and aim to drink 4-5 
liters of fluid per day, or as needed 
to maintain adequate hydration.   
During Days -2 and -1 of CRU 
confinement, subjects should 
continue consuming their usual 
amount of fluids.  Due to the 
expected aquaretic effects of 
lixivaptan, subjects should be 
reminded to maintain adequate 
fluid intake and be mindful of their 
thirst status at each study visit 
starting with Day 1 of CRU 
confinement.  Subjects should be 
instructed to replenish fluids with 
each void and aim to drink 4-5 
liters of fluid per day, or as needed 
to maintain adequate hydration, 
while taking lixivaptan.   
Clarifies fluid intake 
recommendations before the first 
dose of study drug and while 
taking study drug.  
39 
6.1.4 - 12-Lead 
Electrocardiograms 
Electrocardiograms will be 
obtained with the subject 
remaining in a semi-recumbent 
position following 5 minutes of rest.  
Electrocardiograms will be 
obtained with the subject 
remaining in a supine or semi-
recumbent position following 5 
minutes of rest.  All 
electrocardiograms throughout 
the study for a given subject 
should be measured in the same 
position, i.e. either all in a 
supine position or all in a semi-
recumbent position.   
Allows supine position for 
electrocardiograms provided that 
the same position is maintained for 
the same subject throughout the 
study. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 4 dated January 9, 2019 
Confidential                       
 
 
 
 
 
 
           7 
 
Page 
Section 
Version 3 dated April 24, 2018 
Version 4 
Comments 
40 
6.1.6 – MRI 
Assessment 
 
Occasionally, patients may be 
unable to continue into the 
study after completing their 
Screening visit and baseline MRI 
assessment (for example, due to 
personal circumstances or for 
not meeting laboratory inclusion 
criteria).  These patients may 
subsequently qualify for the 
study and be rescreened at a 
later time.  In this case, their 
prior baseline MRI assessment 
may be used instead of 
obtaining a new baseline MRI 
scan; provided, however, that no 
more than 8 weeks have elapsed 
from the time of the initial MRI 
assessment until admission into 
the CRU.    
Clarifies that the baseline MRI 
assessment completed by patients 
who subsequently screen fail or 
are otherwise unable to continue 
into the study is valid for a period 
of 8 weeks.  Patients who 
successfully rescreen must be 
admitted into the CRU within 8 
weeks from the original MRI 
assessment date for such MRI to 
be considered valid.  
41 
6.1.6 – MRI 
Assessment 
Subjects with ferro-magnetic 
prostheses, aneurysm clips, 
severe claustrophobia or other 
contraindications or exclusions 
interfering with MRI measurements 
will be excluded from study 
participation.  
Subjects with ferro-magnetic 
prostheses, aneurysm clips, 
severe claustrophobia or other 
contraindications or exclusions 
interfering with MRI measurements 
will be excused from this 
procedure, but may participate 
in the study providing that all 
other eligibility criteria are met.  
Investigator should seek MRI 
safety guidance from the local 
MRI facility. 
Allows inclusion of subjects with 
contraindications to or interference 
with MRI assessments provided 
they meet all other inclusion 
criteria.  Clarifies that no MRI tests 
will be conducted on these 
subjects. 


Palladio Biosciences 
 
 
 
 
    Summary of Changes 
Study PA-102  
                                                                                  Clinical Study Protocol version 4 dated January 9, 2019 
Confidential                       
 
 
 
 
 
 
           8 
 
Page 
Section 
Version 3 dated April 24, 2018 
Version 4 
Comments 
62 
Footnote 2 to 
Table 12-1 - 
Schedule of 
Assessments 
2. Serum pregnancy test to be 
performed at Screening; Urine 
pregnancy test to be performed at 
Day -2 or Day -1. 
2. Serum pregnancy test to be 
performed at Screening; Urine 
pregnancy test to be performed at 
Day -2 or Day -1 and at End of 
Study. 
Clarifies nature of pregnancy test 
at End of Study visit. 
63 
Footnote 7 to 
Table 12-1 – 
Schedule of 
Assessments 
Electrocardiograms to be obtained 
following 5 minutes rest in 
semi-recumbent position.  
Electrocardiograms to be obtained 
following 5 minutes rest in supine 
or semi-recumbent position. The 
same position must be used 
throughout the study for a given 
subject. 
Allows supine position for 
electrocardiograms provided that 
the same position is maintained for 
the same subject throughout the 
study. 
63 
Table 12-2 - 
Assessment 
Windows.  
PK Blood Samples 
– Assessment Day 
Day 1, Day 2, Day 4, Day 6, Day 7, 
Day 8, Day 9 
Day 1, Day 2, Day 4, Day 6, Day 7, 
Day 8, Day 9, Day 11 
Adds Day 11 to the Assessment 
Window table. 
65 
Table 12-2 - 
Assessment 
Windows.  
PK Blood Samples 
– Window (units) 
- 60 minutes (predose Day 1) 
- 10 minutes (predose Day 7) 
± 3 min (< 1-4 hr) 
± 5 min (> 4-12 hr) 
± 10 min (> 12-24 hr) 
± 1 hr (> 24-48 hr) 
± 2 hr (> 48-96 hr) 
- 60 minutes (predose Day 1) 
- 10 minutes (predose Day 7) 
± 3 min (≤ 4 hr) 
± 5 min (> 4 hr but ≤ 12 hr) 
± 10 min (> 12 hr but ≤ 24 hr) 
± 1 hr (> 24 hr but ≤ 48 hr) 
± 2 hr (> 48) 
Clarifies the appropriate time 
window for time values that lie on 
the extremes of each time interval.   
 

SAP_001.pdf: 
Study Title: A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, 
Pharmacokinetics and Pharmacodynamics of Lixivaptan in Subjects With Autosomal 
Dominant Polycystic Kidney Disease 
 
ClinicalTrials.gov ID: NCT03487913 
 
 
 
Statistical Analysis Plan (Non-PK/PD) Version 1.0, dated April 25, 2019 
 
Statistical Analysis Plan for Pharmacokinetics/Pharmacodynamics Version 1.0, dated August 12, 
2019 
 
Palladio PA-102 Biostatistics Note to File: Urine osmolality and copeptin sample exclusion due 
to non-drug related anomaly, dated June 26, 2020 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL PA-102 
Page 1 of 36 
 
 
STATISTICAL ANALYSIS PLAN (NON-PK/PD) 
 
 
PA-102 
 
A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, Pharmacokinetics 
and Pharmacodynamics of Lixivaptan in Subjects with Autosomal Dominant Polycystic 
Kidney Disease   
 
AUTHOR: Lynda Olinger 
VERSION NUMBER AND DATE: V1.0, 25 APRIL 2019 
 
 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL PA-102 
Page 2 of 36 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE  
Statistical Analysis Plan V1.0 (Dated 25APR2019) for Protocol PA-102. 
 
Name 
Signature 
Date 
(DDMMMYYYY) 
Author: 
Lynda Olinger 
Refer to electronic signature 
 
Position: 
Statistical Team Lead 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date (DDMMMYYYY) 
Approved By: 
Neil Shusterman, MD 
 
 
 
Position: 
Chief Medical Officer 
 
Company: 
Palladio Biosciences 
 
 
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Page 3 of 36 
 
MODIFICATION HISTORY 
 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
V1.0 
25APR2019 
Lynda Olinger 
Not applicable, first version 
 
 
 
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TABLE OF CONTENTS 
1. INTRODUCTION ................................................................................................................................ 8 
2. STUDY OBJECTIVES ......................................................................................................................... 8 
2.1. 
Primary Objective..................................................................................................................................... 8 
2.2. 
Secondary Objectives ............................................................................................................................... 9 
3. STUDY DESIGN .................................................................................................................................. 9 
3.1. 
General Description .................................................................................................................................. 9 
3.2. 
Schedule of Events ................................................................................................................................. 10 
3.3. 
Changes to Analysis from Protocol .......................................................................................................... 10 
4. PLANNED ANALYSES .................................................................................................................... 11 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................ 11 
4.2. 
Interim Analysis ..................................................................................................................................... 11 
4.3. 
Final Analysis ......................................................................................................................................... 11 
5. ANALYSIS SETS .............................................................................................................................. 11 
5.1. 
All Subjects Enrolled Set ......................................................................................................................... 11 
5.2. 
Safety Analysis Set ................................................................................................................................. 12 
6. GENERAL CONSIDERATIONS ..................................................................................................... 12 
6.1. 
Summary Statistics ................................................................................................................................. 12 
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6.2. 
Reference Start Date and Study Day ....................................................................................................... 12 
6.3. 
Baseline ................................................................................................................................................. 13 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 13 
6.5. 
Windowing Conventions ........................................................................................................................ 14 
6.6. 
Common Calculations ............................................................................................................................. 14 
6.7. 
Software Versions .................................................................................................................................. 14 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 14 
7.1. 
Sample Size ............................................................................................................................................ 14 
7.2. 
Estimands .............................................................................................................................................. 15 
7.3. 
Missing Data .......................................................................................................................................... 16 
7.4. 
Examination of Subgroups ...................................................................................................................... 16 
8. OUTPUT PRESENTATIONS ......................................................................................................... 16 
8.1. 
Treatment Summarization ...................................................................................................................... 16 
8.2. 
Precision ................................................................................................................................................ 17 
9. DISPOSITION AND WITHDRAWALS ....................................................................................... 17 
9.1. 
Protocol Deviations ................................................................................................................................ 18 
9.1.1. 
Deviations Related to Study Conduct .......................................................................................................18 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 19 
10.1. 
Derivations ......................................................................................................................................... 19 
11. 
SURGICAL AND MEDICAL HISTORY ..................................................................................... 20 
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12. 
PRIOR AND CONCOMITANT MEDICATIONS ..................................................................... 20 
13. 
STUDY MEDICATION EXPOSURE AND COMPLIANCE .................................................... 21 
13.1. 
Derivations ......................................................................................................................................... 21 
14. 
PHARMACOKINETICS ANALYSIS .......................................................................................... 22 
15. 
PHARMACODYNAMIC ANALYSES ......................................................................................... 22 
16. 
SAFETY OUTCOMES .................................................................................................................. 22 
16.1. 
Adverse Events ................................................................................................................................... 22 
16.1.1. 
Severity .....................................................................................................................................................23 
16.1.2. 
Relationship to Study Medication ............................................................................................................23 
16.1.3. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................24 
16.1.4. 
Serious Adverse Events .............................................................................................................................24 
16.2. 
Deaths ................................................................................................................................................ 25 
16.3. 
Laboratory Evaluations ....................................................................................................................... 25 
16.3.1. 
Laboratory Reference Ranges ...................................................................................................................26 
16.4. 
ECG Evaluation ................................................................................................................................... 26 
16.5. 
Vital Signs ........................................................................................................................................... 27 
16.5.1. 
Vital Signs Markedly abnormal Criteria ....................................................................................................28 
16.6. 
Physical Examination .......................................................................................................................... 29 
16.7. 
Other Safety Assessments .................................................................................................................. 29 
17. 
DATA NOT SUMMARIZED OR PRESENTED ....................................................................... 30 
18. 
REFERENCES ............................................................................................................................... 31 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................... 32 
Output Conventions .......................................................................................................................................... 32 
Dates & Times ................................................................................................................................................... 32 
Spelling Format ................................................................................................................................................. 32 
Presentation of Treatment Groups .................................................................................................................... 32 
Presentation of Visits ........................................................................................................................................ 33 
Presentation of Nominal Times .......................................................................................................................... 34 
Listings .............................................................................................................................................................. 34 
APPENDIX 2. PARTIAL DATE CONVENTIONS .............................................................................. 35 
Algorithm for Treatment Emergence of Adverse Events: .................................................................................... 35 
 
 
 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and 
analysis of efficacy and safety data for Protocol PA-102. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 5, dated 21 March 2019. 
A separate pharmacokinetics/pharmacodynamics (PK/PD) SAP will be written by IQVIA PK and 
will describe the analysis and presentation of PK and PD data for Protocol PA-102.  
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objectives of this study are:  
• To characterize the safety and tolerability of lixivaptan following multiple doses in 
autosomal dominant polycystic kidney disease (ADPKD) subjects with relatively 
preserved kidney function (chronic kidney disease stage 1 [CKD1] and stage 2 [CKD2]) 
and moderately impaired renal function [CKD3].  
• To characterize the PK profile of lixivaptan and its major metabolites (WAY-141624, 
WAY-138451, and WAY-138758) following multiple doses of lixivaptan in ADPKD 
subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately 
impaired renal function (CKD3).  
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Page 9 of 36 
2.2. SECONDARY OBJECTIVES 
The secondary objectives of this study are:  
• To characterize the effect of lixivaptan on urine osmolality over a 24-hour period 
following multiple doses of lixivaptan in ADPKD subjects; and  
• To characterize the time course of the pharmacodynamic effect of lixivaptan on urine 
output, total kidney volume, liver volume, plasma copeptin and serum creatinine in 
ADPKD subjects.  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase 2, open-label, parallel-group, multiple dose study designed to evaluate the PK, 
pharmacodynamic (PD), safety and tolerability of multiple twice daily (BID) doses of 50 mg 
and 200 mg lixivaptan in ADPKD subjects with chronic kidney disease in stages CKD1, CKD2 or 
CKD3. Enrolled subjects will be assigned according to CKD classification to take one of 2 
lixivaptan oral dose regimens for 7 days as shown below (Table 1). Each dose regimen includes 
morning (AM) and evening (PM) oral administration of lixivaptan. 
Table 1  Chronic Kidney disease Classification Summary by Cohort and Dose Group 
CKD Stage 
Cohort  
N  
eGFRa  
Dose 
CKD1 or CKD2  
1  
8 
eGFR ≥ 60 mL/min/1.73 m2  
200 mg BID 
CKD3  
2   
8 
eGFR ≥ 30 to < 60 mL/min/1.73 m2  
200 mg BID 
CKD1 or CKD2  
3  
8 
eGFR ≥ 60 mL/min/1.73 m2  
50 mg BID 
CKD3  
4   
8 
eGFR ≥ 30 to < 60 mL/min/1.73 m2  
50 mg BID 
Abbreviations: CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; BID=twice daily.a 
eGFR is calculated 
by the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 
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Approximately 32 subjects (or more as necessary to achieve 32 study completers) will be 
enrolled at approximately 15 sites in the United States (US). Subjects will take one of 
2 lixivaptan oral dose regimens for 7 days and will be allocated to one of 4 cohorts depending 
on CKD status. At least 2 males or females will be included in the 8 subjects assigned to each 
cohort (i.e. can be up to a 25%/75% split of male/female or 75%/25% split of male/female).  
The 200 mg BID dose cohorts will be enrolled first. 
The study includes a screening period of up to 42 days. Subjects will be confined to the clinical 
research unit (CRU) on 2 separate occasions, with a total period of confinement of up to 7 
days and 5 nights. The first confinement period will last up to 4 days (up to 3 nights), and the 
second confinement period will last 3 days (2 nights). Subjects will return to the CRU on an 
outpatient basis on Day 4 and Day 6 in the morning for a trough PK assessment. Except for the 
AM and PM doses on Days 1, 6 and 7, and the AM doses on Days 2, 4 and 6, all other doses 
will be self-administered by the subject. Subjects will return on Day 35 (±2) for end of study 
(EOS) assessments. 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 12.2 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
There are no meaningful changes in the analysis plans relative to the study protocol. 
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4. PLANNED ANALYSES 
4.1. DATA MONITORING COMMITTEE (DMC) 
There is no DMC for this study requiring statistical outputs. 
4.2. INTERIM ANALYSIS  
No interim analysis is planned for this study. 
4.3. FINAL ANALYSIS  
All final, planned analyses of safety and efficacy data identified in this SAP will be performed 
by IQVIA Biostatistics, following Palladio authorization of this SAP, identification of major 
protocol deviations requiring analysis exclusions, database lock, and determination of analysis 
sets. 
5. ANALYSIS SETS 
5.1. ALL SUBJECTS ENROLLED SET 
The all subjects enrolled set will contain all subjects who provide informed consent for this 
study. Subjects in this population will be used for disposition summaries, and where 
appropriate, will be analyzed according to cohort allocation. Subjects not allocated to a cohort 
due to screen failure will be indicated as Not Allocated. 
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5.2. SAFETY ANALYSIS SET  
The safety analysis set will contain all subjects who receive at least one dose of study 
medication and will be analyzed according to treatment received. This analysis set will be used 
for the safety analyses and for summarization of baseline/demographic characteristics. 
6. GENERAL CONSIDERATIONS 
Some minor modifications may be necessary to the planned design of tables, figures, and 
listings to accommodate data collected during the actual study conduct. 
6.1. SUMMARY STATISTICS 
For categorical variables, the analysis set size (N for sample size and n for available data) and 
percentage (of available data) for each class of the variable will be presented. Percentages will 
be based on the number of subjects within the relevant analysis set and/or the number of 
subjects with data available.  
All continuous variables will be summarized using descriptive statistics, including number of 
non-missing observations (n), mean, standard deviation (SD), median, minimum and 
maximum values.  
6.2. REFERENCE START DATE AND STUDY DAY 
Study day will be calculated from the reference start date and will be used to show the 
start/stop day of assessments and events. 
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The reference start date is defined as the day of the first dose of study medication (Day 1 is 
the day of the first dose of study medication). Study day will be calculated relative to 
reference start date and will appear in every listing where an assessment date or event date 
appears.  
• If the date of the event is on or after the reference date, then:  
Study Day = (date of event – reference date) + 1. 
• If the date of the event is prior to the reference date, then:  
Study Day = (date of event – reference date). 
If the event date is partial or missing, the study day and any corresponding durations will be 
missing in the listings. 
6.3. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 
prior to reference start date (including unscheduled assessments). In the case where the last 
non-missing measurement and the reference start date coincide, that measurement will be 
considered pre-baseline, but Adverse Events (AEs) and medications commencing on the 
reference start date will be considered post-baseline. 
6.4. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
Unscheduled measurements will not be included in summary statistics but will contribute to 
the best/worst case value where required (e.g., shift tables) and assessment of clinical 
outliers.  
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In the case of a retest of a scheduled assessment, the last available measurement for that 
scheduled time (i.e., the retest measurement) will be used for summaries unless flagged as 
invalid.  
Listings will include all scheduled, unscheduled, retest and early discontinuation data. 
6.5. WINDOWING CONVENTIONS 
No visit windowing will be performed for this study. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
• Test value (after baseline) – Baseline value 
6.7. SOFTWARE VERSIONS 
All derivations, statistical analyses, summaries and listings will be generated using SAS version 
9.4 (SAS Institute, Inc., Cary, North Carolina).   
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE 
Calculations to determine sample size were performed assuming a CV of 0.30 and 0.41 for 
lixivaptan maximum concentration in the sampled matrix (ng/mL) (Cmax) and area under the 
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concentration-time curve (AUC), respectively. Assuming a lognormal distribution, this implies 
that the variances for the logarithm of Cmax and AUC are 0.086 and 0.155, respectively. Under 
these assumptions and a random sample of 8 observations per cohort, the probability is 0.90 
that the point estimate of the population central value (observed geometric mean) for 
lixivaptan Cmax and AUC will be within (84.3%, 118.6%) and (79.5%, 125.7%) of the population 
central value (the median), respectively.  
From the perspective of tolerability assessment for multiple dose regimens, for the true 
population incidence rates of 0.10, 0.20, 0.30, 0.40 and 0.50 for a given AE, the probabilities 
that the AE would not be observed in a group of 8 subjects administered lixivaptan are given 
in Table 2: 
Table 2  Probability of Not Observing an Adverse Event for Various True Incidence Rates 
True Incidence Rate 
Probability of Not Observing an AE in Group of 8 Subjects 
0.1 
0.43 
0.2 
0.168 
0.3 
0.058 
0.4 
0.017 
0.5 
0.004 
7.2. ESTIMANDS 
As per ICH E9 (R1), the safety and efficacy estimand for this study is described as follows: 
Primary Estimand: The safety and tolerability of lixivaptan following multiple doses in 
autosomal dominant polycystic kidney disease (ADPKD) subjects. 
• Population: Subjects with ADPKD and defined further through appropriate 
inclusion/exclusion criteria. 
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• Variable (or endpoint): The evaluation of physical examination findings, vital 
signs, 12-lead electrocardiograms (ECG), clinical laboratory findings, 
assessment of adverse events (AE), assessment of aquaretic tolerability.  
• Strategy for addressing intercurrent event: Regardless if subject discontinues 
treatment prematurely. 
• Population-level summary: Descriptive differences in safety variables and 
frequencies of AEs and physical examination findings of the four cohorts. 
7.3. MISSING DATA 
Missing data will not be imputed but analyzed as missing.  
7.4. EXAMINATION OF SUBGROUPS  
Subgroup analyses will not be performed for this study. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows the conventions for presentation of data in outputs.  
8.1. TREATMENT SUMMARIZATION 
In general, data will be presented for each cohort, distinguishing between the different renal 
groups (CKD1/2 and CKD3) and dosages (50 mg, 200 mg). Data will also be presented for all 
study subjects combined where appropriate. 
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8.2. PRECISION 
Safety variables (i.e., clinical laboratory values, vital signs, and electrocardiogram [(ECG)] 
intervals), including derivations thereof, will be reported to the same precision as the source 
data.  
For the reporting of descriptive statistics, SD will be presented to 2 digits more precision than 
the source data and the mean, median and confidence intervals will be presented to 1 digit 
more precision than the source data. The minimum and maximum will be presented to the 
same precision as the source data. Percentages and CV (%) will always be reported to 1 
decimal place. P-values, if any, shall be reported to 4 decimal places or as <0.0001. 
The templates provided with this SAP describe the presentations for this study and therefore 
the format and content of the summary tables, figures and listings to be provided by IQVIA 
Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study. Subject 
disposition will be tabulated for each cohort and for all subjects overall, with the number of 
subjects allocated to a cohort, who complete the study, prematurely discontinue, and the 
reason for early discontinuation presented. A summary of all analysis sets and reasons for 
exclusion from an analysis set will also be presented. Listings will present dates of completion 
or early withdrawal and the reason for early discontinuation as well as exclusion from an 
analysis set and reason for exclusion, if applicable, for each subject.  
Listings of inclusion/exclusion criteria responses, protocol deviations and study treatment 
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administration will be provided. 
9.1. PROTOCOL DEVIATIONS 
A protocol deviation is defined as an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the Investigational Review Board (IRB) 
and agreed to by the Investigator.  
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, which 
will be recorded in the subject’s source documentation. This information will be provided to 
IQVIA Biostatistics to determine inclusion/exclusion from analysis sets. 
9.1.1. 
DEVIATIONS RELATED TO STUDY CONDUCT 
Protocol deviations will be listed including a classification of minor or major, as determined by 
clinical staff. A major deviation occurs when there is not adherence to the protocol by the 
subject or Investigator that results in a significant, additional safety risk to the subject or 
impacts the ability to utilize the data in analyses. Major deviations can include: 
• Not adhering to inclusion or exclusion criteria 
• Enrolment of the subject without prior Sponsor approval, 
• Intentional overdose 
• Non-compliance on multiple occasions with major testing procedures (PK, urine 
osmolality, magnetic resonance imaging) 
• Situations leading to involuntary withdrawal of the subject from the trial (e.g., 
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repeatedly missing visits) 
• Not adhering to US Food and Drug Administration regulations or International 
Conference on Harmonisation Guideline for Good Clinical Practice  
Major deviations may lead to the subject being withdrawn from the study. All other deviations 
will be considered minor. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Individual subject demographics and baseline characteristics, including height, weight, body 
mass index (BMI), CKD history and duration of CKD since initial diagnosis, will be presented in 
listings. In the situation where the date of diagnosis is partial, duration will be determined 
according to available information relative to date of informed consent. If date of diagnosis is 
missing in the listings, duration will also be missing. Age, in years, will be obtained from the 
eCRF and is relative to date of informed consent. 
Demographic characteristics will be summarized by means of descriptive statistics, frequency 
counts and percentages, and will be tabulated by cohort and for all subjects overall. No 
statistical testing will be carried out for demographic or other baseline characteristics. 
10.1. DERIVATIONS 
• Duration of CKD since initial diagnosis of CKD: 
o If full CKD date of diagnosis is available, then: 
Duration since diagnosis of CKD (years) = (Date of Informed Consent – CKD Initial 
Date of Diagnosis) / 365.25.  
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o If only month and year of diagnosis is available, then: 
Duration since diagnosis of CKD (years) = (Year/Month of Informed Consent – CKD 
Initial Year/Month of Diagnosis) / 12. 
o If only year of diagnosis is available, then: 
Duration since diagnosis of CKD (years) = (Year of Informed Consent – CKD Initial 
Year of Diagnosis).  
11. SURGICAL AND MEDICAL HISTORY 
Surgical and medical history will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) and will be listed for the safety analysis set by cohort and 
subject ID. Changes in health or new symptoms occurring during the screening period will be 
recorded as medical history. 
12. PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medication usage will be coded using the most recent WHO Drug 
Dictionary Version and will be summarized and listed for the safety analysis set by cohort and 
subject ID. 
Prior medications are medications which started and stopped prior to the first dose of study 
medication. Concomitant medications are medications which were taken during the 
treatment period and either ended during the treatment period or were ongoing at the end of 
treatment (EOT). Specifically, concomitant medications:  
• Started after the first dose of study medication or  
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• 
Started prior to the first dose of study medication and were continued after the first dose 
of study medication  
Prior and concomitant medications started before study medication and those started after 
first dose of study medication will be flagged in the listing as indicated. No partial start and 
end dates are permitted for concomitant and prior medications.  
13. STUDY MEDICATION EXPOSURE AND COMPLIANCE 
Exposure to study medication, expressed as the number of doses administered and total 
dosage administered, will be presented for each cohort in the safety analysis set by means of 
descriptive statistics, as described in Section 6.1 . Compliance as a percentage will be 
summarized by means of descriptive statistics. 
Subjects will receive 2 doses of the study drug per day for 7 days, i.e., a total of 14 doses per 
subject. The total prescribed dosage in this study for cohorts 1 and 2 is 2800 mg (200 mg BID 
for 7 days). Cohorts 3 and 4 will be prescribed a total dosage of 700 mg (50 mg BID for 7 days). 
13.1. DERIVATIONS 
Compliance with study medication will be based on the drug dosage administration as 
recorded in the eCRF and is calculated as follows:   
• 
Compliance with study medication =  
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑥𝑥 100%  
 
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14. PHARMACOKINETICS ANALYSIS 
See separate document (PK/PD SAP). 
15. 
PHARMACODYNAMIC ANALYSES 
See separate document (PK/PD SAP). 
16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Set.  
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section.  
16.1. ADVERSE EVENTS 
Adverse events (AEs) will be coded using the most recent version of MedDRA. 
Treatment emergent adverse events (TEAEs) are defined as any event not present before 
exposure to study drug and subsequently started, or any event already present that worsens 
in either intensity or frequency, after exposure to study drug. An algorithm for determining 
whether AE is treatment-emergent if AE start date or AE end date is unknown is described in 
Appendix 2. 
Any AEs and serious adverse events (SAEs) related to study participation (e.g., protocol-
mandated intervention) will be recorded from the time the subject signs the informed 
consent form until the start of study treatment. All other AEs and SAEs will be recorded from 
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the start of study treatment until exit from the study.  
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, vital sign measurements), including those that worsen from 
baseline, deemed to be clinically significant in the medical and scientific judgment of the 
investigator are to be recorded as AEs or SAEs. 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. 
16.1.1. 
SEVERITY 
Adverse event severity is classified as mild/moderate/severe/life-threatening/death. TEAEs 
starting after the first dose of study medication with a missing severity will be classified as 
missing. If a subject reports a TEAE more than once within that system organ class 
(SOC)/preferred term (PT), the AE with the worst-case severity will be used in the 
corresponding severity summaries.  
16.1.2. 
RELATIONSHIP TO STUDY MEDICATION 
Relationship to study medication, as indicated by the investigator, is classified as “not 
related”, “unlikely related”, “possibly related”, “probably related”, “definitely related”. If the 
final determination of causality is unknown and the investigator does not know whether the 
study drug caused the event, then the TEAE will be handled as “possibly related to study drug” 
for reporting purposes. 
A “related” TEAE is defined as a TEAE with a relationship to study medication as “possibly 
related”, “probably related” or “definitely related” to study medication. TEAEs with a missing 
relationship to study medication will be recorded as “possibly related to study drug”. If a 
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subject reports the same AE more than once within that SOC/PT, the AE with the worst-case 
relationship to study medication will be used in the corresponding relationship summaries. 
An overview of severe and serious related TEAEs, as well as TEAEs leading to discontinuation 
of study medication, permanent discontinuation from the study and death will be summarized 
for each cohort and dose. Incidence of TEAEs will also be tabulated per cohort by the 
following: 
• 
By SOC and PT 
• 
By SOC, PT and severity 
• 
By SOC, PT and relationship to study medication 
The tables will include the number and percentage of subjects in each category, as well as the 
number of events. All AE data will be listed for all subjects with both the investigator’s 
verbatim terms and the MedDRA preferred terms. Listings will also include the SAEs, start and 
end time and date of AEs, relationship to study drug, severity, action taken for the AEs and 
outcome of the AE. 
16.1.3. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication will be identified by using 
the variable pertaining to “Action taken with drug” on the AE page of the eCRF and listed. 
16.1.4. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) will be recorded as “Serious” on the AE page of the eCRF and 
will be listed. 
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16.2. DEATHS 
A listing of all AEs leading to death will be provided. 
16.3. LABORATORY EVALUATIONS 
Central laboratory results will be included in the reporting of this study for hematology, 
clinical chemistry (including liver function) and urinalysis. A list of laboratory assessments to 
be included in the outputs is included in Table 6-1 of the protocol. Assessment windows for 
laboratory evaluations are presented in Table 12-2 of the protocol. Presentations will use SI 
units, as provided by the laboratories.  
Protocol-specified clinical laboratory tests will be summarized using descriptive statistics. 
Clinical laboratory data collected during study conduct which were not required per protocol, 
such as for special testing to evaluate an AE, will be listed separately and not summarized. 
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 quantitative summaries, but will be presented as recorded, i.e. as “< X” or 
“> X”, in the listings. 
The following summaries will be provided for laboratory data by cohort at each scheduled 
timepoint: 
• Actual and change from baseline (descriptive statistics n, mean, SD, median, minimum 
and maximum for quantitative measurements; frequency and proportion for 
categorical measurements)  
• Shift from baseline (normal, low, high) to last observation on treatment (continuous 
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variables only)  
• Individual data listings of laboratory results, with values outside the laboratory’s 
reference range flagged as low or high. Clinical laboratory reference/normal ranges 
will be included in the listing. 
• For urinalysis, shift tables comparing baseline value to maximum value (using number 
of subjects with results of negative, trace or positive) for categorical variables 
• A listing of serum and urine pregnancy results. 
16.3.1. 
LABORATORY REFERENCE RANGES  
Quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges by the lab vendors and categorized as: 
• Low: Below the lower limit of the laboratory reference range.  
• Normal: Within the laboratory reference range (upper and lower limit included). 
• High: Above the upper limit of the laboratory reference range. 
16.4. ECG EVALUATION 
Results of the ECG assessments will be included in the reporting of this study. Overall 
evaluation of safety ECGs will be summarized by cohort using descriptive statistics as 
described in Section 6.1, as well as with frequency counts and percentage of subjects with 
results classified by the investigator as normal, abnormal – not clinically significant (NCS) and 
abnormal – clinically significant (CS). 
The following ECG parameters will be reported for this study: PR interval, QRS duration, QT 
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interval (uncorrected), QTcF interval, and heart rate and ventricular rate (beats per minute 
(bpm)). Values will be obtained directly from the eCRF and no derivations are required. 
Assessment windows are presented in Table 12-2 Appendix 3 of the Protocol. 
The following summaries will be provided for ECG data for each cohort over each scheduled 
timepoint: 
• Actual ECG parameter values (descriptive statistics for quantitative measurements) 
• Shift from baseline interpretation to the investigator interpretation at each time point 
• Incidence of abnormal criteria (frequency counts and percentage of subjects as 
normal/abnormal NCS/abnormal CS) 
• Listing of subjects’ individual ECG results 
16.5. VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
• Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg)  
• Pulse rate (beats/minute) 
• Respiratory rate (breaths/min) 
• Temperature (⁰C). 
The following summaries will be provided for vital signs data at each scheduled timepoint by 
cohort for the Safety Analysis set using descriptive statistics: 
• Actual and change from baseline 
• Incidence of markedly abnormal values 
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• Shift from baseline to all visits assessed against normal criteria (low, normal, high) 
Table 3 Vital Signs Normal Criteria 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
< 90 mmHg 
> 140 mmHg 
DBP 
mmHg 
< 50 mmHg 
> 90 mmHg  
Pulse 
bpm 
< 60 bpm  
> 100 bpm  
Respiratory rate 
breaths/min 
< 12 breaths/min 
> 20 breaths/min  
Body temperature 
˚C 
< 36.1 ˚C  
> 37.2 ˚C  
 
All vital sign data will be listed individually by each subject based on the Safety Analysis set. 
Assessment windows are presented in Table 12-2 in Appendix 3 of the protocol. 
16.5.1. 
VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative vital signs measurements will be identified in accordance 
with the following predefined criteria: 
 
 
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Table 4 Vital Signs Markedly Abnormal Criteria 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 80 mmHg 
≥ 200 mmHg 
DBP 
mmHg 
≤ 50 mmHg 
≥ 120 mmHg  
Pulse 
bpm 
≤ 40 bpm  
≥ 120 bpm  
Respiratory rate 
breaths/min 
≤ 10 breaths/min 
≥ 25 breaths/min  
Body temperature 
˚C 
≤ 35.5 ˚C  
≥ 37.7 ˚C  
 
16.6. PHYSICAL EXAMINATION  
All physical examination findings, including non-scheduled symptom-directed examination 
results, will be listed individually for each scheduled timepoint, including specification of any 
abnormalities observed. Incidences of physical examination results (Normal, Abnormal NCS, 
Abnormal CS) for every visit, as well as a shift table summarizing the changes in physical 
examination assessments (Normal, Abnormal NCS, Abnormal CS) from baseline to EOS will be 
provided, using counts and percentages for each cohort. New abnormalities occurring after 
administration of study medication will be recorded as adverse events.  
16.7. OTHER SAFETY ASSESSMENTS  
Tolerability data obtained from the Questionnaire for Tolerability will be listed for all subjects. 
Frequencies and proportions of responses to questions will be summarized by cohort and 
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dose. 
17. DATA NOT SUMMARIZED OR PRESENTED 
Details of admission and discharge from the CRU and follicle-stimulating hormones test results 
will not be summarized or presented, but will be available in the clinical study database, SDTM 
and/or ADaM datasets. 
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18. REFERENCES  
1. A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, Pharmacokinetics and 
Pharmacodynamics of Lixivaptan in Subjects with Autosomal Dominant Polycystic Kidney 
Disease. Palladio Biosciences. Protocol PA-102 Version 5, 21 March 2019. 
2. Palladio Biosciences. PA-102 eCRF Version 3, 11 March 2019. 
 
 
 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
Outputs will be presented according to the IQVIA Global Biostatistics Standard Output 
Conventions, which is available upon request. 
DATES & TIMES 
Depending on data available, dates and times will take the format dd-mmm-yyyy; times will 
take the format hh:mm:ss; combined dates and times will take the format dd-mmm-
yyyyThh:mm:ss. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment group 
Treatment label 
CKD1/2 200 mg 
Cohort 1 
CKD3 200 mg 
Cohort 2 
 
 
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CKD1/2 50 mg 
Cohort 3 
CKD3 50 mg 
Cohort 4 
Not allocated to a 
cohort 
Not allocated 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening 
Screening 
Day -1 
D-1 
Day 1 
D1 
… 
 
Day 7  
D7  
Day 8  
D8  
Day 9 
D9 
Day 10 
D10 
Day 11 
D11 
End of Study (Day 35) 
EOS 
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PRESENTATION OF NOMINAL TIMES 
For outputs, nominal times will be represented as follows: 
Long Name (default) 
Short Name  
Day 1 (0 hr) 
D1_0h 
Day 1 (1 hr) 
D1_1h 
Day 1 (2 hr) 
D1_2h 
… 
… 
Day 8 (0 hr) 
D8_0h 
Day 8 (10 hr) 
D8_10h 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
Cohort 
• 
Center-Subject ID (note no dash in actual output, e.g. Center 01, Subject 01 is 0101, by earliest 
enrolled to latest enrolled within the cohort),  
• 
Date (where applicable), 
• 
For listings where subjects not allocated to a cohort are included, these will appear in a category 
after the cohorts labelled ‘Not allocated’. 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
The only items that may have partial dates are medical history start/end dates, CKD initial 
diagnosis date and AE start/end dates. All other dates collected in the study should be a 
complete date with dd-mmm-yyyy format.  
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not 
TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known 
components show that 
Known 
Not TEAE 
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START DATE 
STOP 
DATE 
ACTION 
it cannot be on or after 
study med start date 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start 
date 
Known 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Assumed TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not 
TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Assumed TEAE 
 
Missing 
Assumed TEAE 
 
 
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STATISTICAL ANALYSIS PLAN FOR 
PHARMACOKINETICS/PHARMACODYNAMICS 
 
 
PA-102 
 
A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, Pharmacokinetics, 
and Pharmacodynamics of Lixivaptan in Subjects with Autosomal Dominant Polycystic 
Kidney Disease   
 
AUTHOR: Andrew Ralya 
VERSION NUMBER AND DATE: V1.0, 12 AUG 2019 
 
The data related to the sponsor and study contained in the document are confidential 
and proprietary to the sponsor. 
 
 
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1SHeafth & Quintiles are now
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Page2of39
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
Statistical Analysis Plan V1.O (Dated 12Aug2019) for Protocol PA-102.
Name
Signature
Date
(DDMMMYYYY)
Author:
Andrew Ralya
/3AA
Position:
Pharmacokinetics Manager
Company:
IUVIA
Upon review of this document, the undersigned approves this version of the Statistical
Analysis Plan, authorizing that the content is acceptable for the reporting of this study.
Name
Signature
Date
13Aug2019
Approved By:
Elaine Richardson
Position:
Vice President, Clinical Operations
Company:
Palladio Biosciences
Approved By:
Neil Shusterman, MD
jJ%/7
12Aug2019
Position:
Chief Medical Officer
Company:
Palladio Biosciences
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MODIFICATION HISTORY 
 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
V1.0 
12AUG2019 
Andrew Ralya 
N/A 
 
 
 
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TABLE OF CONTENTS 
1. INTRODUCTION .......................................................................................................................... 8 
2. STUDY OBJECTIVES ................................................................................................................... 8 
2.1. 
Primary Objective ........................................................................................................................................8 
2.2. 
Secondary Objectives ..................................................................................................................................9 
3. STUDY DESIGN ............................................................................................................................ 9 
3.1. 
General Description .....................................................................................................................................9 
3.2. 
Schedule of Events ..................................................................................................................................... 10 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 10 
4. PLANNED ANALYSES ............................................................................................................... 10 
4.1. 
Data Monitoring Committee ...................................................................................................................... 10 
4.2. 
Interim Analysis ......................................................................................................................................... 10 
4.3. 
Final Analysis ............................................................................................................................................. 11 
5. ANALYSIS SETS ......................................................................................................................... 11 
5.1. 
All Subjects Enrolled Set ............................................................................................................................ 11 
5.2. 
Safety Analysis Set ..................................................................................................................................... 11 
5.3. 
Pharmacokinetics Analysis Set ................................................................................................................... 11 
5.4. 
Pharmacodynamic Analysis Set ................................................................................................................. 12 
6. GENERAL CONSIDERATIONS ................................................................................................. 12 
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6.1. 
Summary Statistics .................................................................................................................................... 12 
6.2. 
Reference Start Date and Study Day .......................................................................................................... 13 
6.3. 
Baseline ..................................................................................................................................................... 14 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 14 
6.5. 
Windowing Conventions ............................................................................................................................ 14 
6.6. 
Common Calculations ................................................................................................................................ 15 
6.7. 
Software Versions...................................................................................................................................... 15 
7. STATISTICAL CONSIDERATIONS .......................................................................................... 15 
7.1. 
Sample Size................................................................................................................................................ 15 
7.2. 
Estimands .................................................................................................................................................. 16 
7.3. 
Missing Data .............................................................................................................................................. 17 
7.4. 
Examination of Subgroups ......................................................................................................................... 17 
8. OUTPUT PRESENTATIONS ..................................................................................................... 18 
8.1. 
Treatment Summarization ......................................................................................................................... 18 
8.2. 
Precision .................................................................................................................................................... 18 
9. DISPOSITION AND WITHDRAWALS .................................................................................... 19 
9.1. 
Protocol Deviations ................................................................................................................................... 19 
9.1.1. 
Deviations Related to Study Conduct .................................................................................................. 20 
9.1.2. 
Deviations Related to PK and PD Analysis ............................................................................................ 20 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................................... 21 
11. 
SURGICAL AND MEDICAL HISTORY ................................................................................. 21 
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12. 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................... 21 
13. 
STUDY MEDICATION EXPOSURE AND COMPLIANCE .................................................. 21 
14. 
PHARMACOKINETIC ANALYSIS ......................................................................................... 21 
14.1. 
Plasma Concentration Data ................................................................................................................... 22 
14.2. 
Pharmacokinetic Parameters ................................................................................................................. 23 
15. 
PHARMACODYNAMIC ANALYSIS ...................................................................................... 33 
15.1. 
Pharmacodynamic Endpoints................................................................................................................. 33 
15.2. 
Pharmacokinetic-Pharmacodynamic Relationships ................................................................................ 35 
16. 
SAFETY OUTCOMES.............................................................................................................. 36 
17. 
DATA NOT SUMMARIZED OR PRESENTED .................................................................... 36 
18. 
REFERENCES .......................................................................................................................... 37 
APPENDIX 1.PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................. 38 
Output Conventions .............................................................................................................................................. 38 
Dates & Times ....................................................................................................................................................... 38 
Spelling Format ..................................................................................................................................................... 38 
Presentation of Treatment Groups........................................................................................................................ 38 
APPENDIX 2.PARTIAL DATE CONVENTIONS ........................................................................... 39 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
AM 
morning 
AUC 
area under the plasma concentration-time curve 
AUC(0-14) 
area under the plasma concentration-time curve from time 0 until 
14 hours post-dose 
AUC(0-inf) 
area under the plasma concentration-time curve extrapolated to 
infinity 
AUC(0-last) 
area under the plasma concentration-time curve from time 0 until 
the last quantifiable concentration 
BID 
twice daily 
BLQ 
below the lower limit of quantification 
CKD 
chronic kidney disease 
CKD1 
chronic kidney disease stage 1 
CKD2 
chronic kidney disease stage 2 
CKD3 
chronic kidney disease stage 3 
CL/F 
apparent systemic clearance after extravascular dosing 
Cmax 
maximum observed plasma drug concentration 
CSR 
clinical study report 
CV 
coefficient of variation 
eGFR 
estimated glomerular filtration rate 
N 
sample size 
n 
number of non-missing observations 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PM 
evening 
SAP 
statistical analysis plan 
SD 
standard deviation 
t1/2 
terminal elimination phase half-life 
tmax 
time to reach maximum plasma concentration 
VZ/F 
apparent volume of distribution after extravascular dosing 
λZ 
apparent terminal elimination rate constant 
 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and 
analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data for Protocol PA-102. It 
describes the data to be summarized and analyzed, including specifics of the statistical 
analyses to be performed. This statistical analysis plan (SAP) is based on protocol version 5, 
dated 21 March 2019. The analysis and presentation of the data not related to PK or PD are 
described in an analysis plan (dated 25 April 2019) referred to as the “Non-PK/PD SAP” in this 
document. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objectives of this study are:  
 To characterize the safety and tolerability of lixivaptan following multiple doses in 
autosomal dominant polycystic kidney disease (ADPKD) subjects with relatively 
preserved kidney function (chronic kidney disease stage 1 [CKD1] and stage 2 [CKD2]) 
and moderately impaired renal function [CKD3].  
 To characterize the PK profile of lixivaptan and its major metabolites (WAY-141624, 
WAY-138451, and WAY-138758) following multiple doses of lixivaptan in ADPKD 
subjects with relatively preserved kidney function (CKD1 and CKD2) and moderately 
impaired renal function (CKD3).  
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2.2. SECONDARY OBJECTIVES 
The secondary objectives of this study are:  
 To characterize the effect of lixivaptan on urine osmolality over a 24-hour period 
following multiple doses of lixivaptan in ADPKD subjects. 
 To characterize the time course of the pharmacodynamic effect of lixivaptan on urine 
output, total kidney volume, liver volume, plasma copeptin, and serum creatinine in 
ADPKD subjects.  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase 2, open-label, parallel-group, multiple dose study designed to evaluate the PK, 
PD, safety and tolerability of multiple twice daily (BID) doses of 50 mg and 200 mg lixivaptan 
in ADPKD subjects with chronic kidney disease in stages CKD1, CKD2 or CKD3. Enrolled 
subjects will be assigned according to CKD classification to take one of 2 lixivaptan oral dose 
regimens for 7 days as shown below (Table 1). Each dose regimen includes morning (AM) and 
evening (PM) oral administration of lixivaptan. 
Table 1  Chronic Kidney disease Classification Summary by Cohort and Dose 
Group 
CKD Stage 
Cohort  
N  
eGFRa  
Dose 
CKD1 or CKD2  
1  
8 
eGFR ≥ 60 mL/min/1.73 m2  
200 mg BID 
CKD3  
2   
8 
eGFR ≥ 30 to < 60 mL/min/1.73 m2  
200 mg BID 
CKD1 or CKD2  
3  
8 
eGFR ≥ 60 mL/min/1.73 m2  
50 mg BID 
CKD3  
4   
8 
eGFR ≥ 30 to < 60 mL/min/1.73 m2  
50 mg BID 
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Abbreviations: CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; BID=twice daily.a 
eGFR is calculated 
by the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 12.2 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Some safety and/or PD endpoints were not clearly identified/categorized in the protocol. This 
SAP clarifies which endpoints are considered to be PD endpoints. 
Some minor changes were made to some PK parameter abbreviations and/or definitions. 
4. PLANNED ANALYSES 
4.1. DATA MONITORING COMMITTEE 
There is no Data Monitoring Committee for this study requiring statistical outputs. 
4.2. INTERIM ANALYSIS  
An interim “dry run” analysis is planned on partial data for this study to aid in pre-
programming of databases and programs. However, only the results of the final analysis will 
be included in the clinical study report (CSR). 
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4.3. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics and 
PK scientist, following Palladio authorization of this SAP, identification of major protocol 
deviations/events requiring analysis exclusions, database lock, and determination of analysis 
sets. 
5. ANALYSIS SETS 
5.1. ALL SUBJECTS ENROLLED SET 
The all subjects enrolled set will contain all subjects who provide informed consent for this 
study. Subjects in this population will be used for disposition summaries, and where 
appropriate, will be analyzed according to cohort allocation. Subjects not allocated to a cohort 
due to screen failure will be indicated as Not Allocated. 
5.2. SAFETY ANALYSIS SET  
The safety analysis set will contain all subjects who receive at least one dose of study 
medication and will be analyzed according to treatment received. This analysis set will be used 
for the safety analyses and for summarization of baseline/demographic characteristics, as well 
as listings of individual PK and PD data. 
5.3. PHARMACOKINETICS ANALYSIS SET 
The PK analysis set will consist of all subjects who undergo plasma PK sampling and have 
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evaluable PK assay results, without protocol deviations or events deemed to affect PK 
evaluation. This analysis set will be used for the statistical analysis/summarization of PK 
concentration/parameter data and will be analyzed according to treatment received.  
5.4. PHARMACODYNAMIC ANALYSIS SET 
The PD analysis set will consist of all subjects who receive study drug and have at least one 
post-dose assessment of any PD endpoint, without protocol deviations or events deemed to 
affect PD evaluation. This analysis set will be used for the statistical analysis/summarization of 
PD data and will be analyzed according to treatment received.  
6. GENERAL CONSIDERATIONS 
Some minor modifications may be necessary to the planned design of tables, figures, and 
listings to accommodate data collected during the actual study conduct. 
6.1. SUMMARY STATISTICS 
For categorical variables, the analysis set size (N for sample size and n for number of non-
missing observations) and percentage (of the number of non-missing observations) for each 
class of the variable will be presented. Percentages will be based on the number of subjects 
within the relevant analysis set and/or the number of subjects with non-missing observations. 
All continuous variables, except time to reach maximum plasma concentration (tmax), will be 
summarized using descriptive statistics, including N, n, mean, standard deviation (SD), 
coefficient of variation (CV), median, minimum, and maximum values. The CV will not be 
presented for change from baseline results. Geometric mean and geometric CV will 
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additionally be included for PK parameters, where applicable. The tmax will be summarized 
using descriptive statistics, including N, n, median, minimum, and maximum only.  
For continuous variables, at least 3 (non-missing) observed values for each category will be 
required for calculation/presentation of descriptive statistics for that category.  If n = 2, the 2 
values will be presented as minimum and maximum, and no other descriptive statistics will be 
calculated.  If n <2, only n will be reported. If n <2 for all categories for a summary, the 
summary table/figure may be omitted. 
For categorical variables, no minimum number of observed values will be required for 
calculation/presentation of descriptive statistics (e.g., n and percentage). 
6.2. REFERENCE START DATE AND STUDY DAY 
Study day will be calculated from the reference start date and will be used to show the 
start/stop day of assessments and events. 
The reference start date is defined as the day of the first dose of study medication (Day 1 is 
the day of the first dose of study medication). Study day will be calculated relative to 
reference start date and will appear in every listing where an assessment date or event date 
appears.  
 If the date of the event is on or after the reference date, then:  
Study Day = (date of event – reference date) + 1. 
 If the date of the event is prior to the reference date, then:  
Study Day = (date of event – reference date). 
If the event date is partial or missing, the study day and any corresponding durations will be 
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missing in the listings. 
6.3. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken 
prior to start date of study drug administration (including unscheduled assessments). In the 
case where the last non-missing measurement and the start date of study drug administration 
coincide, that measurement will be considered pre-baseline. 
 
6.4. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
Post-baseline unscheduled measurements will not be included in summary statistics.  
In the case of a retest of a scheduled assessment, the last available measurement for that 
scheduled time (i.e., the retest measurement) will be used for summaries unless flagged as 
invalid.  
Listings will include all scheduled, unscheduled, retest and early discontinuation data. 
6.5. WINDOWING CONVENTIONS 
See Section 9.1.2 for handling specifications of data collected outside of protocol-specified 
windows. 
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6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 Test value (after baseline) – Baseline value 
6.7. SOFTWARE VERSIONS 
All derivations, statistical analyses, summaries, and listings will be generated using SAS version 
9.4 (SAS Institute, Inc., Cary, North Carolina). Noncompartmental PK parameter calculations 
will be performed using Phoenix® WinNonlin® 8.0 or higher (Certara, Princeton, New Jersey). 
Graphics may be prepared using the same versions of SAS or Phoenix WinNonlin.   
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE 
Calculations to determine sample size were performed assuming a CV of 0.30 and 0.41 for 
lixivaptan maximum observed plasma drug concentration (Cmax) and area under the plasma 
concentration-time curve (AUC), respectively. Assuming a lognormal distribution, this implies 
that the variances for the logarithm of Cmax and AUC are 0.086 and 0.155, respectively. Under 
these assumptions and a random sample of 8 observations per cohort, the probability is 0.90 
that the point estimate of the population central value (observed geometric mean) for 
lixivaptan Cmax and AUC will be within (84.3%, 118.6%) and (79.5%, 125.7%) of the population 
central value (the median), respectively.  
From the perspective of tolerability assessment for multiple dose regimens, for the true 
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population incidence rates of 0.10, 0.20, 0.30, 0.40 and 0.50 for a given adverse event (AE), 
the probabilities that the AE would not be observed in a group of 8 subjects administered 
lixivaptan are given in Table 2: 
Table 2  Probability of Not Observing an Adverse Event for Various True 
Incidence Rates 
True Incidence Rate 
Probability of Not Observing an AE in Group of 8 Subjects 
0.1 
0.43 
0.2 
0.168 
0.3 
0.058 
0.4 
0.017 
0.5 
0.004 
7.2. ESTIMANDS 
As per International Council for Harmonisation E9 (R1), the estimands for this study are 
described as follows: 
Primary Estimand 1: See Non-PK/PD SAP. 
 
Primary Estimand 2: The PK profile of lixivaptan and its major metabolites (WAY-141624, 
WAY-138451, WAY-138758) following first and multiple doses of lixivaptan in ADPKD subjects. 
 Population: ADPKD subjects with at least one post-dose PK assessment and 
defined further through appropriate inclusion/exclusion criteria. 
 Variables (or endpoints): PK concentrations and parameters (Cmax, tmax, AUC 
from time 0 until the last quantifiable concentration [AUC(0-last)], AUC 
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extrapolated to infinity [AUC(0-inf)], AUC from time 0 until 14 hours post-dose 
[AUC(0-14)], terminal elimination phase half-life [t1/2], apparent terminal 
elimination rate constant [λZ], apparent systemic clearance after extravascular 
dosing [CL/F; lixivaptan only], and apparent volume of distribution after 
extravascular dosing [VZ/F; lixivaptan only]). 
 Strategy for addressing intercurrent event: Regardless if subject discontinues 
treatment prematurely. 
 Population-level summary: Descriptive differences in PK parameter means of 
the four cohorts. 
 
7.3. MISSING DATA 
Missing data will not be imputed but analyzed as missing, except as specified in Section 14.2.  
7.4. EXAMINATION OF SUBGROUPS  
Additional exploratory stratification will be made for summarizing some of the PK and/or PD 
endpoints, including: 
 Male versus female (PK only) 
 CKD1 versus CKD2 (within Cohorts 1 and 3) 
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8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows the conventions for presentation of data in outputs. The output shells 
provided with this SAP describe the presentations for this study and therefore the format and 
content of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
Some minor modifications may be necessary to the planned design of tables, figures, and 
listings to accommodate data collected during the actual study conduct. 
8.1. TREATMENT SUMMARIZATION 
In general, data will be presented for each cohort, distinguishing between the different renal 
groups (CKD1/2, CKD1, CKD2, and CKD3) and dosages (50 mg, 200 mg). Data may also be 
presented for all study subjects combined where appropriate. 
8.2. PRECISION 
All PK concentrations and PD variables will be reported and analyzed with the same precision 
as the source data provided by the bioanalytical laboratory regardless of how many significant 
figures or decimal places the data carry. Elapsed time variables for PK or PD will be reported 
with 2 decimal places with unit of hours. Derived percentages for PD variables (if any) will be 
reported in listings with 1 decimal place. Derived PK parameters will be rounded for reporting 
purposes in by-subject listings. The rounded derived PK data will be considered the source 
data for the calculation of descriptive statistics. For most derived PK parameters, 3 significant 
figures will be used as the standard rounding procedure for listings, with the following 
exceptions: 
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 Parameters directly derived from source data (e.g., Cmax) will be reported and analyzed 
with the same precision as the source data. 
 Parameters derived from actual elapsed sample collection times (e.g., tmax) will be 
reported with the same precision as the actual elapsed sampling time value of the 
source data (specified as 2 decimal places with unit of hours). 
For the reporting of descriptive statistics, the mean, geometric mean, median, and SD will be 
presented to 1 digit more precision than the source data. The minimum and maximum will be 
presented to the same precision as the source data. Summary percentages (e.g., for 
categorical variables), CV (%), and geometric CV (%) will always be reported to 1 decimal 
place.  
9. DISPOSITION AND WITHDRAWALS 
See Non-PK/PD SAP. 
9.1. PROTOCOL DEVIATIONS 
A protocol deviation is defined as an unintended or unanticipated departure from the 
procedures or processes that were approved by the Sponsor and the Investigational Review 
Board and agreed to by the Investigator.  
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, which 
will be recorded in the subject’s source documentation. This information will be provided to 
IQVIA Biostatistics to determine inclusion/exclusion from analysis sets. 
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9.1.1. 
DEVIATIONS RELATED TO STUDY CONDUCT 
Major deviations can include, but may not be limited to: 
 Deviations related to PK and PD analysis (see Section 9.1.2) 
Refer to Non-PK/PD SAP for other examples. 
9.1.2. 
DEVIATIONS RELATED TO PK AND PD ANALYSIS 
Protocol deviations or events will also be reviewed by the study pharmacokineticist and 
biostatistician to identify deviations or events which have the potential to affect the PK or PD 
results. Deviations resulting in no evaluable PK or PD results for a subject, and thus exclusion 
from PK or PD analysis set, will be documented as reasons for exclusion from these analysis 
sets. 
Changes to the procedures which may impact the quality of the PK or PD data will be 
considered major protocol deviations and will be described within the CSR body text. Other 
events which may impact the quality of the PK or PD data will be described within the CSR 
body text. These changes or events will include any circumstances that will alter the 
evaluation of the PK or PD. Examples include, but may not be limited to, vomiting following 
oral dosing occurring within the time frame of 2 times the median tmax (within that cohort, 
excluding data potentially affected), sample processing errors that lead to inaccurate 
bioanalytical results, and/or inaccurate dosing for the dosing interval for which PK or PD 
sampling occurs. In the case of a major protocol deviation or event, PK and/or PD data 
collected during the relevant time period will be listed but excluded from summaries. Other 
changes to the procedures or events which do not impact the quality of the PK or PD data will 
not be considered major protocol deviations. Common examples of minor protocol deviations 
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are a missed sample or minor deviations from sample collection times/windows. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
See Non-PK/PD SAP. 
11. SURGICAL AND MEDICAL HISTORY 
See Non-PK/PD SAP. 
12. PRIOR AND CONCOMITANT MEDICATIONS 
See Non-PK/PD SAP. 
13. STUDY MEDICATION EXPOSURE AND COMPLIANCE 
See Non-PK/PD SAP. 
14. PHARMACOKINETIC ANALYSIS 
Derivation of the PK parameters from lixivaptan and lixivaptan metabolite (WAY-141624, 
WAY-138451, and WAY-138758) concentrations will be the responsibility of the clinical 
pharmacokineticist at IQVIA. The PK and PD summaries, listings, tables, and figures will be the 
responsibility of the PK/PD biostatistician at IQVIA. Primary PK variables include lixivaptan and 
lixivaptan metabolite concentrations and parameters. 
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14.1. PLASMA CONCENTRATION DATA 
A listing of PK blood sample collection times as well as derived sampling time deviations will 
be provided. A subject listing of all concentration-time data will be presented. Presentation of 
individual sampling times/concentrations will be based on the Safety Analysis Set. 
Lixivaptan and lixivaptan metabolite (WAY-141624, WAY-138451, and WAY-138758) plasma 
concentrations will be tabulated and summarized by analyte, cohort (equivalent to 
stratification by renal function/CKD stage and dose), Study Day, dosing interval (AM/PM), and 
nominal time point using descriptive statistics as described in Section 6.1 and Section 8. 
Additional summarization will be made with further stratification by gender (male versus 
female), and, independently, by CKD stage within cohort. Plasma concentrations that are 
below the lower limit of quantification (BLQ) will be treated as zero for the computation of 
summary statistics. Concentration summaries will be based on the PK Analysis Set. 
The following plots will be presented for the concentration-time data: 
 Arithmetic mean concentration versus time data (±SD) for Day 1 and Day 7 will be 
presented on linear and semi-logarithmic scales, stratified by analyte, cohort 
(equivalent to stratification by renal function/CKD stage and dose; and further 
stratified by CKD stage within cohort), Study Day, and dosing interval (AM/PM), based 
on the PK Analysis Set. Additional figure(s) will be made with further stratification by 
gender (male versus female). 
 Arithmetic mean trough concentration versus nominal Study Day data (±SD) will be 
presented on a linear scale, stratified by analyte, cohort (equivalent to stratification by 
renal function/CKD stage and dose; and further stratified by CKD stage within cohort), 
and dosing interval (AM/PM), based on the PK Analysis Set. Additional figure(s) will be 
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made with further stratification by gender (male versus female). 
 Individual subject concentration versus time data will be graphically presented on 
linear and semi-logarithmic scales, by analyte, cohort (and CKD stage within cohort), 
Study Day, and dosing interval (AM/PM), based on the Safety Analysis Set. 
14.2. PHARMACOKINETIC PARAMETERS 
Subjects with partial data will be evaluated on a case-by-case basis to determine if sufficient 
data are available for reliable estimation of PK parameters. Any anomalous concentration 
values (e.g., quantifiable predose concentration for first dose) observed at predose will be 
identified in the CSR and used for the computation of PK parameters. For first dose, if the 
anomalous predose concentration is greater than 5% of Cmax of the profile in that dosing 
interval, the PK parameters for the given subject/profile will be calculated and reported in the 
listing but flagged and excluded from statistical summaries and analyses. Predose 
concentrations will be considered as collected simultaneously with the dose for purpose of PK 
parameter calculation. 
For PK parameter calculations for first dose, predose samples that are missing will be assigned 
a numerical value of zero. For calculating parameters, no imputation/substitution will be 
made for missing predose and/or trough concentrations for Day 1 PM or Day 7 AM or PM. For 
all dosing intervals, any BLQ concentrations (including predose) will be assigned a value of 
zero if they precede quantifiable samples in the initial portion of the profile. A BLQ value that 
occurs between quantifiable data points, especially prior to Cmax, will be evaluated to 
determine if an assigned concentration of zero makes sense, or if exclusion of the data is 
warranted. Following Cmax, BLQ values embedded between 2 quantifiable data points will be 
treated as missing when calculating PK parameters. If a BLQ value occurs at the end of the 
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collection interval (after the last quantifiable concentration), it will be set to zero. If 
consecutive BLQ concentrations are followed by quantifiable concentration(s) in the terminal 
portion of the concentration curve, these quantified values will be excluded from the PK 
analysis by setting them to missing, unless otherwise warranted by the concentration-time 
profile.  
The following PK parameters ( 
 
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Table 3) will be estimated for lixivaptan and lixivaptan metabolites by non-compartmental 
methods using validated software and actual elapsed time from dosing. See Table 5 for 
specific Study Days and dosing intervals for which each PK parameters will be calculated. A 
minimum of 3 quantifiable post-dose concentration-time data points will be required for 
calculation of PK parameters.  
 
 
 
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Table 3  Estimation of PK Parameters 
Day 1 AM: 
PK Parameter 
Definition 
Cmax 
Maximum observed plasma drug concentration (ng/mL), obtained 
directly from the observed concentration versus time data. 
tmax 
Time to reach maximum plasma concentration (h), obtained directly from 
the observed concentration versus time data. 
AUC(0-last) 
Area under the concentration-time curve from time 0 until the last 
quantifiable concentration (ng·h/mL), calculated by linear up/log down 
trapezoidal summation. 
AUC(0-inf) 
Area under the concentration-time curve from time 0 extrapolated to 
infinity (ng·h/mL), calculated by linear up/log down trapezoidal 
summation and extrapolated to infinity by addition of the last 
quantifiable observed concentration divided by the elimination rate 
constant:  AUC(0-last) + Clast/λZ.  
λZ 
Apparent terminal elimination rate constant (1/h), determined by linear 
regression of the terminal points of the log-linear concentration-time 
curve. The Best Fit method utilized by WinNonlin will be used to identify 
the terminal linear phase of the concentration-time profile, with visual 
assessment and adjustment of the selected data points by the PK scientist 
if warranted. A minimum of 3 data points will be used for determination. 
t1/2 
Apparent terminal elimination phase half-life (h), determined as ln2/λZ. 
CL/F 
Apparent systemic clearance after extravascular dosing (L/h), calculated 
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PK Parameter 
Definition 
as (lixivaptan only): 
 
Day 1 AM: dose divided by AUC(0-inf), or 
 
Day 7 AM: dose divided by AUC(0-last). 
VZ/F 
Apparent volume of distribution following extravascular dosing (L), 
calculated as CL/F divided by λZ (lixivaptan only). 
 
Day 1 PM: 
PK Parameter 
Definition 
Cmax 
Maximum observed plasma drug concentration (ng/mL), obtained 
directly from the observed concentration versus time data. 
tmax 
Time to reach maximum plasma concentration (h), obtained directly from 
the observed concentration versus time data. 
AUC(0-last) 
Area under the concentration-time curve from time 0 until the last 
quantifiable concentration (ng·h/mL), calculated by linear up/log down 
trapezoidal summation. 
 
 
 
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Day 7 AM: 
PK Parameter 
Definition 
Cmax 
Maximum observed plasma drug concentration (ng/mL), obtained 
directly from the observed concentration versus time data. 
tmax 
Time to reach maximum plasma concentration (h), obtained directly from 
the observed concentration versus time data. 
AUC(0-last) 
Area under the concentration-time curve from time 0 until the last 
quantifiable concentration (ng·h/mL), calculated by linear up/log down 
trapezoidal summation. 
CL/F 
Apparent systemic clearance after extravascular dosing (L/h), calculated 
as (lixivaptan only): 
 
Day 1 AM: dose divided by AUC(0-inf), or 
 
Day 7 AM: dose divided by AUC(0-last). 
VZ/F 
Apparent volume of distribution following extravascular dosing (L), 
calculated as CL/F divided by λZ (lixivaptan only). 
RCmax 
Accumulation ratio for Cmax, calculated as (lixivaptan only): 
[Cmax on Day 7]/[Cmax on Day 1]. 
RAUC(0-last) 
Accumulation ratio for AUC(0-last), calculated as (lixivaptan only): 
[AUC(0-last) on Day 7]/[AUC(0-last) on Day 1]. 
 
 
 
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Day 7 PM: 
PK Parameter 
Definition 
Cmax 
Maximum observed plasma drug concentration (ng/mL), obtained 
directly from the observed concentration versus time data. 
tmax 
Time to reach maximum plasma concentration (h), obtained directly from 
the observed concentration versus time data. 
AUC(0-last) 
Area under the concentration-time curve from time 0 until the last 
quantifiable concentration (ng·h/mL), calculated by linear up/log down 
trapezoidal summation. 
AUC(0-14) 
Area under the concentration-time curve from time 0 until 14 hours post-
dose (ng·h/mL), calculated by linear up/log down trapezoidal summation. 
Actual elapsed time for the nominal 14-hour sample will be used for the 
calculation. If the time deviation at 14 hours is larger than ±15.0%, then 
AUC(0-14) will only be listed for that profile and excluded from 
statistics/summaries. 
λZ 
Apparent terminal elimination rate constant (1/h), determined by linear 
regression of the terminal points of the log-linear concentration-time 
curve. The Best Fit method utilized by WinNonlin will be used to identify 
the terminal linear phase of the concentration-time profile, with visual 
assessment and adjustment of the selected data points by the PK scientist 
if warranted. A minimum of 3 data points will be used for determination. 
t1/2 
Apparent terminal elimination phase half-life (h), determined as ln2/λZ. 
MRCmax 
Ratio of metabolite Cmax to parent lixivaptan Cmax, calculated for all 
metabolites and corrected for molecular weight of metabolite and parent 
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PK Parameter 
Definition 
as: (Cmax,m/Cmax,p)(MWp/MWm), where Cmax,m and MWm are Cmax and 
molecular weight of metabolite, respectively, and Cmax,p and MWp are Cmax 
and molecular weight of parent lixivaptan, respectively. The following 
molecular weights are to be used in all MR parameter [MRCmax and 
MRAUC(0-14)] calculations: 
 
lixivaptan:  473.93 g/mol 
 
WAY-141624:  505.95 g/mol 
 
WAY-138451:  488.92 g/mol 
 
WAY-138758:  426.82 g/mol 
MRAUC(0-14) 
Ratio of metabolite AUC(0-14) to parent lixivaptan AUC(0-14), calculated for 
all metabolites and corrected for molecular weight of metabolite and 
parent as: (AUC(0-14),m/AUC(0-14),p)(MWp/MWm), where AUC(0-14),m and MWm 
are AUC(0-14) and molecular weight of metabolite, respectively, and 
AUC(0-14),p and MWp are AUC(0-14) and molecular weight of parent 
lixivaptan, respectively. 
 
 
 
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The following PK parameters (Table 4) will be calculated for diagnostic purposes, when 
appropriate, and listed but will not be summarized. 
Table 4 Calculation of PK Parameters for Diagnostic Purposes 
PK Parameter  
Definition 
λZ_low 
The starting time point (h) of the time interval of the log-linear regression 
to determine λZ. 
λZ_upp 
The ending time point (h) of the time interval of the log-linear regression 
to determine λZ. 
t1/2, Interval 
The time interval duration (h) of the log-linear regression to determine λZ, 
calculated as λZ_upp − λZ_low. 
t1/2, N 
Number of data points included in the log-linear regression analysis to 
determine λZ. A minimum of 3 data points will be used for determination. 
Rsq_adj 
Adjusted coefficient of determination for calculation of Z. If Rsq_adj 
<0.800, then Z and parameters derived from it will be listed but flagged 
and excluded from summaries. 
%AUCex 
Percentage of AUC(0-inf) obtained by extrapolation, calculated as 
[(Clast/z)/AUC(0-inf)100]. If the %AUCex is greater than 30.0% of AUC(0-inf), 
then AUC(0-inf) will be listed but flagged and excluded from summaries. 
 
 
 
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Table 5 lists the above non-diagnostic PK parameters to be calculated by Study Day and dosing 
interval. 
Table 5   Calculation of PK Parameters at Specific Study Days and Dosing 
Intervals  
Study Day & Dosing Interval 
PK Parameter 
Day 1 AM Dose 
Cmax, tmax, AUC(0-last), AUC(0-inf), Z, t1/2, CL/F, VZ/F 
Day 1 PM Dose 
Cmax, tmax, AUC(0-last) 
Day 7 AM Dose 
Cmax, tmax, AUC(0-last), CL/F, VZ/F, RCmax, RAUC(0-last) 
Day 7 PM Dose 
Cmax, tmax, AUC(0-last), AUC(0-14), Z, t1/2, MRCmax, MRAUC(0-14) 
 
In accordance with molecular formula and formulation for lixivaptan, no dose adjustment 
calculations will be made for any molecular conversions between administered drug product 
and analyte measure. 
A subject listing of individual PK parameters for lixivaptan and lixivaptan metabolites will be 
provided. Parameter listings will be based on the Safety Analysis Set. The PK parameters will 
be summarized by analyte, cohort (renal function/CKD stage/dose), Study Day, and dosing 
interval (AM/PM) using descriptive statistics as described in Section 6.1 and Section 8. 
Additional summarization will be made with further stratification by gender (male versus 
female), and, independently, by CKD stage within cohort. Parameter summaries will be based 
on the PK Analysis Set. 
Scatter plots of individual and geometric mean PK parameters versus cohort will be presented 
for lixivaptan only, stratified by Study Day and dosing interval (AM/PM), based on the PK 
Analysis Set. Additional figure(s)/plot(s) will be made with further stratification by gender 
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(male versus female), and, independently, by CKD stage within cohort. Additional, graphical 
presentations of PK data may be added if further illustration of the PK results is deemed 
appropriate. 
15. PHARMACODYNAMIC ANALYSIS 
15.1. PHARMACODYNAMIC ENDPOINTS 
The following are PD endpoints: 
 Urine osmolality 
 Specific gravity by refractometer 
 Specific gravity by dipstick 
 (24-hour) urine output 
 (24-hour) fluid intake 
 Fluid balance 
 Total kidney volume (TKV) 
 Liver volume (LV) 
 Plasma copeptin 
 Estimated glomerular filtration rate (eGFR); calculated by the 2009 Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation presented in Appendix 1 of the 
protocol. 
A listing of all PD sample collection times will be provided. Subject listings of all PD data will be 
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presented for the observed values and change from baseline, based on the Safety Analysis 
Set. The observed value and the change from baseline in the PD endpoints will be summarized 
by cohort (renal function/CKD stage/dose), Study Day, dosing interval, and/or at each 
scheduled time point, as applicable, using descriptive statistics as described in Section 6.1 and 
Section 8. Additional summarization will be made with further stratification CKD stage within 
cohort. Pharmacodynamic summaries will be based on the PD Analysis Set. Any BLQ 
concentrations will be treated as 1/2 × LLOQ for the computation of change from baseline and 
descriptive statistics. 
Any values after first administration of study drug are regarded as post-baseline values. 
Except for urine osmolality, the baseline value is the last value observed prior to first 
administration of study drug. For urine osmolality assessments, the baseline value for each 
time point after first administration of study drug is the value observed at the corresponding 
time point on Day -1 (or Day 1 for the AM predose assessment only). 
The number and percentage of subjects who show uninterrupted suppression of urine 
osmolality over 24 hours, defined as spot urine osmolality <300 mOsm/kg at each time point 
during a 24-hour measurement period, as well as over 14 hours following the PM dose, will be 
determined for Day -1, Day 1, and Day 7 by dose and by cohort. The above summary will 
additionally be presented similarly for subjects who show uninterrupted urine osmolality 
≤250 mOsm/kg over 24 hours or 14 hours (PM). The 24-hour measurement periods will be 
calculated as follows: 
 For Day -1, from time = 0 on Day -1 until time = 0 (AM predose) on Day 1; 
 For Day 1, from time = 1 h on Day 1 until time = 0 (AM predose) on Day 2; and  
 For Day 7, from time = 1 h on Day 7 until time = 0 on Day 8  
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In addition, the number and percentage of subjects with spot urine osmolality <300 mOsm/kg 
at each time point during the three 24-hour measurement periods (Day -1, Day 1, and Day 7) 
will be determined by dose and by cohort. The above summary will additionally be presented 
similarly for subjects who with spot urine osmolality ≤250 mOsm/kg at each time point. 
Figure(s) of mean (±SD) urine osmolality versus time by Day (overlaid within plot), cohort, and 
CKD stage within cohort, will be produced. Figure(s) of mean (±SD) PD endpoint versus Day by 
cohort and CKD stage within cohort will be produced for urine output, fluid intake, fluid 
balance, TKV, LV, and plasma copeptin. All the above PD figures will use a linear scale for the 
PD dependent variable, using the observed values. 
15.2. PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS 
Figures of individual/mean observed and/or change from baseline PD variables versus 
individual/mean PK endpoint(s) (lixivaptan only) will be produced for urine osmolality, urine 
output, TKV, LV, plasma copeptin, and eGFR, based on overlapping subjects/data in the PK 
analysis set and PD analysis set (excluding subjects/data affected by protocol 
deviations/events). Plot(s) for urine osmolality will use PK concentrations at all nominal time 
points coinciding with urine osmolality. Plot(s) for plasma copeptin and eGFR will plot Day 2 
PD versus Day 1 PK parameter AUC(0-inf) or AUC(0-last), depending on appropriateness. An 
additional plot will show Day 2 plasma copeptin versus Day 1 PK parameter Cmax. Plot(s) for 
urine output will plot Day 1 PD versus Day 1 PK parameter AUC(0-inf) or AUC(0-last), depending on 
appropriateness. Plot(s) for eGFR will plot Day 8 PD versus Day 7 PK parameter AUC(0-14). 
Plot(s) for urine output, TKV, LV, and plasma copeptin will plot Day 7 PD versus Day 7 PK 
parameter AUC(0-14). An additional plot will show Day 7 plasma copeptin versus Day 7 PK 
parameter Cmax. Plot(s) will use PK parameters for Day 1 AM or Day 7 PM. All PD versus PK 
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Document: 
PK/PD STATISTICAL ANALYSIS PLAN 
Author: 
Andrew Ralya 
Version Number: 
1.0 
 
 
Version Date: 
12 Aug 2019 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
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Page 36 of 39 
figures will use a linear scale for the PD dependent variable. 
16. SAFETY OUTCOMES 
See Non-PK/PD SAP. 
17. DATA NOT SUMMARIZED OR PRESENTED 
See Non-PK/PD SAP. 
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Document: 
PK/PD STATISTICAL ANALYSIS PLAN 
Author: 
Andrew Ralya 
Version Number: 
1.0 
 
 
Version Date: 
12 Aug 2019 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
Palladio BiosciencesInsert Customer Name/ Logo 
PK/PD STATISTICAL ANALYSIS PLAN: PROTOCOL PA-102 
Page 37 of 39 
18. REFERENCES  
1. A Phase 2, Open-Label, Multi-Center Study to Evaluate the Safety, Pharmacokinetics and 
Pharmacodynamics of Lixivaptan in Subjects with Autosomal Dominant Polycystic Kidney 
Disease. Palladio Biosciences. Protocol PA-102 Version 5, 21 March 2019. 
2. Palladio Biosciences. PA-102 eCRF Version 3, 11 March 2019. 
 
 
 
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Document: 
PK/PD STATISTICAL ANALYSIS PLAN 
Author: 
Andrew Ralya 
Version Number: 
1.0 
 
 
Version Date: 
12 Aug 2019 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
Palladio BiosciencesInsert Customer Name/ Logo 
PK/PD STATISTICAL ANALYSIS PLAN: PROTOCOL PA-102 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
Outputs will be presented according to the IQVIA Global Biostatistics Standard Output 
Conventions, which is available upon request. 
DATES & TIMES 
Depending on data available, dates and times will take the format dd-mmm-yyyy; times will 
take the format hh:mm:ss; combined dates and times will take the format dd-mmm-
yyyyThh:mm:ss. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment group 
Treatment label 
CKD1/2 200 mg 
Cohort 1 
CKD3 200 mg 
Cohort 2 
CKD1/2 50 mg 
Cohort 3 
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Document: 
PK/PD STATISTICAL ANALYSIS PLAN 
Author: 
Andrew Ralya 
Version Number: 
1.0 
 
 
Version Date: 
12 Aug 2019 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
Palladio BiosciencesInsert Customer Name/ Logo 
PK/PD STATISTICAL ANALYSIS PLAN: PROTOCOL PA-102 
Page 39 of 39 
Treatment group 
Treatment label 
CKD3 50 mg 
Cohort 4 
Not allocated to a 
cohort 
Not allocated 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
The only items that may have partial dates are medical history start/end dates, CKD initial 
diagnosis date and AE start/end dates. All other dates collected in the study should be a 
complete date with dd-mmm-yyyy format. 
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qrc$#vlA
Biostatistics File Note
Page 1 of 1
1.0 INSTRUCTIONS
1.1 Use this form to document project specific file notes to be made part of the
permanent study flle. This may include some type of process deviation or simply an
explanatory note. lf the form is used to document process deviations which impact
on other functions, ensure that the file note is circulated to those functional groups
and the Project Leader.
Form No.: CS_FM_BSO20 Revision 4 
Referen@: CS-OP-BS001
Effective Date: 29Nov2019
Copyright @ 2010, 2012,20'17 ,2019 lQVlA. All rights reserved. The contents of this document are confidential and proprietary to
tOVt,n HoUings lnc. and its subsidiaries. Unauthorized use, disdosurc or reptoduction is stric'tly prohibited.
Palladio Biosciences
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ffi H,htsrs1\€r*.!ii,;.irtr*
#N$.{$+i}:i.v*irt\-ixiD
ffi.B$F-+.1,il $ffiV*A
Biostatistics File Note
Page 1 of 2
$ection A
Customer: 
Palladio Biosciences
Project Code: 
WYA34000
Protocol Number: PA-102
Ti*e of Note: 
Urine Osmolality and Copeptin sample exclusion due to non-drug related
anomaly
Section B
DESCRIPTION:
Further action required:
1) Urine Osmolality and Specific Gravity data for subject 0101 at Day -1 and Day 1 will be
flagged in analysis ADPD dataset by means of "hardcoding" and excluded from summary
tables and mean figures. The data will be included in subject data listings with footnote
added for reason of exclusion from summary statistics and mean figures.
2) Plasma Copeptin for subject '1504 at Day 7 will be flagged in analysis ADPD dataset by
means of "hardcoding".
The data will be included in subject data listings with a footnote added for reason of
exclusion from summary statistics and mean figures.
The data will be included in the original set of summary tables and mean figures.
Additional summary tables and mean figures (only for the affec'ted tables and flgures) to
be added with the data mentioned above to be excluded.
Form No.: CS_FM_8S020 Revision 4 
Reference: CS_OP_8S001
Effective Date: 29Nov2019
Copyright @ 2010,2012,2017,2A19lQVlA. All rights reserved. The contents of this document are confidential and proprietary to
IQVIA HoUings lnc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited.
1)
Subject 0101 - Removal of Urine Osmolality and Specific Gravity data from Day -'t and
Day 1, re-running all impacted TLFs, and updating CSR.
A serious issue was identified during clinical conduct with the Urine Osmolality/Specific
Gravity collection tubes that impacted only subject 0101 enrolled at Site 01. A
preservative, tartaric acid, was present in the tubes but shouldn't have been because that
adds osmoles to the urine giving an invalid assessment of Urine Osmolality and Specific
Gravity. The errorwas caught after Day 1 but before Day 7. All Urine Osmolality and
Specific Gravity samples for subject 0101 only taken on Day -1 and Day 1 were affected.
Extensive correspondence and documentation on this matter (including a CAPA from
vendor lab Q2) was performed. Urine Osmolality and Specific Gravity data for the affected
samples on Day -1 and Day 1 for this subject, were not supposed to be included in the
statistical analyses.
Plasma Copeptin in subject 1504 - Re-running allimpacted TLFs with and without
affected sample and updating CSR.
Subject 1 504, enrolled at Site 1 5, experienced vasovagal syncope 10 minutes before the
blood draw of the affected sample resulting in an acute stress response with a
compensatory increase in vasopressin to support blood pressure. The true copeptin level
in response to the study drug for this subject is not known due to the above-mentioned
anomaly. An additional analysis should be performed without this extraordinary copeptin
value as this value is non-drug related.
2)
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s::m#$ryvllf,"
%.lffi,ffi $
Biostatistics File Note
Page 2 of 2
Section C
AUTHOR:
Name:
Job Title:
sPgNSoR:
Name:
Job Title:
ffiuller Heyns
$r" $tati*iica} Prc$ramrc*r
N*il H. $hust*rrnam, MB 
Signature:
Sh$ef ffiedie*l Sffl*sr
signature, ,,,,, 
"
Date: GS *Jul-?S2S
Date: gS=Jun-*StS
Form No.: CS FM 85020 Revision 4
Reference: CS OP BS001
Effective Date: 29Nov201 9
Copyright@2010,2012,2017,2019|QVIA. 
All rights reserved. The contents of this document are cpnfidential and proprietaryto
tQVh Houings lnc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited.
Palladio Biosciences
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