Clinical trial NCT03203642
Conditions: Autosomal Dominant Polycystic Kidney ADPKD
Keywords: ADPKD Autosomal Dominant Polycystic Kidney Disease Polycystic Kidney Tesevatinib Polycystic Kidney Disease PKD
Sponsor: Kadmon, a Sanofi Company
Start date: 2017-10-12; Completion date: 2022-01-25
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of the study was to compare and evaluate safety and efficacy of tesevatinib 50 milligrams (mg) versus placebo in participants with autosomal dominant polycystic kidney disease (ADPKD).

Detailed description:
Safety and efficacy of 50 mg tesevatinib in comparison to placebo in participants with ADPKD was assessed.

The primary purpose of this study was focused on evaluating the change from Baseline in height-adjusted total kidney volume (htTKV) as measured by magnetic resonance imaging (MRI) at Months 12, 18, and 24, and 30 days post-dose in participants with ADPKD treated with tesevatinib or placebo.

If eligible for the study participation, participants were randomly assigned to either investigational treatment group or placebo group. Treatment group received 50 mg tesevatinib once daily for 24 months and control group received the placebo once daily for 24 months.

Arms: arm 1: Participants received tesevatinib 50 mg tablet orally once daily (QD) for up to 25.3 months. arm 2: Participants received placebo matched to tesevatinib tablet orally QD for up to 25.3 months.
Interventions: intervention 1: Tesevatinib intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Tablet; Route of administration: orally intervention 2: Pharmaceutical form: Tablet (identical to tesevatinib); Route of administration: orally

Protocol documents:
Prot_000.pdf: 
PROTOCOL:  KD019-211 
TITLE: 
A Double-blind Randomized Parallel Group Study of the 
Efficacy and Safety of Tesevatinib in Subjects with 
Autosomal Dominant Polycystic Kidney Disease 
DRUG: 
Tesevatinib (KD019) 
IND: 
110588 
SPONSOR: 
Kadmon Corporation, LLC 
450 East 29th Street 
New York, NY 10016 
PROTOCOL 
VERSION AND 
DATE: 
Version 2.0, 31 August 2018 
NCT03203642




Kadmon Corporation, LLC 
CONFIDENTIAL 
31 August 2018 
Protocol KD019-211 
Version 2.0, Final 
Page 3 of 74 
 
Investigator’s Acknowledgement 
I have read this protocol KD019-211. 
Title:  A Double-blind Randomized Parallel Group Study of the Efficacy and Safety of 
Tesevatinib in Subjects with Autosomal Dominant Polycystic Kidney Disease 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the Sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to my 
participation as an Investigator for this study to be terminated. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the Sponsor. 
 
Investigator Name, Address, and 
Telephone Number: 
(please hand print or type) 
 
 
 
 
 
 
 
Signature: 
 
 
 
Date: 
 
 


Kadmon Corporation, LLC 
CONFIDENTIAL 
31 August 2018 
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Version 2.0, Final 
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EMERGENCY CONTACT INFORMATION 
All serious adverse events (SAE) occurring in subjects while on-study or within 30 days of 
receiving study drug regardless of relationship, must be promptly reported (within 24 hours) 
by telephone, email, or telefax to the Pharmacovigilance vendor. 
Table 1: 
Reporting of Serious Adverse Events 
 
For SAE/Pregnancy reporting: 
For any other questions or to contact the 
Medical Monitor: 
APCER Life Sciences, Inc. 
Fax Number:  1-646-430-9549 
In the event of an issue with the fax line, forward 
the serious adverse event information via email 
to:  clinicalsaereporting@kadmon.com 
 
 
 
 
 
 
 
 
  


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31 August 2018 
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PRODUCT QUALITY COMPLAINTS 
Once a Product Quality Complaint is identified, investigators must report it to Kadmon.  This 
includes any instances wherein the quality or performance of a Kadmon investigational 
product does not meet expectations (eg, inadequate or faulty closure, product contamination), 
the product does not meet the specifications defined in the application for the product (eg, 
wrong product such that the label and contents are different products), or the product does not 
meet appearance specifications (eg, broken or chipped tablets). For instructions on reporting 
adverse events (AEs) related to product complaints, see Section 8. 
Please use the information below as applicable to report the Product Quality Complaint: 
Phone: (724) 778-6155 
Email Address: productcomplaints@kadmon.com 
Please use the address below if investigational medicinal product needs to be returned: 
Kadmon Corporation, LLC 
Quality Assurance Department 
119 Commonwealth Dr. 
Warrendale, PA 15086 


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CONFIDENTIAL 
31 August 2018 
Protocol KD019-211 
Version 2.0, Final 
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TABLE OF CONTENTS 
PRODUCT QUALITY COMPLAINTS ......................................................................................... 5 
TABLE OF CONTENTS ................................................................................................................ 6 
LIST OF TABLES ......................................................................................................................... 10 
LIST OF APPENDICES ............................................................................................................... 10 
ABBREVIATIONS ....................................................................................................................... 11 
1. 
BACKGROUND INFORMATION ........................................................................... 21 
1.1. 
Polycystic Kidney Disease ......................................................................................... 21 
1.2. 
Tesevatinib ................................................................................................................. 21 
1.2.1 
Nonclinical Toxicology .............................................................................................. 22 
1.2.2 
Clinical Experience with Tesevatinib ......................................................................... 22 
1.3. 
Study Rationale .......................................................................................................... 27 
1.3.1 
Rationale for the ADPKD Indication ......................................................................... 27 
1.3.2 
Rationale for Dosage Selection .................................................................................. 27 
2. 
STUDY OBJECTIVES AND PURPOSE .................................................................. 28 
2.1. 
Primary Objective ....................................................................................................... 28 
2.2. 
Secondary Objective ................................................................................................... 28 
3. 
STUDY DESIGN ....................................................................................................... 29 
4. 
STUDY POPULATION ............................................................................................. 30 
4.1. 
Inclusion Criteria ........................................................................................................ 30 
4.2. 
Exclusion Criteria ....................................................................................................... 31 
4.3. 
Withdrawal of Subjects .............................................................................................. 33 
4.3.1 
Subject Stopping Criteria ........................................................................................... 33 
4.3.2 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit....................................... 33 
5. 
CONCOMITANT MEDICATION ............................................................................ 35 
5.1. 
Concomitant Medication and Potential Interactions .................................................. 35 
5.2. 
Management of Subjects Requiring Concomitant Medications Associated 
with QT Interval Prolongation.................................................................................... 35 
6. 
INVESTIGATIONAL PRODUCT ............................................................................ 37 
6.1. 
Identity of Investigational Product ............................................................................. 37 
6.2. 
Administration of Investigational Product(s) ............................................................. 37 


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6.2.1 
Interactive Voice/Web Response System for Investigational Product 
Management ............................................................................................................... 37 
6.2.2 
Dosing......................................................................................................................... 37 
6.2.3 
Blinding the Treatment Assignment ........................................................................... 37 
6.2.4 
Allocation of Subjects to Treatment ........................................................................... 37 
6.2.5 
Unblinding the Treatment Assignment ...................................................................... 38 
6.3. 
Labeling, Packaging, Storage, and Handling ............................................................. 39 
6.3.1 
Labeling ...................................................................................................................... 39 
6.3.2 
Packaging ................................................................................................................... 39 
6.3.3 
Storage ........................................................................................................................ 39 
6.4. 
Investigational Product Quality Complaints .............................................................. 39 
6.5. 
Drug Accountability ................................................................................................... 40 
6.6. 
Subject Compliance .................................................................................................... 41 
6.7. 
Warnings, Precautions, and Management .................................................................. 41 
6.7.1 
Diarrhea ...................................................................................................................... 41 
6.7.2 
Skin Rash .................................................................................................................... 42 
6.7.3 
QT Interval Prolongation ............................................................................................ 44 
6.7.4 
Elevated Amylase ....................................................................................................... 45 
6.7.5 
Elevated Creatinine Phosphokinase ........................................................................... 45 
6.7.6 
Pulmonary Toxicity .................................................................................................... 45 
6.7.7 
Hepatotoxicity ............................................................................................................ 45 
6.7.8 
Pericardial Effusion .................................................................................................... 46 
6.7.9 
Adrenal Insufficiency ................................................................................................. 46 
7. 
STUDY PROCEDURES ............................................................................................ 47 
7.1. 
Study Schedule ........................................................................................................... 47 
7.2. 
Informed Consent Process .......................................................................................... 47 
7.3. 
Demographics and Medical History ........................................................................... 47 
7.4. 
Randomization ............................................................................................................ 47 
7.5. 
Safety Measurements.................................................................................................. 48 
7.5.1 
Physical Examination, Height and Weight ................................................................. 48 
7.5.2 
Vital Signs .................................................................................................................. 48 


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7.5.3 
Electrocardiogram ...................................................................................................... 48 
7.5.4 
Echocardiogram .......................................................................................................... 49 
7.5.5 
Ocular Monitoring ...................................................................................................... 49 
7.5.6 
Clinical Laboratory Evaluations ................................................................................. 49 
7.5.7 
Concomitant Medications ........................................................................................... 51 
7.5.8 
Adverse Events ........................................................................................................... 51 
7.6. 
Efficacy Measurements .............................................................................................. 51 
7.6.1 
Magnetic Resonance Imaging .................................................................................... 51 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ........................ 52 
8.1. 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events ........................................................................................................... 52 
8.1.1 
Severity Categorization .............................................................................................. 52 
8.1.2 
Relationship Categorization ....................................................................................... 53 
8.1.3 
Outcome Categorization ............................................................................................. 55 
8.1.4 
Symptoms of the Disease Under Study ...................................................................... 56 
8.1.5 
Clinical Laboratory Evaluations ................................................................................. 56 
8.1.6 
Pregnancy ................................................................................................................... 56 
8.1.7 
Overdose and Medication Error ................................................................................. 57 
8.2. 
Serious Adverse Event Procedures ............................................................................. 57 
8.2.1 
Reference Safety Information ..................................................................................... 57 
8.2.2 
Reporting Procedures ................................................................................................. 57 
8.2.3 
Serious Adverse Event Definition .............................................................................. 57 
8.3. 
Serious Adverse Event Collection Timeframe ........................................................... 58 
8.3.1 
Serious Adverse Event Onset and Resolution Dates .................................................. 58 
8.3.2 
Fatal Outcome ............................................................................................................ 58 
8.3.3 
Regulatory Agency, Institutional Review Board, Independent Ethics 
Committee, and Site Reporting .................................................................................. 59 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ................................... 60 
9.1. 
Data Collection ........................................................................................................... 60 
9.2. 
Clinical Data Management ......................................................................................... 60 
9.3. 
Statistical Analysis Process ........................................................................................ 60 


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9.4. 
Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee .................................................................................................................. 60 
9.5. 
Selection of Subjects to be Included in the Analyses ................................................. 60 
9.6. 
Subject Disposition ..................................................................................................... 61 
9.7. 
Demographic and Baseline Characteristics ................................................................ 61 
9.8. 
Investigational Product Exposure ............................................................................... 61 
9.9. 
Prior and Concomitant Medication ............................................................................ 61 
9.10. 
Efficacy Analyses ....................................................................................................... 61 
9.11. 
Safety Analyses .......................................................................................................... 62 
9.12. 
Sample Size Calculation and Power Considerations .................................................. 62 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ............................... 63 
10.1. 
Sponsor’s Responsibilities.......................................................................................... 63 
10.1.1 
Good Clinical Practice Compliance ........................................................................... 63 
10.1.2 
Public Posting of Study Information .......................................................................... 63 
10.1.3 
Study Suspension, Termination, and Completion ...................................................... 63 
10.2. 
Investigator’s Responsibilities .................................................................................... 63 
10.2.1 
Good Clinical Practice Compliance ........................................................................... 63 
10.2.2 
Protocol Adherence and Investigator Agreement ....................................................... 64 
10.2.3 
Documentation and Retention of Records .................................................................. 64 
10.3. 
Ethical Considerations ................................................................................................ 65 
10.3.1 
Informed Consent ....................................................................................................... 66 
10.3.2 
Institutional Review Board or Independent Ethics Committee .................................. 66 
10.4. 
Privacy and Confidentiality ........................................................................................ 66 
10.5. 
Publication Policy ....................................................................................................... 67 
11. 
REFERENCES ........................................................................................................... 68 
12. 
APPENDICES ............................................................................................................ 69 
 


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LIST OF TABLES 
Table 1: 
Reporting of Serious Adverse Events........................................................................... 4 
Table 2: 
Schedule of Assessments ............................................................................................ 19 
Table 3: 
Summary of KD019-101 Dose / Schedule, Demographics and Median 
Total Kidney Volume (mL) at Baseline ..................................................................... 23 
Table 4: 
Suggestions for Skin Rash .......................................................................................... 43 
Table 5: 
Management Guidelines for Liver Function Abnormalities ...................................... 46 
Table 6: 
Clinical Laboratory Tests ........................................................................................... 50 
Table 7: 
5-point Clinical Symptom and Adverse Event Grading Scale ................................... 52 
Table 8: 
Relationship Assessment for Adverse Events ............................................................ 54 
 
LIST OF APPENDICES 
Appendix 1 Concomitant Drugs That Inhibit CYP3A4 and Should Not be 
Administered .............................................................................................................. 70 
Appendix 2 Concomitant Medications Associated With a Risk of QTc(F) Interval 
Prolongation and/or Torsades de Pointes ................................................................... 71 
Appendix 3 Topical Steroid Potency Chart.................................................................................... 72 


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ABBREVIATIONS 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALT 
alanine transaminase 
ARPKD 
autosomal recessive polycystic kidney disease 
AST 
aspartate transaminase 
AUC 
area under the plasma drug concentration time curve 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CPK 
creatine phosphokinase 
CRA 
Clinical Research Associate 
CYP 
cytochrome P450 
CV% 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGRF 
estimated glomerular filtration rate 
EGFR 
epithelial growth factor receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
htTKV 
height-adjusted total kidney volume 
ICH 
International Council for Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
KDR 
kinase insert domain receptor 
LLN 
lower limit of normal 
mITT 
modified intent to treat 
MRI 
magnetic resonance imaging 


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MTD 
maximum tolerated dose 
PK 
Pharmacokinetic(s) 
PKD 
Polycystic kidney disease 
PKD1/2 
polycystin 1 or 2 gene 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SSRI 
Selective serotonin reuptake inhibitor 
Tmax 
observed time to reach peak plasma concentration 
TK 
tyrosine kinase 
ULN 
upper limit of normal 
VEGFR2 
vascular endothelial growth factor receptor 2 


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CONFIDENTIAL 
31 August 2018 
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STUDY SYNOPSIS 
Protocol number:   
KD019-211 
Study drug: Tesevatinib (KD019) 
Title of the study:   
A Double-blind Randomized Parallel Group Study of the Efficacy and Safety of Tesevatinib in 
Subjects with Autosomal Dominant Polycystic Kidney Disease 
Number of subjects (total and for each treatment arm): 
Approximately 160 subjects will be screened in order to enroll 100 subjects (50 subjects 
randomized to tesevatinib, 50 subjects randomized to placebo) of which at least 80 subjects 
(40 per group) are anticipated to complete all study procedures.  
Investigator(s):   
Multicenter study in the United States. Coordinating Principal Investigator – 
 
 
Site(s): Approximately 25-30 sites in the United States 
Study period (planned): 
June 2017 to June 2020 
Clinical phase: 
2b 
Objectives: 
Primary:   
To evaluate the change from baseline in height-adjusted total kidney volume (htTKV) as 
measured by magnetic resonance imaging (MRI) at Months 12, 18, 24, and 30 days post-dose 
in patients with autosomal dominant polycystic kidney disease (ADPKD) treated with 
tesevatinib or placebo. 
Secondary:   
To evaluate the safety and tolerability of tesevatinib 50 mg once daily (QD) in patients with 
ADPKD. 
To evaluate the change in eGFR using the MDRD-4 formula at the Month 12, 18, 24, and 30 
days post-dose time points. 
 
Rationale: 
In nonclinical studies, tesevatinib selectively inhibited key kinases and validated targets in 
animal models of polycystic kidney disease (PKD). This Phase 2b, double-blind, 
placebo-controlled study in subjects with ADPKD will provide initial evidence of the treatment 
effect of tesevatinib in ADPKD subjects and allow for a better understanding of tesevatinib’s 
safety profile in this patient population. 
Investigational product, dose, and mode of administration: 
Tesevatinib (KD019) 50 mg or matched placebo tablets will be administered orally QD. 


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Methodology: 
This is a multicenter, double-blind, randomized, parallel group study of tesevatinib tablet 
formulation administered to male and female subjects with ADPKD, 18 to 60 years of age and 
with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and 
≤ 80 mL/min/1.73 m2.  
Subjects will be screened up to 28 days before initiation of treatment with tesevatinib or 
placebo (certain screening assessments may be conducted up to 42 days prior to dosing). 
Screening assessments will include medical and PKD history, physical examination, vital signs, 
electrocardiograms (ECGs), clinical laboratory evaluation (including hematology, serum 
chemistry, coagulation, thyroid stimulating hormone, urinalysis, and pregnancy), ocular 
examination, echocardiogram, and MRI. Calculation of htTKV at screening for eligibility 
determination may be performed by a local radiologist.  
Starting on Day 1, subjects will receive 50 mg QD of tesevatinib or placebo for up to 
24 months. During the Early Treatment Period (Days 1 to 28), subjects will report to the study 
site on Days 1, 14, and 28; subjects will be followed every 28 days from Months 2 to 12 and 
every other month from Months 12 to 24. Safety assessments will be performed at regular 
intervals throughout the study and will include physical examinations, vital signs, ECGs, 
clinical laboratory evaluations, ocular examination and echocardiograms. Magnetic resonance 
imaging to determine the change from baseline in htTKV will be performed at Months 12, 18, 
and 24. Entry into the study will be based on local MRI readings, but central MRI readings and 
htTKV calculation will be performed at baseline and during the study. 
All subjects will undergo an end-of-study evaluation approximately 30 days after the last dose 
of study drug. 
Inclusion and exclusion criteria: 
Inclusion criteria:  
Subjects will be included in the study if they meet all of the following inclusion criteria: 
1. Confirmed diagnosis of ADPKD based on Ravine’s criteria. Subjects < 30 years of age 
must have at least 2 cysts (unilateral or bilateral) while subjects ≥ 30 years of age must 
have at least 2 cysts in each kidney (ie, total ≥ 4 cysts). 
2. Cysts must be at least 1 cm in size to be considered. 
3. At least 18 years old and no more than 60 years old at the time of consent. 
4. eGFR ≥ 25 mL/min/1.73 m2 and ≤ 90mL/min/1.73 m2, using the Modification of Diet in 
Renal Disease-4 variable formula. 
5. htTKV must meet the following requirements (htTKV is calculated using total kidney 
volume obtained from MRI divided by height in meters): 
 >500 mL for subjects 18-35 year of age 
 >750 mL for subjects 36-49 years of age 
 >900 mL for subjects 50-60 years of age 
6. Subject has the following laboratory values: 
 Platelets > lower limit of normal (LLN) 


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 Hemoglobin > 9 g/dL 
 Total bilirubin ≤ 1.5 mg/dL 
 Aspartate aminotransferase < 2.5 × upper limit of normal (ULN) 
 Alanine aminotransferase < 2.5 × ULN 
 Prothrombin time/partial thromboplastin time ≤ 1.5 × ULN 
 International normalized ratio (INR) ≤ 1.5, except those subjects taking warfarin 
who must have INR ≤ 3 
 Albumin ≥ LLN 
 Amylase < 1.5 x ULN 
 Lipase < 1.5 x ULN 
 Serum potassium within normal limits 
 Serum magnesium within normal limits 
7. Female subjects of childbearing potential must have a negative pregnancy test at 
screening. Females of childbearing potential are defined as sexually mature women 
without prior hysterectomy, bilateral tubal ligation, or who have had any evidence of 
menses in the past 12 months. However, women who have been amenorrheic for 12 or 
more months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression. 
 Women of childbearing potential must have a negative urine pregnancy test 
(positive urine tests are to be confirmed by serum test) documented within the 
24-hour period prior to the first dose of study drug. 
 Sexually active women of childbearing potential enrolled in the study must agree to 
use 2 forms of accepted methods of contraception during the course of the study and 
for 6 months after their last dose of study drug. Effective birth control includes (a) 
intrauterine device plus 1 barrier method; (b) on stable doses of hormonal 
contraception for at least 3 months (eg, oral, injectable, implant, and transdermal) 
plus 1 barrier method; or (c) 2 barrier methods. Effective barrier methods are male 
or female condoms, diaphragms, and spermicides (creams or gels that contain a 
chemical to kill sperm); or (d) a vasectomized partner. 
8. For male subjects who are sexually active and are partners of premenopausal women: 
agreement to use 2 forms of contraception as in criterion 7 above during the treatment 
period and for at least 6 months after the last dose of study drug, unless the male subject 
had a vasectomy. 
9. Capable of understanding and complying with the protocol and has signed the informed 
consent form. 
Exclusion criteria: 
Subjects meeting any of the following criteria will be excluded from participation:   
1. Previous partial or total nephrectomy or a kidney transplant. 
2. Tuberous sclerosis, Hippel-Lindau disease, or acquired cystic disease. 


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3. Congenital absence of 1 kidney and/or need for dialysis or transplantation in the 
foreseeable future. 
4. Moderate hematuria. Subjects with microhematuria may be enrolled, unless 
microhematuria is suspected to be due to infection or recent cyst rupture. If hematuria is 
due to cyst rupture, the subject may be rescreened after discussion with the Medical 
Monitor.  
5. Uncontrolled hypertension (systolic blood pressure > 160 mmHg; diastolic blood pressure 
> 100 mmHg) while receiving antihypertensive therapy. 
6. Uncontrolled diabetes mellitus (glycated hemoglobin > 8%). 
7. Presence of renal or hepatic calculi (stones) causing symptoms. 
8. Received any investigational therapy within 30 days prior to initiation of therapy (Day 1). 
9. Received tolvaptan within 30 days prior to initiation of therapy (Day 1). 
10. Received active treatment (within 4 weeks of initiation of therapy [Day 1]) for urinary 
tract infection. 
11. History of pancreatitis or known risk factors for pancreatitis. 
12. Subject meets any of the following cardiac criteria: 
 Mean QTc interval corrected for heart rate using Fridericia’s formula (QTcF) of 
> 450 msec. 
 History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus 
bradycardia (< 50 beats per minute), heart block (excluding first-degree block, being 
PR interval prolongation only), congenital long QT syndrome or new ST segment 
elevation or depression or new Q wave on ECG. Inclusion of subjects with a history 
of atrial arrhythmias should be discussed with the Medical Monitor. 
 Family history of congenital long QT syndrome or unexplained cardiac death. 
 History of ventricular rhythm disturbances. 
 Symptomatic heart failure (per New York Heart Association guidelines), unstable 
angina, myocardial infarction, or cerebrovascular accident within 6 months prior to 
study entry. 
 Has a cardiac pacemaker. 
 History of pericardial effusion or presence of pericardial effusion on screening 
echocardiogram 
13. Subject is taking any medication known to inhibit the cytochrome P450 (CYP)3A4 
isozyme or any drugs that are CYP3A4 inducers, or any drugs associated with torsade de 
pointes or known to prolong the QTcF interval, including anti-arrhythmic medications 
within 2 weeks prior to screening. A stable regimen (≥ 4 weeks) of antidepressants of the 
selective serotonin reuptake inhibitor (SSRI) class is allowed (common SSRIs include 
escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine).  
14. Uncontrolled intercurrent illness that would limit compliance with study requirements 
including, but not limited to ongoing or active infections or psychiatric illness.  
15. Subject is pregnant, plans to become pregnant, or nursing. 


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16. Known to be positive for the human immunodeficiency virus or hepatitis B or C, as 
indicated by a positive test at screening. 
17. Known to be immunocompromised. 
18. Documented presence of renal vascular disease resulting in uncontrolled hypertension. 
19. Has previously received an epithelial growth factor receptor (EGFR) inhibitor (including, 
but not limited to, erlotinib, gefitinib, osimertinib, afatinib, cetuximab, panitumumab, or 
an investigational agent). 
20. Allergy or hypersensitivity to components of either tesevatinib, matched placebo, or their 
formulations. 
21. Aphakic due to previous cataract surgery or congenital abnormality. 
Note:  The sponsor has the option to exclude a subject from enrollment, if, based upon the 
subject’s medical history or screening results, it is felt that a subject’s safety may be at risk 
and/or if the safety data may confound the study results. 
Maximum duration of subject involvement in the study: 
The planned duration of the screening period is no more than 28 days prior to dosing (42 days 
for MRI and ocular assessments). The planned duration of treatment period is approximately 
730 days (or 24 months). The follow-up period will be 30 days from the last dose of study drug. 
Endpoints and statistical analysis:   
Study data will be summarized for disposition, demographic and baseline characteristics, 
efficacy, and safety parameters. Unless otherwise noted, study data will be summarized by 
treatment group. Categorical data will be summarized by frequency distributions (number and 
percentages of subjects) and continuous data will be summarized by descriptive statistics 
(mean, standard deviation, median, minimum, and maximum). All data will be presented in 
subject listings. 
Efficacy analyses will be based on the Efficacy Population, defined as all randomized subjects 
who have completed 12 months of tesevatinib or placebo treatment and have a centrally read 
MRI at baseline and after 12 months of treatment. The primary efficacy endpoint will be the 
change from baseline in htTKV at Month 12. An analysis of covariance model including 
treatment group as a factor and the baseline htTKV as a covariate will be used for efficacy 
analyses. The Type I error rate will be set at an alpha level of 0.05. Additional efficacy 
endpoints include change from baseline in htTKV at Months 18 and 24. 
Safety analyses will be based on the modified Intent-To-Treat Population, defined as all 
randomized subjects who received at least 1 dose of study drug. Treatment-emergent adverse 
events (AEs) will be summarized using Medical Dictionary for Regulatory Activities (Version 
19.0 or higher) system organ class and preferred term and presented by treatment group. Safety 
endpoints will include AEs and clinical laboratory evaluations (including serum creatinine, 
cystatin C, and calculated eGFR).  
Based on the results presented in Caroli, et.al.1 it is anticipated that the mean change from 
baseline in htTKV at 12 months will be 83.6 (± 90.0) mL in the placebo group. Assuming the 
mean change from baseline in htTKV at 12 months is 26.4 mL for the tesevatinib group, 
40 subjects per group would yield approximately 80% power to detect a difference between 


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treatment groups based on a 2-sided t-test with a Type I error rate of 0.05. Ten additional 
subjects per group will be added (ie, for a total of 50 subjects per group) to adjust for drop-outs 
and differences in analysis methodologies (eg, the htTKV data will be log-transformed). 


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STUDY SCHEDULE 
Table 2: 
Schedule of Assessments 
Assessments 
Screeninga 
(-28 Days) 
Early Treatment Period 
Monthly 
Follow-up 
Treatment 
Period 
End of 
Studyc 
Day 1 
Day 14 
(± 1 Day) 
Day 28 
(± 1 Day) 
Every 
28 Daysb 
Beginning 
at Month 2 
(± 1 or 
±3 Days) 
30 Days 
from Last 
Dose  
(± 3 Days) 
Informed consent 
 
 
 
 
 
 
Medical and PKD history 
(include genotype, if 
available)  
 
 
 
 
 
 
Physical examinationd 
(including weight) 
 
 
 
 
 
 
Vital signse 
 
 
 
 
 
 
Supine 12-lead ECGf 
 
 
 
 
 
 
Clinical laboratory testsg 
 
 
 
 
 
 
Ocular evaluationh 
 
 
 
 
 
 
Echocardiogrami 
 
 
 
 
 
 
Pregnancy testj 
 
 
 
 
 
 
MRIk 
 
 
 
 
 
(every 
6 months 
beginning 
at 
Month 12) 
 
Randomization 
 
 
 
 
 
 
Study drug/placebo 
dispensed 
 
 
 
 
 
 
Record adverse events 
 
 
 
 
 
 
Record concomitant 
medication 
 
 
 
 
 
 
Drug compliance/collectionl 
 
 
 
 
 
 


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Abbreviations:  ECG, electrocardiogram; MRI, magnetic resonance imaging; PKD, polycystic kidney disease; 
QTc(F), QT interval corrected for heart rate using Fridericia’s formula; TSH, thyroid stimulating hormone 
a. 
Screening evaluations may be combined with Day 1 pre-treatment laboratory evaluations if both are done 
within 4 days before first dose of study drug. Screening MRI and ocular assessments may be performed up 
to 6 weeks prior to Day 1. 
b 
Follow-up treatment period visits to be performed monthly (every 28 ± 1 day). For those subjects continuing 
on study beyond 12 months, visits will occur every 2 months ± 3 days between Months 12 and 24. 
c. 
The End-of-study visit is to be performed 30 days (± 3 days) after last dose of study drug. 
d. A complete physical examination is to be done at the Screening and End-of-study visits. Height will only be 
measured at Screening. Symptom-driven physical examinations will be performed on Days 1, 14, 28, every 
28 days from Months 2 to 12, and every 2 months from Months 12 to 24. See Section 7.5.1 for a description 
of the body systems and evaluations to be performed at each visit (eg, cardiac tamponade, ocular toxicity 
and xerostomia assessments). 
e. 
Vital sign measurements will include sitting blood pressure, heart rate, respiratory rate, and oral or tympanic 
temperature. On Day 1, measurements should be performed predose and 1 and 4 hours postdose. See 
Section 7.5.2 for details on vital signs measurement. 
f. 
Supine 12-Lead ECGs will be performed at Screening, predose, 1, 4, and 8 hours postdose on Days 1 and 
14; predose on Days 28 and Months 2 to 12, at each visit on Months 12 to 24; and at the End-of-study visit. 
Supine ECGs should be repeated 3 times consecutively within 30 minutes (with an interval of at least 
1-2 minutes between ECGs). If QTc(F) is prolonged to > 60 msec above baseline at any evaluation or to the 
level of ≥ 480 msec based on local ECG read, refer to Section 6.7.1.2 for a description of the procedures to 
be followed. 
g. Clinical laboratory tests will include hematology, serum chemistry, coagulation, TSH, and urinalysis (see 
Section 7.5.6 for a complete list of assessments). Thyroid stimulating hormone levels will be evaluated at 
Screening and then every 2 months. Serology testing will be done at Screening only. 
h. Ocular evaluations are to be performed at Screening and at Months 3, 6, 9, 12, 18, and 24, and at the 
End-of-study visit (if applicable). The following assessments will be performed:  evaluation of best 
corrected visual acuity, fundoscopic exam with non-dilated pupils, slit lamp photography of the iris, non-
mydriatic photography of retina within the arcade, and optical coherence tomography of the optic nerve 
head and macula. Note:  if a subject has had ocular evaluations within 3 months of the End-of-study visit, 
there is no need to repeat ocular evaluations at the End-of-study visit. 
i. 
Echocardiograms are to be obtained at Screening, on Day 28, at Months 3, 6, 12, 18, and 24, and at the 
End-of-study visit (if applicable). Echocardiograms should include measurement of ejection fraction and 
assessment for pericardial effusion and valvular abnormalities. Note:  If a subject has had an 
echocardiogram within 3 months of the End-of-study visit, there is no need to obtain an echocardiogram at 
the End-of-study visit. If pericardial effusion is diagnosed via echocardiogram, the subject should be 
rechecked within 1–3 months to monitor for progression. 
j. 
Pregnancy testing in women of childbearing potential will be performed using urine samples. Subjects must 
have a negative urine pregnancy test documented within the 24-hour period prior to the first dose of study 
drug. Pregnancy tests are to be performed at Screening, predose on Day 1, Day 28, Month 3, every 3 months 
through Month 12, at every visit between Months 12 and 24, and at the End-of-study visit only. Positive 
urine samples will be confirmed via serum testing. 
k. Screening MRI will be performed after informed consent form has been signed and prior to other screening 
assessments. Magnetic resonance imaging will be performed at Month 12, 18, and 24, and at the 
End-of-study visit  
l. 
Subject diaries will be dispensed on Day 1 and reviewed/collected at each visit. 


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1. 
BACKGROUND INFORMATION 
1.1. 
Polycystic Kidney Disease 
Polycystic kidney disease (PKD) is the most common inherited kidney disease in the United 
States, occurring in approximately 1 in every 1,000 live births. It affects more than 
600,000 people in the United States and 12 million worldwide 2. It is the third most common 
single cause of kidney failure.  
Polycystic kidney disease is characterized by the growth of numerous renal cysts, which cause 
abnormalities in both structure and function of the kidneys. Cysts also develop in other 
organs, particularly in the liver. Other manifestations of PKD include high blood pressure, 
urinary tract infections, kidney stones, hematuria, and aneurysms. Pain in the back, abdomen, 
and pelvis affects many PKD patients. 
There are 2 types of PKD, autosomal dominant (ADPKD) and autosomal recessive (ARPKD). 
In the more common form, ADPKD, the abnormal PKD gene (polycystin 1 or 2 [PKD1 or 
PKD2]) is inherited from 1 parent who also has PKD. Affected individuals become aware of 
the disease at varying times from childhood to adulthood. If a family history exists, 
individuals are assessed regularly for manifestations of the disease. Others may have cysts 
detected during routine medical evaluations for hematuria or hypertension or an ultrasound 
examination for other medical symptoms and conditions. There is, however, a small 
percentage of people with ADPKD who do not have a family member with the disease. 
Autosomal recessive PKD is associated with abnormal function of the kidneys and liver, and 
is usually diagnosed by ultrasound during fetal development or shortly after birth. Unlike 
ADPKD, a mutant PKHD1 gene must be contributed by each parent in order for ARPKD to 
occur in an offspring. Parents are usually unaware of being carriers of the mutant gene 
because they are asymptomatic. 
In ADPKD, the mutation in either the PKD1 or PKD2 gene results in the abnormal, 
uncontrolled growth of renal tubular epithelial cells 3. Epithelial growth factor receptor 
(EGFR) is overexpressed and mislocated from the basolateral to the luminal surface of renal 
tubular cells 4. Epithelial growth factor receptor ligands are secreted by tubular cells and are 
found in human PKD cyst fluids. The combination of EGFR mislocation and ligand secretion 
establishes an autocrine loop resulting in persistent renal tubular cell proliferation 5. Chronic 
proliferation results in renal cyst formation 6. The cysts then cause a structural distortion of 
the renal architecture, impeding normal nephron function. Cyst enlargement results in a 
massive increase in kidney volume and a progressive impairment of renal function 7. 
Associated clinical symptoms include hypertension, recurrent flank pain, hematuria, and 
recurrent pyelonephritis. Currently, there are no disease-modifying therapies for ADPKD; all 
existing treatment strategies are palliative and aimed at controlling symptoms 8. 
1.2. 
Tesevatinib 
Tesevatinib (formerly named XL647 and KD019) is a new chemical entity that inhibits 


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multiple tyrosine kinases (TKs) (ErbB family members [EGFR and human epidermal growth 
factor receptor 2], vascular endothelial growth factor receptor 2/kinase insert domain receptor 
[VEGFR2/KDR]), and Src family kinases. 
Nonclinical Toxicology  
Tesevatinib nonclinical toxicology has been characterized in multiple species using a variety 
of dosing regimens. Details can be found in the Investigator’s Brochure. 
Clinical Experience with Tesevatinib 
Tesevatinib has been evaluated in over 350 subjects, including 232 subjects with solid tumor 
malignancies in 3 Phase 1 studies, 4 Phase 2 studies, and 1 Phase 3 study; 66 healthy subjects 
in 4 clinical pharmacology studies; and 73 subjects with PKD (Study KD019-101).   
1.2.1.1. 
Tesevatinib in Oncology Indications 
Details on completed and ongoing studies of tesevatinib in oncology indications, including 
advanced solid tumors, non-small cell lung carcinoma, breast cancer, and glioblastoma can be 
found in the Investigator’s Brochure. 
1.2.1.2. 
Tesevatinib in ADPKD 
One Phase 1b/2a study, Study KD019-101, is currently ongoing in subjects with ADPKD. As 
of March 2017, 73 subjects were enrolled into 5 dosing cohorts in the study, including 
9 subjects receiving 50 mg once daily (QD) (Cohort 1), 8 subjects receiving 100 mg QD 
(Cohort 2), 5 subjects receiving 150 mg QD (Cohort 3), 14 subjects receiving 150 mg 
Monday, Wednesday, and Friday (Cohort 4), and 10 subjects receiving 150 mg Monday and 
Thursday (Cohort 5); 15 additional subjects were enrolled in the Phase 2a portion of the 
study, and are receiving 50 mg QD (Table 3). In addition, 12 more subjects with baseline 
height-adjusted total kidney volume (htTKV) ≥ 1000 mL are currently enrolled and receiving 
tesevatinib 50 mg QD (SILK cohort).  


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Table 3: 
Summary of KD019-101 Dose / Schedule, Demographics and Median 
Total Kidney Volume (mL) at Baseline 
Dose/Schedule 
No. Subjects 
Gender (M/F) 
Median Age 
(Years) 
Median TKV 
(mL) 
50 mg/daya 
24 
9M/15F 
39 
1200b 
100 mg/day 
8 
5M/3F 
37 
1197 
150 mg/day 
5 
2M/3F 
41 
923 
150 mg MWF 
14 
4M/10F 
36 
1158 
150 mg MT 
10 
4M/6F 
37 
644 
50 mg/day 
(SILK) 
12 
6M/6F 
51 
2371 
Total 
73 
30M/43F 
39 (19-74) 
1225* 
(324-6930) 
Abbreviations: F, female; M, male; MT, Monday, Thursday; MWF, Monday, Wednesday, Friday; TKV, total 
kidney volume 
a Includes 9 subjects from Cohort 1 and 15 subjects who were enrolled in the Phase 2a portion of the study. 
b One subject did not have a baseline TKV value. 
 
To date, there have been a total of 3 subjects with treatment-emergent serious adverse events 
(SAEs) in Study KD019-101. One subject experienced a Grade 2 episode of gastroesophageal 
reflux disease leading to hospitalization that was determined to be unlikely related to study 
drug. The episode resolved with no sequelae. One subject experienced a Grade 2 episode of 
angioedema leading to admission to an urgent care center. This event was determined to be 
unlikely related to study drug and resolved with no sequelae. One subject experienced a Grade 
4 episode of depression and suicidal ideation status post-suicide attempt leading to prolonged 
hospitalization. This subject had previously withdrawn consent and had received their last 
dose of study drug approximately 11 months prior to this ongoing event. 
The most common AEs (≥15%) seen in Study KD019-101 were diarrhea (38%), nausea 
(30%), rash (29%), blood creatine phosphokinase (CPK) increased (25%), nasopharyngitis 
(21%), muscle spasms (19%), vomiting (18%), blood creatinine increased (15%), and 
headache (15%). In addition, amylase elevations were noted in 12% of subjects. Most of the 
AEs experienced were mild to moderate. 
Adverse events of special interest as of the data cutoff of October 2016 are described below. 
Diarrhea and Rash 
Diarrhea and rash were both expected as they are a class effect of all EGFR inhibitors. 
At 150 mg QD, 3 of 5 patients had moderate rash occurring during the first 28 days, the event 
led to study discontinuation in 2 of the patients. The tolerability of intermittent dosing 
schedules using 150 mg (Monday, Wednesday, and Friday or Monday and Thursday) was 


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improved over 150 mg QD, but 1 case of severe rash occurred in a patient receiving 150 mg 
on Monday and Thursday. While rash at the 150 mg dose level did not meet strict safety 
criteria for defining the maximum tolerated dose (MTD), this dose level was considered 
intolerable for long-term administration in this population. Therefore, the MTD for daily 
dosing was determined to be 100 mg daily.   
Creatine Phosphokinase Elevations 
There were 41 subjects with elevations of CPK above the normal range in Study KD019-101. 
Ten subjects experienced moderate CPK elevation (> 2.5 × upper limit of normal [ULN] – 
5.0 × ULN), and 7 subjects experienced severe CPK elevation (> 5.0 × ULN). Quantitative 
whole body radiography in rats indicates relatively low accumulation of tesevatinib in skeletal 
muscle. In Study KD019-101, muscle AEs correlated poorly with CPK levels. While 
elevations of CPK commonly occur with exercise, the lack of a control group in Study 
KD019-101 makes it difficult to fully evaluate the relationship between tesevatinib and CPK 
elevations.  
Amylase Elevations 
Mild, asymptomatic increases in amylase were also seen in Study KD019-101, including in 
subjects in the 50 mg QD cohort. Across dose levels, 22 cases of asymptomatic subjects with 
elevated amylase levels were reported. Eighteen of these elevations were mild (> ULN – 
1.5 × ULN), 2 were moderate (> 1.5 × ULN – 2.0 × ULN), and 2 were severe (> 2.0 × ULN). 
Four subjects had elevated amylase levels at Screening and in 2 of these subjects’ amylase 
levels rose to moderate or severe levels, leading to discontinuation from the study. One 
subject developed severe elevated amylase during infection with mononucleosis, and amylase 
levels returned to normal after recovery from that illness. A second subject with a baseline 
amylase level of 185 U/L had levels which continued to rise to a maximum of 365 U/L at 
Day 110. While this subject remained asymptomatic, with no clinical signs or symptoms of 
pancreatitis, this subject was discontinued from the study. Both of these subjects with severe 
amylase elevations had elevations of both lipase and pancreatic amylase isozyme. Other 
subjects with amylase elevations have not had progressive increases in amylase levels during 
tesevatinib administration. 
Previous studies of tesevatinib have been reviewed for cases of elevated amylase or 
pancreatitis. Amylase had not routinely been evaluated in previous studies. There was only 
1 AE of increased amylase level or of possible pancreatitis. This was an elevation of amylase 
to 922 U/L in a subject with Stage IV non-small cell lung cancer who received tesevatinib at a 
dose of 300 mg/day. The subject was admitted to the hospital with diarrhea and abdominal 
pain, but lipase was normal and there were no computed tomography findings consistent with 
pancreatitis. On serum amylase isoenzyme analysis, the subject had an elevation in salivary 
amylase. The investigator’s conclusion was that the subject appeared to have an increase in 
amylase due to salivary amylase secretion by the tumor.  
Quantitative whole body autoradiography was performed in rats with 14C–labeled tesevatinib. 
Among other findings, there was a high concentration (approximately 10 times that found in 
the blood) of tesevatinib in the salivary glands and pancreas. While tesevatinib could 


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concentrate there for many reasons, it’s at least possible that tesevatinib at high concentrations 
in the salivary gland and pancreas could lead to increased serum levels of amylase.  
In summary, mild asymptomatic increases in amylase levels have been seen frequently in 
Study KD019-101, including in subjects in the 50 mg daily cohort, and appear to be due to 
increases in pancreatic amylase. Subjects with baseline elevations in amylase are no longer 
eligible for tesevatinib ADPKD studies. If amylase levels rise to 1.5 × ULN, evaluation of 
lipase, amylase isoenzymes, and lipid levels are performed (see Section 7.5.6). 
Serum Creatinine Elevations 
The initial data indicate that subjects with ADPKD receiving tesevatinib have experienced 
elevations of creatinine without elevations in cystatin C. The median changes from screening 
values for creatinine and cystatin C from all subjects receiving the 50 mg dose reveal that 
creatinine values were increased by 11.1% at Day 3, by 14.3% at Day 7, and increased by 
10% at Day 28. Data after Day 28, including several subjects who have received tesevatinib 
for 24 months, do not indicate any significant ongoing change in creatinine. During the same 
time period, cystatin C levels did not change (median decreases were 0%, 1.9%, and 1.7% at 
Days 3, 7, and 28, respectively). Data from the 8 subjects enrolled into the 100 mg dose 
cohort, as well as subjects enrolled in subsequent cohorts, exhibited a similar pattern. This 
increase in creatinine occurs early and after approximately 7 days, does not continue to 
increase, similar to the increase in serum creatinine seen with cimetidine. Increases in 
creatinine were seen in previous clinical studies of tesevatinib; however, most of the previous 
studies were in subjects with malignancies, and in previous studies, cystatin C levels were not 
evaluated, so increases in serum creatinine that may not represent renal dysfunction were not 
recognized. 
QTc Prolongation 
Four incidences of asymptomatic prolongation of QTc interval to > 480ms or > 60 ms over 
the baseline value were reported in Study KD019-101. One subject in the 100 mg QD cohort 
had a mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) of 
510 msec at Month 5 of dosing. The subject had study drug interrupted and was dose reduced 
to 50 mg QD with resolution of QTcF prolongation. Another subject in that cohort presented 
on Day 7 with a mean QTcF of 487 msec. Study drug was held. On rechallenge at the same 
dose, QTcF was again prolonged at 485 msec. Study drug again was held and restarted at a 
reduced dose of 50 mg with resolution of QTcF prolongation. One subject receiving 150 mg 
every Monday, Wednesday and Friday on Day 12 presented with a mean QTcF of 485 msec. 
Study drug was held and restarted at 100 mg every Monday, Wednesday, and Friday with 
resolution of QTcF prolongation. One subject receiving 150 mg every Monday and Thursday 
presented on Month 12 with a mean QTcF of 484 msec. Study drug was held and restarted at 
50 mg QD with resolution of QTcF prolongation. 
An initial evaluation of QTc duration was performed with data from 37 subjects who received 
doses of 50 mg to 150 mg QD in Study KD019-101. The 50 mg QD dose of tesevatinib 
produced modest QTcF increases. The time-averaged increase in QTcF was 4-6 ms. The time 
point analyses demonstrated a peak increase in QTcF of 11-15 ms at 4 hours postdose on Day 


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14. At the mean maximum plasma concentration (Cmax) of 72.5 mg/mL for the pooled 50 mg 
dose groups, the pharmacokinetic/pharmacodynamic model predicted a mean QTcF increase 
of 13.3 ms, with a 1-sided upper 95% confidence bound of 16.8 ms. The magnitude of the 
QTc effect of the tesevatinib 50 mg QD dose is similar to that produced by moxifloxacin 400 
mg. 
Pericardial Effusion 
One subject in Study KD019-101 receiving 50 mg QD developed a small pericardial effusion 
while on study. An echocardiogram performed per protocol on Day 28 revealed trace 
pericardial effusion, which was not seen on the screening echocardiogram. This result was 
reported as an AE and assessed by the investigator to be of moderate intensity and probably 
related to study drug. The subject was asymptomatic. Subsequent echocardiograms performed 
over the following 6 months while the subject continued to receive tesevatinib revealed no 
change in the pericardial effusion. 
Conclusions 
Safety conclusions from Study KD019-101 are that tesevatinib 150 mg in various schedules 
was associated with skin rash that was not well tolerated. While the MTD dose of 100 mg QD 
was based on criteria defined in the protocol, the occurrence of moderate QTc prolongation in 
2 subjects dosed at that level led to a decision later in the study to recommend 50 mg QD as 
the best tolerated daily dose. Tesevatinib 50 mg QD appeared to be a well-tolerated dose in 
patients with ADPKD, although some acneiform rash occurred. 
Further details on Study KD019-101 can be found in the Investigator’s Brochure. 
1.2.1.3. 
Clinical Pharmacokinetics  
A preliminary noncompartmental analysis of tesevatinib pharmacokinetics (PK) from Phase 1 
studies of intermittent dosing indicated that tesevatinib was rapidly absorbed following oral 
administration, with a median observed time to reach peak plasma concentration (Tmax) of 
4-8 hours. Area under the plasma drug concentration time curve (AUC) and the Cmax 
generally increased approximately in proportion with dose over the full dose range (ie, 3.4 to 
586 mg). Mean terminal half-life after 5 consecutive QD doses ranged from 50 to 92 hours, 
and appeared generally independent of dose. High inter-subject variability in exposure was 
observed with coefficient of variation (CV%) values of 46% and 43% for dose normalized 
Cmax and AUC0-24, respectively. Results from 5 subjects in the Phase 2 study who received 
350 mg tesevatinib on the intermittent schedule showed that the concentration of tesevatinib 
appeared unchanged from cycle to cycle. These results suggest that tesevatinib does not 
accumulate significantly from one 14-day cycle to the next. 
A preliminary noncompartmental PK analysis has been completed for 15 subjects given 
tesevatinib QD for at least 29 consecutive days. Tesevatinib was rapidly absorbed following 
oral administration (mean Tmax ranged from 3.3 to 7.3 hours) and steady state appeared to 
have been reached by about Day 15. The estimated median accumulation ratio was 4.6 
(accumulation ratio based on 300 mg QD dose). The median Tmax at the MTD was 4 hours. 


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1.3. 
Study Rationale 
Rationale for the ADPKD Indication 
In nonclinical studies, tesevatinib selectively inhibited key kinases and validated targets in 
animal models of PKD. Results from nonclinical efficacy studies demonstrated that tesevatinib 
possesses significant potential to prevent the formation of cysts due to an increased 
proliferation of renal ductal epithelial cells. Nonclinical studies using 2 rodent models (BPK 
mouse and PCK rat) of PKD have demonstrated that tesevatinib reaches its target, the kidneys, 
and inhibits the signaling pathway for MEK/ERK by inhibiting the phosphorylation of EGFR 
(and Src, Erb2, VEGFR2/KDR). The decreased phosphorylation of EGFR and Erb2 
contributes towards decreased proliferation of epithelial cells in the kidneys and reduces renal 
enlargement in these 2 disease models. 
In summary, both the nonclinical and clinical results to date suggest that tesevatinib may be a 
promising therapeutic for ADPKD.  
Rationale for Dosage Selection  
Safety reviews after the first 2 cohorts in Study KD019-101 (50 mg QD and 100 mg QD) 
deemed these cohorts to have adequate safety and to be tolerable. In the 150 mg QD cohort, 
3 of 5 subjects enrolled withdrew consent primarily due to concerns with rash. It was noted 
that all 5 subjects in this cohort experienced rash within the first 28 days of treatment. In 
comparison, 4 out of 9 subjects in the 50 mg cohort and 1 out of 8 subjects in the 100 mg 
cohort experienced rash within the first 28 days. While rash at the 150 mg dose level did not 
meet strict safety criteria for defining the MTD, this dose level was considered intolerable for 
long-term administration in this population. Therefore, the MTD for daily dosing was 
determined to be 100 mg QD. While the MTD dose of 100 mg QD was based on criteria 
defined in the protocol, the occurrence of moderate QT prolongation in 2 subjects dosed at 
that level led to a decision later in the study to recommend 50 mg QD as the best tolerated 
daily dose. 
Study KD019-101 is currently enrolling additional subjects at the dose of 50 mg QD (SILK 
cohort) in order to increase the robustness of the safety data in subjects with ADPKD treated 
with tesevatinib.  


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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the change from baseline in htTKV as 
measured by magnetic resonance imaging (MRI) at Months 12, 18, 24, and 30 days post-dose 
in patients with ADPKD treated with tesevatinib or placebo. 
2.2        Secondary Objective 
The secondary objective of the study is to evaluate the safety and tolerability of tesevatinib 
50 mg QD in patients with ADPKD, and to also evaluate the change in eGFR using the 
MDRD-4 formula at the Month 12, 18, 24, and 30 days post-dose time points. 
 


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3. 
STUDY DESIGN 
This is a Phase 2b, multicenter, double-blind, randomized, parallel group study to evaluate the 
change from baseline in htTKV as measured by MRI in subjects with ADPKD treated with 
tesevatinib or placebo. Male and female subjects with ADPKD, 18 to 60 years of age and with 
an eGFR ≥ 30 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2 will be enrolled. Up to 100 male 
and female subjects will be randomized 1:1 to receive 50 mg of tesevatinib QD or placebo. 
The study will be conducted at approximately 25-30 sites in the United States. 
Subjects will be screened up to 28 days before initiation of treatment with tesevatinib or 
placebo (certain screening assessments may be conducted up to 42 days prior to dosing). 
Screening assessments will include medical and PKD history, physical examination, vital 
signs, electrocardiograms (ECGs), clinical laboratory evaluation (including hematology, 
serum chemistry, coagulation, thyroid stimulating hormone, urinalysis, and pregnancy), 
ocular examination, echocardiogram, and MRI. Calculation of htTKV at screening for 
eligibility determination may be performed by a local radiologist.  
Starting on Day 1, subjects will receive 50 mg QD of tesevatinib or placebo for up to 
24 months. During the Early Treatment Period (Days 1 to 28), subjects will report to the study 
site on Days 1, 14, and 28; subjects will be followed every 28 days from Months 2 to 12 and 
every other month from Months 12 to 24. Safety assessments will be performed at regular 
intervals throughout the study and will include physical examinations, vital signs, ECGs, 
clinical laboratory evaluations, ocular examination and echocardiograms. Magnetic resonance 
imaging to determine the change from baseline in htTKV will be performed at Months 12, 18, 
and 24. Entry into the study will be based on local MRI readings, but central MRI readings 
and htTKV calculation will be performed at baseline and during the study. 
All subjects will undergo an end-of-study evaluation approximately 30 days after the last dose 
of study drug. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects will be included in the study if they meet all of the following inclusion criteria: 
1. Confirmed diagnosis of ADPKD based on Ravine’s criteria. Subjects < 30 years of 
age must have at least 2 cysts (unilateral or bilateral) while subjects ≥ 30 years of age 
must have at least 2 cysts in each kidney (ie, total ≥ 4 cysts). 
2. Cysts must be at least 1 cm in size to be considered. 
3. At least 18 years old and no more than 60 years old at the time of consent. 
4. eGFR ≥ 25 mL/min/1.73 m2 and ≤ 90 mL/min/1.73 m2, using the Modification of Diet 
in Renal Disease-4 variable formula. 
5. htTKV  must meet the following criteria (htTKV is calculated using total kidney 
volume obtained from MRI divided by height in meters): 
 > 500 mL for subjects 18-35 years of age 
 > 750 mL for subjects 36-49 years of age 
 > 900 mL for subjects 50-60 years of age  
6. Subject has the following laboratory values: 
 Platelets > lower limit of normal (LLN) 
 Hemoglobin > 9 g/dL 
 Total bilirubin ≤ 1.5 mg/dL 
 Aspartate aminotransferase < 2.5 × ULN 
 Alanine aminotransferase < 2.5 × ULN 
 Prothrombin time/partial thromboplastin time ≤ 1.5 × ULN 
 International normalized ratio (INR) ≤ 1.5, except those subjects taking warfarin 
who must have INR ≤ 3 
 Albumin ≥ LLN 
 Amylase < 1.5 x ULN 
 Lipase < 1.5 x ULN 
 Serum potassium within normal limits 
 Serum magnesium within normal limits 
7. Female subjects of childbearing potential must have a negative pregnancy test at 
screening. Females of childbearing potential are defined as sexually mature women 
without prior hysterectomy, bilateral tubal ligation, or who have had any evidence of 
menses in the past 12 months. However, women who have been amenorrheic for 12 or 


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more months are still considered to be of child bearing potential if the amenorrhea is 
possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression. 
 Women of childbearing potential must have a negative urine pregnancy test 
(positive urine tests are to be confirmed by serum test) documented within the 
24-hour period prior to the first dose of study drug. 
 Sexually active women of childbearing potential enrolled in the study must agree 
to use 2 forms of accepted methods of contraception during the course of the study 
and for 6 months after their last dose of study drug. Effective birth control includes 
(a) intrauterine device plus 1 barrier method; (b) on stable doses of hormonal 
contraception for at least 3 months (eg, oral, injectable, implant, and transdermal) 
plus 1 barrier method; or (c) 2 barrier methods. Effective barrier methods are male 
or female condoms, diaphragms, and spermicides (creams or gels that contain a 
chemical to kill sperm); or (d) a vasectomized partner. 
8. For male subjects who are sexually active and are partners of premenopausal women: 
agreement to use two forms of contraception as in criterion 7 above during the 
treatment period and for at least 6 months after the last dose of study drug, unless the 
male subject had a vasectomy. 
9. Capable of understanding and complying with the protocol and has signed the 
informed consent form. 
4.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from participation.  
1. Previous partial or total nephrectomy or a kidney transplant. 
2. Tuberous sclerosis, Hippel-Lindau disease, or acquired cystic disease. 
3. Congenital absence of 1 kidney and/or need for dialysis or transplantation in the 
foreseeable future. 
4. Moderate hematuria. Subjects with microhematuria may be enrolled, unless 
microhematuria is suspected to be due to infection or recent cyst rupture. If hematuria 
is due to cyst rupture, the subject may be rescreened after discussion with the Medical 
Monitor. 
5. Uncontrolled hypertension (systolic blood pressure > 160 mmHg; diastolic blood 
pressure > 100 mmHg) while receiving antihypertensive therapy. 
6. Uncontrolled diabetes mellitus (glycated hemoglobin > 8%). 
7. Presence of renal or hepatic calculi (stones) causing symptoms. 
8. Received any investigational therapy within 30 days prior to initiation of therapy 
(Day 1). 
9. Received tolvaptan within 30 days prior to initiation of therapy (Day 1). 


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10. Received active treatment (within 4 weeks of initiation of therapy [Day 1]) for urinary 
tract infection. 
11. History of pancreatitis or known risk factors for pancreatitis. 
12. Subject meets any of the following cardiac criteria: 
 Mean QTc interval corrected for heart rate using Fridericia’s formula (QTcF) of 
> 450 msec. 
 History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic 
sinus bradycardia (< 50 bpm), heart block (excluding first-degree block, being PR 
interval prolongation only), congenital long QT syndrome or new ST segment 
elevation or depression or new Q wave on ECG. Inclusion of subjects with a 
history of atrial arrhythmias should be discussed with the Medical Monitor. 
 Family history of congenital long QT syndrome or unexplained cardiac death. 
 History of ventricular rhythm disturbances. 
 Symptomatic heart failure (per New York Heart Association guidelines), unstable 
angina, myocardial infarction, or cerebrovascular accident within 6 months prior to 
study entry. 
 Has a cardiac pacemaker. 
 History of pericardial effusion or presence of pericardial effusion on screening 
echocardiogram 
13. Subject is taking any medication known to inhibit the CYP3A4 isozyme or any drugs 
that are CYP3A4 inducers, or any drugs associated with torsade de pointes or known 
to prolong the QTcF interval, including anti-arrhythmic medications within 2 weeks 
prior to screening. A stable regimen (≥ 4 weeks) of antidepressants of the selective 
serotonin reuptake inhibitor (SSRI) class is allowed (common SSRIs include 
escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine).  
14. Uncontrolled intercurrent illness that would limit compliance with study requirements 
including, but not limited to ongoing or active infections or psychiatric illness.  
15. Subject is pregnant, plans to become pregnant, or nursing. 
16. Known to be positive for the human immunodeficiency virus or hepatitis B or C, as 
indicated by a positive test at screening. 
17. Known to be immunocompromised. 
18. Documented presence of renal vascular disease resulting in uncontrolled hypertension. 
19. Has previously received an EGFR inhibitor (including, but not limited to, erlotinib, 
gefitinib, osimertinib, afatinib, cetuximab, panitumumab, or an investigational agent). 
20. Allergy or hypersensitivity to components of either tesevatinib, matched placebo, or 
their formulations. 
21. Aphakic due to previous cataract surgery or congenital abnormality. 


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Note:  The sponsor has the option to exclude a subject from enrollment, if, based upon the 
subject’s medical history or screening results, it is felt that a subject’s safety may be at risk 
and/or if the safety data may confound the study results. 
4.3. 
Withdrawal of Subjects 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The Investigator or Sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The withdrawal of a 
subject from investigational product by the Investigator should be discussed where possible 
with the Medical Monitor before the subject stops investigational product. 
If a subject is withdrawn from the study, every effort will be made by the Investigator to 
complete and report the reasons for withdrawal as thoroughly as possible. The reason for 
termination must be clearly documented on the appropriate page of the electronic case report 
form (eCRF). Study withdrawal should include the final assessments, as required by the 
protocol and every effort should be made to perform the End-of-study procedures (see Table 
2).  
A termination eCRF must be completed for all enrolled subjects. 
Subjects who discontinue will not be replaced.  
Subject Stopping Criteria 
If an adverse event (AE) is a reason for discontinuation, then “Adverse event” must be 
recorded as the reason for discontinuation on the eCRF. 
Reasons for discontinuation include but are not limited to:  
 Adverse event (including, but not limited to, symptomatic pericardial effusion or 
cardiac tamponade) 
 Intercurrent event preventing the administration of tesevatinib for more than 28 days  
 Protocol violation 
 Request by a regulatory agency (eg, institutional review board [IRB]) 
 Withdrawal by subject 
 Lost to follow-up 
 Lack of efficacy 
 Pregnancy 
 Other (must be specified). 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit 
At least 3 documented attempts must be made to contact any subject lost to follow-up at any 
time point prior to the last scheduled contact (office visit or telephone contact). One of these 


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documented attempts must include a written communication sent to the subject’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they 
return any unused investigational product and return to the site for final safety evaluations. 


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5. 
CONCOMITANT MEDICATION 
5.1. 
Concomitant Medication and Potential Interactions 
Subjects should not receive additional therapeutic treatment during the study period without 
the approval of the Sponsor’s Medical Monitor. 
If the subject must use a concomitant medication during the study, it is the responsibility of 
the Principal Investigator to ensure that details regarding the medication are recorded on the 
eCRF. 
Subjects should avoid ingesting grapefruit and grapefruit juice with study drug or at any time 
during the study. Subjects are not permitted to take concomitant medications that inhibit (eg, 
ketoconazole, itraconazole, erythromycin, clarithromycin) or induce (eg, dexamethasone, 
phenytoin, carbamazepine, rifampicin, or phenobarbital) the CYP3A4 isozyme (see Appendix 
1). Additionally, subjects should not take medications that are associated with a risk of QTcF 
interval prolongation and/or torsades de pointes (see Appendix 2).  
Tesevatinib is highly protein bound, and other drugs that are also highly protein bound with 
the exception of warfarin (eg, diazepam, furosemide, dicloxacillin, propranolol, and 
phenytoin) should be avoided.  
Based on in vitro evaluation, tesevatinib may be a weak substrate for P-glycoprotein (P-gp). 
Since P-gp is extensively expressed in multiple tissues and is involved in the transport of a 
vast variety of biological molecules, drugs such as colchicine, verapamil, tamoxifen, 
cyclosporine, and digoxin should be monitored. 
Anti-emetics and antidiarrheal medications should not be administered prophylactically 
before initial treatment with study drug. At the discretion of the Investigator, treatment of 
symptoms with anti-emetic and antidiarrheal medications may be undertaken per standard 
clinical practice. 
Since tesevatinib is a potent inhibitor of multidrug and toxic compound extrusion (MATE) 
transporter proteins, increased levels of concomitant medications that are secreted by the 
kidney proximal tubule cells into the renal tubule by MATE transporter proteins may occur. 
Thus, subjects taking cephalexin, cimetidine, dofetilide, fexofenadine, metformin, 
procainamide, and pyrimethamine should be monitored carefully. 
5.2. 
Management of Subjects Requiring Concomitant Medications 
Associated with QT Interval Prolongation 
Tesevatinib has been associated with prolongation of the QT interval. Subjects requiring 
treatment with drugs known to be associated with torsades de pointes or significant QT 
interval prolongation may not be enrolled into this study. This includes Class IA 
anti-arrhythmics (eg, quinidine, procainamide); Class III anti-arrhythmics (eg, amiodarone, 
sotalol, dofetilide); phenothiazine anti-psychotics: (eg, chlorpromazine, mesoridazine, 
pimozide, thioridazine); quinolone antibiotics (eg, gatifloxacin, moxifloxacin, sparfloxacin); 


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macrolide antibiotics (eg, erythromycin, clarithromycin, and troleandomycin) and other drugs 
that have a contraindication or boxed warning regarding QT prolongation in the prescribing 
information. A list of concomitant medications associated with a risk of QTc interval 
prolongation and/or torsades de pointes can be found in Appendix 2. 
Drugs associated with QT interval prolongation should be avoided in subjects receiving 
study drug. Should a subject develop a condition for which a medication known to affect QT 
interval is indicated, consideration should be given to the additive risk of QT interval 
prolongation versus the potential benefit of treatment with the required medication and/or 
study drug. Contact the Medical Monitor prior to the administration of the concomitant 
medication. 
Beginning at Month 2, subjects who require short-term (2 to 3 weeks, not to exceed 21 days) 
treatment with a concomitant medication associated with QT interval prolongation should 
have the study drug held until the concomitant treatment course is complete. The decision on 
whether the subject can continue on study following this interruption will be determined by 
the Medical Monitor. If the subject restarts study drug after discussion with the Medical 
Monitor, an ECG will be performed prior to restarting study drug. 


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6. 
INVESTIGATIONAL PRODUCT 
6.1. 
Identity of Investigational Product 
Tesevatinib will be provided in 50 mg tablets; matched placebo will also be provided.  
Tesevatinib tablets are white to off-white round tablets that contain 50% (w/w) active product 
ingredient in the current lactose-based immediate-release formulation.  
6.2. 
Administration of Investigational Product(s) 
Interactive Voice/Web Response System for Investigational Product Management 
Study drug assignment and administration will use an interactive voice/web response system 
(IVRS/IWRS). Details are provided in Section 7.4. 
Dosing 
Subjects will be provided with an adequate supply of study drug and instructions for taking 
the study drug at home. Unused drug must be returned to the study site at each visit for 
accounting and reconciliation.  
Study drug may be taken with or without food at approximately the same time every morning. 
Subjects should drink a full glass of water (approximately 8 ounces [240 mL]) immediately 
after study drug administration. Grapefruit and similar (pomelo fruit, Seville orange, etc.) 
products should be avoided for the duration of study treatment. On days when subjects report 
to the study site for study procedures, study drug dosing will be done at the study site.  
Subjects must be instructed not to make up missed doses unless the missed dose can be taken 
within 12 hours of the normal dosing time. Subjects should not re-take study drug doses in the 
event of vomiting. 
Subjects will receive study drug for 28 days after the initiation of treatment. After the initial 
28-day safety and tolerability assessment period, subjects will, at the Investigator’s discretion, 
continue to receive study drug for a total of 24 months from the initiation of treatment or until 
the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the 
subject, or investigator decision.  
Blinding the Treatment Assignment 
This is a double-blind, placebo-controlled study.  
Allocation of Subjects to Treatment  
This is a randomized, double-blind, placebo-controlled study. The actual treatment given to 
individual subjects is determined by a randomization schedule. 


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Subject screening numbers are assigned to all subjects as they consent to take part in the 
study. Within each site (numbered uniquely within a protocol), this number is assigned to 
subjects according to the sequence of presentation for study participation.  
A randomization number/unique identifier is allocated once eligibility has been determined. 
Once a randomization number/unique identifier has been assigned, that number must not be 
used again if, for example, a subject is withdrawn from the study. If a randomization 
number/unique identifier is allocated incorrectly the Clinical Research Associate 
(CRA)/Study Monitor must be notified as soon as the error is discovered.  
Individual subject treatment is automatically assigned by the IVRS/IWRS. 
Unblinding the Treatment Assignment 
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability 
data) will be handled with special care during the data cleaning and review process. Any data 
that may unblind study team personnel will be presented as blinded information or otherwise 
will not be made available. If applicable, unblinded data may be made available to quality 
assurance representatives for the purposes of conducting independent drug audits.  
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. In the event that the treatment assignment is broken, the date, the signature of the 
person who broke the code, and the reason for breaking the code are recorded on the 
IVRS/IWRS and the source documents. Upon breaking the blind, the subject is withdrawn 
from the study, but should be followed up for safety purposes. Any code-breaks that occur 
must be reported to the Sponsor. Code-break information is held by the pharmacist/designated 
person at the site and by Medical Monitor for the study or designee. 


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6.3. 
Labeling, Packaging, Storage, and Handling 
Labeling 
The following information will be printed on the label for clinical lots of study drug: 
KD019 or Placebo 50 mg Tablets – 32 count 
Lot: xxxxx.xxx 
Direction:  Take as directed by physician. 
Store at controlled room temperature of 20°-25°C (66°-77°F). Brief excursions permitted 
between 15°C and 30°C (59°F and 86°F). 
Caution:  Federal law prohibits the transfer of this drug to any person other than the 
patient for whom it was prescribed. 
Caution:  New Drug – Limited by Federal Law to Investigational Use 21CFR312.6 (a). 
Keep out of the reach of children and pets. 
Kadmon Corporation, LLC  New York, NY 10016 USA 
Packaging 
Tesevatinib 50 mg tablets and matched placebo tablets are packaged in 30-cc high-density 
polyethylene bottles capped with 28-mm, childproof caps. 
Changes to Sponsor-supplied packaging prior to dosing may not occur without full agreement 
in advance by the Sponsor. 
Storage 
The Investigator has overall responsibility for ensuring that investigational product is stored 
in a secure, limited-access location. Limited responsibility may be delegated to the pharmacy 
or member of the study team, but this delegation must be documented. 
Study drug must be stored at a controlled room temperature of 20°-25°C (66°-77°F). Brief 
excursions are permitted between 15°C and 30°C (59°F and 86°F). The Sponsor must be 
notified upon discovery of any excursion from the established range. Temperature excursions 
will require site investigation as to cause and remediation. The Sponsor will determine the 
ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. 
Under no circumstances should product be dispensed to subjects until the impact is 
determined and product is deemed appropriate for use by Sponsor. 
Study drug must be inventoried according to applicable regulations. 
6.4. 
Investigational Product Quality Complaints 
Once a Product Quality Complaint is identified, investigators must report it to Kadmon. This 
includes any instances wherein the quality or performance of a Kadmon investigational 
product does not meet expectations (eg, inadequate or faulty closure, product contamination), 
the product does not meet the specifications defined in the application for the product (eg, 


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wrong product such that the label and contents are different products), or the product does not 
meet appearance specifications (eg, broken or chipped tablets). 
6.5. 
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry 
out this protocol for the agreed number of subjects. The Investigator or designee will 
acknowledge receipt of the investigational product documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.  
The Investigator has overall responsibility for administering/dispensing investigational 
product. Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) 
who is adequately trained in the protocol and who works under the direct supervision of the 
Investigator. This delegation must be documented in the applicable study delegation of 
authority form. 
Dispensing records will document quantities received from Kadmon and quantities dispensed 
to subjects, including lot number, date dispensed, subject identification number, subject 
initials, and the initials of the person dispensing study drug. Reasons for deviation from the 
expected dispensing regimen also must be recorded. 
The Investigator or his/her designee (as documented by the Investigator in the applicable 
study delegation of authority form) will administer/dispense the investigational product only 
to subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. 
All dispensing will be documented on the eCRFs and/or other investigational product record. 
The Investigator is responsible for assuring the retrieval of all investigational product from 
subjects. No investigational product stock may be removed from the site where originally 
shipped without prior knowledge and consent by the Sponsor. If such transfer is authorized by 
the Sponsor, all applicable local, state, and national laws must be adhered to for the transfer. 
The Sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised. 
At study initiation, the study monitor will evaluate and obtain a copy of each site’s written 
standard operating procedure for study drug disposal/destruction in order to ensure that it 
complies with the Sponsor’s requirements.  
With the written agreement of the Sponsor, at the end of the study all unused stock, subject 
returned investigational product, and empty/used investigational product packaging may be 
destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how must be obtained with copies provided to the Sponsor. If the site 
cannot meet the Sponsor requirements for disposal, arrangements will be made between the 
site and the Sponsor or its representative for destruction or return of unused study drug 
supplies. Investigational products being returned to the Sponsor’s-designated contractors must 
be counted and verified by clinical site personnel and the Sponsor (or designated contractor). 
For unused supplies where the original supplied tamper-evident feature is verified as intact, 


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the tamper evident feature must not be broken and the labeled amount is to be documented in 
lieu of counting. All certificates of delivery/drug receipts should be signed by the site 
representative to confirm contents of shipment. Shipment return forms, when used, must be 
signed prior to shipment from the site. Validated electronic return systems (ie, IVRS/IWRS) 
do not require a shipment form. Returned investigational products must be packed in a 
tamper-evident manner to ensure product integrity. Authorization from the Sponsor should be 
sought prior to any shipment of investigational products. Shipment or destruction of 
investigational products must be in accordance with local, state, and national laws.  
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the Sponsor’s 
satisfaction.  
6.6. 
Subject Compliance 
Subjects must be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the 
original tamper evident sealed container (eg, bottles, trays, vials) or at the individual count 
level for opened containers/packaging. The pharmacist/nominated person will record details 
on the drug accountability form. 
In addition, subject diaries will be used to evaluate compliance. Subject diaries will be 
dispensed on Day 1 and reviewed at each visit. 
6.7. 
Warnings, Precautions, and Management 
Adverse events that have been associated with tesevatinib include the following:  diarrhea, 
skin rash, QTcF prolongation, hepatotoxicity, and pulmonary toxicity. Study drug may be 
held for up to 28 days at the discretion of the Investigator (unless otherwise specified below), 
except during the first 28 days of dosing (Early Treatment Period). 
Diarrhea 
Diarrhea should be managed according to accepted practice (eg, with loperamide). Subjects 
with severe diarrhea who are unresponsive to loperamide or who become dehydrated may 
require interruption of study drug until resolution to ≤ mild in intensity. If subjects are in the 
monthly treatment period, drug may be held for up to 28 days. If severe diarrhea occurs 
during the 28-day Early Treatment Period, subjects must be discontinued from the study. In 
the event of severe or persistent diarrhea, nausea, anorexia, or vomiting associated with 
dehydration, study drug should be discontinued, and appropriate measures should be taken to 
rehydrate the subject intensively via intravenous administrations. Subjects should be advised 
to contact the investigator immediately if they develop significant diarrhea; should this occur, 
an electrolyte panel, including magnesium and potassium, and ECG should be performed.  


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Skin Rash  
Skin rash should be managed according to locally accepted clinical recommendations. Study 
drug may be held up to 28 days at the discretion of the investigator and after discussion with 
the Medical Monitor. The following guidelines may be considered. 
6.7.1.1. 
Suggestions for Rash Management  
Papulopustular (acneiform) rash is the most common rash seen with EGFR inhibitors, and is 
typically seen in the first few weeks of treatment. It usually peaks at Weeks 4 to 6 and 
decreases in severity between Weeks 6 and 8. Post-inflammatory skin changes can last for 
months, so prevention and reactive treatment are important.  
Suggestions for the management of skin rash are provided in Table 4. 


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Table 4: 
Suggestions for Skin Rash 
Stage 
Suggested Treatment for Skin Rash 
Preventative 
Treatment 
 
Subject education prior to starting treatment on what to expect 
 
Gentle cleansing of skin using mild soap products 
 
Use of moisturizer twice daily making sure to include hands, feet, and nails 
 
Avoid sun when possible and use of sunscreen SPF 30 or higher (preferably 
titanium dioxide or zinc oxide) 
 
Use UVA ocular protection (ie, sunglasses with UVA filtering) when outside 
 
Hypoallergenic makeup when possible 
Once Rash 
Appearsa 
 
Ongoing use of treatments from preventative treatments above 
 
Mild (<10% BSA involved, without pruritus or tenderness) 
o Topical steroids (refer to Appendix 3 for a steroid potency chart that 
categorizes brand- name topical steroid medications) 
 
For face, use medium potency 
 
For body, use strong potency 
 
Note: As soon as rash improves the lowest strength steroid that 
controls rash should be used, especially on the face 
 
Moderate (10%–30% BSA involved, ± pruritus/tenderness; limiting instrumental 
ADLs and causing psychosocial impact) 
o Topical steroids 
 
For face, use strong potency 
 
For body, use very strong potency 
 
Note: As soon as rash improves the lowest strength steroid that 
controls rash should be used, especially on the face 
o Systemic Treatment 
 
Doxycycline 100 mg BID (less renal toxic than minocycline, but can 
cause photosensitivity) 
 
Severe (> 30% BSA involved, limiting ADLs) 
o Refer to dermatology 
o Topical steroids 
 
All areas very strong potency 
 
Note: As soon as rash improves the lowest strength steroid that 
controls rash should be used, especially on the face 
o Systemic treatment 
 
Doxycycline 100 mg BID 
 
Oral steroids: prednisolone 10 mg QD for 1 week or equivalent 


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Once Rash 
Reappears 
 
Over the course of treatment rash may come and go 
o Hydrocortisone 1% cream with moisturizer and sunscreen BID, in 
combination with doxycycline 100 mg BID 
o May need to follow guidelines above if rash worsens 
If unacceptable rash recurs on reintroduction of tesevatinib at the same dose, then 
discontinuation of tesevatinib should be discussed with the Medical Monitor.  
Abbreviations: ADL, activity of daily living; BID, twice daily; BSA, body surface area; QD, once daily; 
SPF, sun protection factor; UVA, ultraviolet A 
a See Appendix 3 for steroid potency chart. 
Source: Lacouture, 20119, Kiyohara 201310, www.psoriasis.org 
QT Interval Prolongation 
Risk factors for occurrence of arrhythmia include hypokalemia, hypomagnesemia, 
bradycardia, and concurrent use of multiple medications that prolong the QTcF interval. In 
vivo observations of QTcF prolongation in association with use of tesevatinib have been 
observed, including severe QTcF prolongation. However, the lack of a clearly discernible 
pattern to such occurrence makes prediction of individual subject risk difficult. Therefore, the 
following are recommended: 
 Study drug should be administered to subjects who have normal serum potassium and 
serum magnesium levels. 
 Study drug should not be administered to subjects with pathologic bradycardia. 
 Medications with potential for QTcF prolongation should not be used concurrently or 
started within 24 hours of study drug administration. 
Subjects should be carefully monitored for symptoms of arrhythmia (ie, dyspnea, chest pain 
or tightness, palpitations, dizziness) and for episodes of syncope. An ECG should be obtained 
if these symptoms occur. In addition, serum potassium and magnesium must be maintained 
within the normal range11 and may require additional monitoring or adjustment if subjects 
develop diarrhea. 
6.7.1.2. 
Response to QTcF Interval Prolongation 
The following guidelines should be used in the management of QTcF prolongation. Subjects 
will have ECGs performed as outlined in Table 2. If the average QTcF interval (from 
3 consecutive ECGs taken with an interval of at least 1-2 minutes within 30 minutes) 
increases to > 60 msec above the highest average predose value (average of Day 1 predose 
and screening values) or to the level of ≥ 480 msec according to local site analysis: 
 Hold study drug until central read is confirmed.  
 Check electrolytes, especially magnesium and potassium; correct abnormalities as 
clinically indicated. 
 Manage as clinically indicated with cardiology consultation as needed. 
 Contact the Medical Monitor to discuss additional monitoring. 


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If results are confirmed by the central reader, the subject may be removed from the study after 
discussion with the Medical Monitor. If the subject continues in the study, appropriate 
management and ECG follow-up should be discussed with the Medical Monitor. 
Elevated Amylase 
If subjects develop an elevated serum amylase during the study that is > 2.0 × ULN, then 
additional evaluations should be performed. These should include evaluating serum lipase, 
amylase isoenzymes, and fasting triglycerides as well as obtaining history regarding 
symptoms of pancreatitis, symptoms of dry mouth, and use of alcohol. The subject should 
have a drug holiday for 28 days, with amylase measured at the end of the drug holiday. If the 
amylase is back to the baseline value after the end of the drug holiday, study drug may be 
restarted, and amylase measured approximately 14 days later, and then at the start of each 
cycle of study drug administration. If results continue to be abnormal, the subject will be 
removed from study. If an elevated serum amylase that is > 2.0× ULN occurs a second time, 
the subject will be removed from the study. 
Elevated Creatinine Phosphokinase 
If subjects develop an elevated serum CPK during the study that is > 2.0 × ULN, additional 
evaluations should be performed. These should include evaluating serum CPK isoenzymes as 
well as obtaining history regarding muscle-related symptoms or strenuous or prolonged 
exercise. 
Pulmonary Toxicity 
If subjects experience an acute onset of new and/or progressive, unexplained pulmonary 
symptoms such as dyspnea, cough, and fever, study drug should be held while subjects are 
evaluated. If interstitial lung disease is diagnosed, study drug should be discontinued and 
treatment administered as necessary. 
Hepatotoxicity 
Rare cases of hepatic failure have been reported. Confounding factors have included 
pre-existing liver disease or concomitant hepatotoxic medications. Liver function test 
abnormalities (including elevated ALT, AST, and bilirubin) have been observed in clinical 
studies with tesevatinib. Interruption of study drug should be considered in subjects 
developing liver function abnormality > 3 × ULN. 
Management guidelines for liver function abnormalities are provided in Table 5. 


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Table 5: 
Management Guidelines for Liver Function Abnormalities 
Liver Function 
Abnormality 
Occurrence 
Action 
Hyperbilirubinemia 
 
 
2.5 – < 3 × ULN 
1st 
Hold dose; resume dosing when recovered or reduced to 
mild intensity. 
2nd 
Off study. 
> 3 × ULN 
1st 
Off study. 
AST/ALT elevations 
 
 
2.5 – < 3 × ULN 
1st 
Hold dose; resume dosing when recovered or reduced to 
mild intensity. 
2nd 
Hold dose and discuss management with Medical Monitor. 
> 3 × ULN 
1st 
Hold dose and discuss management with Medical Monitor. 
2nd 
Off study. 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal  
Pericardial Effusion 
Pericardial effusions have been seen in oncology studies with tesevatinib. In addition, 
1 subject with ADPKD receiving 50 mg tesevatinib daily developed a trace pericardial 
effusion. The guidelines outlined below should be followed in the event that a subject 
develops a pericardial effusion while receiving tesevatinib. 
For an asymptomatic pericardial effusion that is at least moderate in size, a follow-up 
echocardiogram should be performed within 1–3 months to monitor for progression. Results 
of the additional echocardiogram should be discussed with the Medical Monitor to determine 
subject management. 
Subjects should be monitored for signs and symptoms of cardiac tamponade. In addition to 
the monthly to bimonthly physical exam of blood pressure, pulse, respiration, weight, heart, 
and lung, physical exam should also asses for tachycardia, dyspnea, neck vein distension, and 
edema. 
Adrenal Insufficiency 
One case of adrenal insufficiency has been reported in an oncology subject receiving 
tesevatinib. Subjects should be monitored for signs or symptoms of adrenal insufficiency and 
the Medical Monitor immediately notified if symptoms are observed. 


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7. 
STUDY PROCEDURES 
7.1. 
Study Schedule 
The schedule of assessments for this study is provided in Table 2. 
All screening assessments are to be performed within 28 days prior to the first dose of study 
drug, unless otherwise specified. Study eligibility will be based on satisfying all of the study 
inclusion and exclusion criteria. Day 1 is defined as the date the subject takes the first dose of 
study drug. 
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or meet at least 1 of the exclusion criteria and has not been randomized or administered 
investigational product(s) as defined by the protocol.  
7.2. 
Informed Consent Process 
The subject will be given a verbal explanation of the study, including information about the 
study drug and the study procedures, and will have all questions adequately addressed. The 
subject must sign and date a consent form that has been approved by the IRB before the 
screening procedures are initiated. All subjects will be given a copy of the signed and dated 
informed consent form. 
7.3. 
Demographics and Medical History 
A complete medical history will be taken. Information to be documented includes 
demographic information, prior medical illnesses and conditions (including PKD genotype, if 
available), and surgical procedures. 
7.4. 
Randomization 
Each subject who completes the study screening assessments, meets all eligibility criteria will 
be assigned a unique identification number and will receive the corresponding treatment 
according to a randomization scheme generated by the IVRS/IWRS vendor. The 
randomization schedule will be prepared by the IVRS/IWRS vendor using a validated 
program. The IVRS/IWRS will assign a randomization number to subjects that will be used to 
link the subject to a treatment group and will specify a unique medication number for the 
study drug to be dispensed to the subject. Randomized subjects who terminate their study 
participation for any reason, regardless of whether study treatment was taken or not, will 
retain their randomization number. IVRS/IWRS personnel not involved with any of the 
protocol operations will prepare the randomization schedule. 


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7.5. 
Safety Measurements 
Physical Examination, Height and Weight 
A complete physical examination to include documentation of height (at Screening) and 
weight will be performed by a physician or staff member who is qualified to perform such 
examinations (eg, physician’s assistant, nurse practitioner). Any abnormal or clinically 
significant findings from the physical examination must be recorded in the appropriate eCRF. 
Findings at screening and prior to dosing on Day 1 will be recorded as medical history. 
At study visits in which a complete physical examination is required, the investigator should 
perform a thorough examination of all body systems (exception: genitourinary and 
reproductive should be symptom-directed). At study visits in which a limited physical 
examination is required, the investigator should inquire about signs/symptoms, general 
appearance, eyes (pupillary reaction, ophthalmoscopy, eye movements), oral mucosa, heart 
and pulses, lungs, abdomen (liver/spleen), kidneys, and neurological (symptom-directed and 
may include mental state, speech, gait/posture, arm swinging, facial movements, tongue, 
muscle wasting [power and tone], coordination, reflexes, and sensation.) 
Vital Signs 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes. 
Vital sign assessments will include measurements of sitting blood pressure (mm Hg), heart 
rate (beats per minute), respiration rate (breaths per minute), and temperature (Celsius). 
Predose vital signs should be collected within 4 hours prior to dosing, and postdose vital signs 
should be taken within ± 15 minutes of the scheduled time point. 
Blood pressure measurements are to be performed using appropriate technique (per guidelines 
of the American Heart Association). Specifically, subjects should be seated quietly for at least 
5 minutes in a chair with their backs supported, their legs uncrossed, and their arms bared on a 
hard surface, with the arm slightly abducted and bent, with palm up and the midpoint of upper 
arm at heart level. The correct cuff and bladder size should be utilized and recorded. Two or 
more readings separated by 1–2 minutes should be averaged. If the first 2 readings differ by 
more than 5 mm Hg, 1 or 2 additional readings should be obtained and averaged.  
Electrocardiogram 
Electrocardiograms will be performed with the subject in a supine position having rested in 
this position for at least 5 minutes before each reading. Triplicates should be obtained, with an 
interval of 1-2 minutes between ECGs.  
During the study, all ECGs will be digitally analyzed by a validated central ECG vendor. 
Additional details on collection of ECGs will be provided in a separate manual. 
The QT interval will be corrected using Fridericia’s formula, adapted from Fridericia, 1920 12: 
𝑄𝑇𝐹=
𝑄𝑇
𝑅𝑅1/3 


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All subjects must demonstrate an average screening QTcF value of ≤ 450 msec by central 
digital analysis in order to be enrolled in the study. During the study, immediate clinical 
management of subjects will be based on results of machine-read ECGs at the sites. However, 
the central digital analysis will prevail as it becomes available. In addition, the central digital 
analysis will be used for any AE and SAE documentation. 
An increase in QTcF interval (by central digital analysis) to a value > 60 msec above baseline 
or to the level of ≥ 480 msec requires further monitoring and, after collection of a PK blood 
sample and discussion with the Medical Monitor on appropriate management, the subject may 
be removed from the trial (see guidelines in Section 6.7.1.2). 
Abnormalities in the ECG that lead to a change in subject management (eg, requirement for 
additional medication or monitoring) or result in clinical signs and symptoms are considered 
clinically significant for the purposes of this study and will be recorded on the AE eCRF. If 
ECG abnormalities meet criteria defining them as serious, they must be reported as an SAE 
(see Section 8.2.3). 
Echocardiogram 
Echocardiograms for determination of ejection fraction and evaluation of pericardial effusion 
and cardiac valve function will be collected at the time points specified in Table 2. 
Ocular Monitoring 
Ocular monitoring will be performed at the time points specified in Table 2. Ocular 
monitoring will include an assessment of best corrected distance visual acuity, fundoscopic 
exam with non-dilated pupils, slit lamp photography of the iris, non-mydriatic photography of 
retina within the arcade, and optical coherence tomography of the optic nerve head and 
macula.  
Clinical Laboratory Evaluations 
A central laboratory will perform clinical laboratory evaluations. 
The Investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. 
Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, 
dose delay, requirement for additional medication or monitoring) are considered clinically 
significant for the purposes of this study, and will be recorded on the AE eCRF page. 
Abnormal clinical laboratory values, which are unexpected or not explained by the subject’s 
clinical condition may be, at the discretion of the Investigator or Sponsor, repeated until 
confirmed, explained, or resolved as soon as possible. If laboratory values constitute part of 
an event that meets criteria defining it as serious, the event (and associated laboratory values) 
must be reported as an SAE (see Section 8.2.3). 
At the investigator’s discretion, any subset of the laboratory panels in Table 6 may be 
duplicated in local laboratories for an immediate medical assessment. However, inclusion and 


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exclusion criteria as well as the final statistical analysis will be based on results from the 
central laboratory. 
Table 6: 
Clinical Laboratory Tests  
Serum Chemistry 
 albumin 
 amylase 
 alkaline phosphatase 
 ALT 
 AST 
 bicarbonate 
 BUN 
 calcium 
 chloride 
 creatinine 
 CPK (plus CPK isoenzymes 
if CPK is elevated) 
 lactate dehydrogenase 
 phosphorous 
 potassium 
 random glucose 
 sodium 
 total & direct bilirubin 
 total protein 
 magnesium 
Hematology 
 RBC count 
 WBC with differential 
(including neutrophils, 
basophils, eosinophils, 
lymphocytes, monocytes) 
 hemoglobin 
 hematocrit 
 platelet count 
 MCV 
 MCH 
 MCHC 
Coagulation 
 PT 
 PTT 
 INR 
Urinalysis 
 appearance 
 color 
 pH 
 specific gravity 
 ketones 
 leukocytes 
 protein 
 glucose 
 bilirubin 
 urobilinogen 
 occult blood (microscopic 
examination of sediment 
will be performed only if 
the results of the urinalysis 
dipstick evaluation are 
positive) 
Other 
 Creatinine clearancea 
 Pregnancy testb 
 
cystatin C 
 
fasting triglyceridesc 
 
lipased 
 
amylase isoenzymese 
 
CPK isoenzymesf 
 TSH 
 Hepatitis and HIVf 
 HbA1cf 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; 
CPK, creatine phosphokinase; HbA1c, glycated hemoglobin; HIV, human immunodeficiency virus; INR, 
international normalized ratio; MCH, mean cell hemoglobin; MCHC, mean cell hemoglobin concentration; 
MCV, mean cell volume; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell; TSH, 
thyroid stimulating hormone; ULN, upper limit of normal; WBC, white blood cell 
a. To be calculated using serum creatinine (Modification of Diet in Renal Disease-4 variable formula). 


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b. Pregnancy tests will be done using urine samples. A positive test result (confirmed by serum testing) will 
require immediate discontinuation from the study. 
c. To be collected in the event that serum amylase increases to > 1.5 × ULN 
d. To be collected at Screening and in the event of that serum amylase increases to > 1.5 × ULN 
e. To be collected in the event that CPK increases to > 2.0 × ULN. 
f. To be collected only at Screening. 
 
Concomitant Medications 
Prior and concomitant medications will be recorded throughout the study (from Screening 
through 28 days following the last dose of study drug). Refer to Section 5 for details on 
concomitant medications that should be avoided or taken with caution during the study. 
Adverse Events 
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). Adverse events collection is detailed in Section 8. 
7.6. 
Efficacy Measurements 
Magnetic Resonance Imaging 
Magnetic resonance imaging measurements will be used to explore the efficacy of tesevatinib. 
Kidney volume will be determined by MRI at the time points specified in Table 2. 
The volume of each kidney should be measured in T1-weighted images with use of a 
stereologic method and calculated from the set of contiguous images by summing the 
products of the area measurements and slice thickness. Height-adjusted total kidney volume is 
calculated using total kidney volume obtained from MRI divided by height in meters. 


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8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
8.1. 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  
All AEs should be captured on the AE eCRF.  
Findings at screening and prior to dosing on Day 1 will be recorded as medical history. Where 
possible, a diagnosis, rather than a list of symptoms, should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE eCRF. 
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), an outcome is reached, stabilization (the 
Investigator does not expect any further improvement or worsening of the event), or the event 
is otherwise explained regardless of whether the subject is still participating in the study. 
When appropriate, medical tests and examinations are performed so that resolution of event(s) 
can be documented. 
Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pre-treatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate eCRF). 
The medical assessment of severity is determined by the 5-point Clinical Symptom and 
Adverse Event Grading Scale provided in Table 7. 
Table 7: 
5-point Clinical Symptom and Adverse Event Grading Scale 
Clinical Adverse Event Grading Scale 
Severity 
Grade 
Definition 


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Mild 
1 
Awareness of symptom, but easily tolerated. Usually transient 
requiring no special treatment; does not interfere with usual status or 
activities 
Moderate 
2 
May be ameliorated by simple therapeutic measures; may interfere 
with usual activities 
Severe 
3 
Incapacitating; unable to perform usual activities 
Life-threatening 
4 
Requires immediate intervention; need for emergency treatment 
Death 
5 
Resulting in the subsequent death of the subject 
 
Relationship Categorization 
A Physician/Investigator must make the assessment of relationship to investigational product 
for each AE. The Investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as ‘not 
related’. Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered ‘related’. The causality 
assessment must be documented in the source document. 
The additional guidance in Table 8 may be helpful. 


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Table 8: 
Relationship Assessment for Adverse Events 
Term 
Relationship 
Definition 
Definitely Related 
Yes 
The event is felt to be related to the administration of the study 
drug. The relationship of an AE to the study drug can be 
considered related if: 
 It follows a reasonable temporal sequence from 
administration of the drug or drug levels have been 
established in body fluids or tissues;  
 It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental 
or toxic factors or other modes of therapy administered to 
the subject; and 
 It disappears or decreases* upon cessation of drug or 
reduction on dose and appears upon rechallenge;   
 It follows a known response pattern to the suspected drug. 
*There are exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug relatedness clearly exists. 
The first 3 criteria must be met for the event to be considered 
definitely related. 
Probably Related 
Yes 
The event is felt with a high degree of certainty to be related 
to the administration of study drug.  The relationship can be 
considered probably related if: 
 It follows a reasonable temporal sequence from the 
administration of study drug; 
 It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environment 
or toxic factors or other modes of therapy administered to 
the subject; and 
 It disappears or decreases upon cessation of drug or 
reduction of dose;* 
 It follows a known response pattern to the suspected drug. 
*There are exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug relatedness clearly exists. 
The first 3 criteria must be met for the event to be considered 
probably related. 


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Term 
Relationship 
Definition 
Possibly Related 
Yes 
The event is felt to be unlikely due to the administration of 
study drug but the possibility cannot be ruled out with 
certainty. The relationship to study drug can be considered 
possibly related if: 
 It follows a reasonable temporal sequence from the 
administration of study drug; and 
 It could readily have been the result of the subject’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subjects; 
 It follows a known response pattern to the suspected drug. 
The first 2 criteria must be met for the event to be considered 
possibly related. 
Unlikely Related 
No 
The event is felt to be unlikely due to the administration of 
study drug after careful medical consideration. The 
relationship to study drug can be considered unlikely related 
if: 
 It does not follow a reasonable temporal sequence from 
administration of the drug; and 
 It could readily have been a result of the subject’s clinical 
state, environmental or toxic factors, or other modes of 
therapy administered to the subjects; 
 It does not follow a known response pattern to the 
suspected drug; 
 It does not reappear or worsen when the drug is re-
administered. 
The first 2 criteria must be met for the event to be considered 
unlikely related. 
Not Related 
No 
The event is felt to be due to extraneous causes (disease, 
environment, etc.) that are not related to the administration of 
study drug. 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows: 
 Resolved 
 Resolved with Sequelae 
 Ongoing 
 Death 
 Unknown 


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Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease. However, 
significant worsening of the symptoms should be recorded as an AE. 
Clinical Laboratory Evaluations 
A change in the value of a clinical laboratory investigation can represent an AE if the change 
is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an 
already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing 
treatment or after the end of treatment with the investigational product, and the range of 
variation of the respective parameter within its reference range, must be taken into 
consideration. 
If, at the end of the treatment phase, there are abnormal clinical laboratory values which were 
not present at baseline, further clinical or laboratory investigations should be performed until 
the values return to within the reference range or until a plausible explanation (eg, 
concomitant disease) is found for the abnormal clinical laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory parameter is clinically significant and 
therefore represents an AE. 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Table 2. 
Any report of pregnancy for any female subject or the partner of a male subject must be 
reported within 1 business day to the Pharmacovigilance vendor (see Table 1). The female 
subject must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the Investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
post-partum.  
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported within 24 hours using the Serious Adverse Event 
Form. Note:  An elective abortion is not considered an SAE. 
In addition to the above, if the Investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Serious Adverse Event Form as well as the 
Pregnancy Report Form. The test date of the first positive serum/urine pregnancy test or 
ultrasound result will determine the pregnancy onset date. 


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Overdose and Medication Error 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the Medical Monitor. An overdose of study drug without 
any associated signs or symptoms, unless the subject is hospitalized for observation, will not 
constitute an AE but will be recorded as a protocol deviation. 
Cases of subjects missing doses of product are not considered reportable as medication errors. 
Medication errors should be collected/reported for all products under investigation. The 
administration and/or use of the unassigned treatment is always reportable as a medication 
error. The administration and/or use of an expired product should be considered as a 
reportable medication error.  
8.2. 
Serious Adverse Event Procedures 
Reference Safety Information 
The reference for safety information for this study is the Investigator’s Brochure which the 
Sponsor has provided under separate cover to all Investigators. 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the Investigator to the 
Pharmacovigilance vendor (see Table 1) within 24 hours of the first awareness of the event. 
Note:  The 24 hours reporting requirement for SAEs does not apply to reports of abuse, 
misuse, or overdose (see Section 8.1.7) unless they result in an SAE.  
The Investigator must complete, sign, and date the Serious Adverse Event Form and verify 
the accuracy of the information recorded on the form with the corresponding source 
documents and fax or e-mail the form to the Pharmacovigilance vendor.  
Serious Adverse Event Definition 
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose: 
 Results in death 
 Is life-threatening 
NOTE:  The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital abnormality/birth defect 


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 Is an important medical event. Note:  Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency 
or drug abuse.  
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE.  
However, complication(s) resulting from a hospitalization for an elective or previously 
scheduled surgery that meets serious criteria must be reported as SAE(s). 
8.3. 
Serious Adverse Event Collection Timeframe 
All SAEs (regardless of relationship to study) are collected from the time the subject signs 
informed consent until the defined follow-up period stated in Table 2, and must be reported to 
the Pharmacovigilance vendor (see Table 1) within 24 hours of the first awareness of the 
event.  
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the Investigator at any interval after the study has completed must be reported to the 
Pharmacovigilance vendor (see Table 1) within 24 hours of the first awareness of the event. 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the SAE onset and resolution dates, 
respectively. 
In addition, any signs or symptoms experienced by the subject prior to study entry or leading 
up to the onset date of the SAE or following the resolution date of the SAE, must be recorded 
as an AE, if appropriate. 
Fatal Outcome 
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at time of death that did not contribute to the 
subject’s death, the outcome should be considered not resolved, without a resolution date 
recorded. 


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For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product). 
Regulatory Agency, Institutional Review Board, Independent Ethics Committee, and 
Site Reporting 
Kadmon Regulatory Affairs (or designee) is responsible for notifying the relevant regulatory 
authorities of related, unexpected SAEs. 
In addition, the Sponsor is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the tesevatinib program.  
The Investigator is responsible for notifying the local IRB and the Sponsor of all SAEs that 
occur at his or her site as required. 


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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1. 
Data Collection 
The Investigators’ authorized site personnel must enter the information required by the 
protocol on the eCRF. A Study Monitor will visit each site in accordance with the monitoring 
plan and review the eCRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the eCRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the Investigator’s Meeting. It is expected that site personnel 
will complete the eCRF entry within 5 business days of the subject’s visit. 
9.2. 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy 
of the clinical database. 
9.3. 
Statistical Analysis Process 
Details regarding the statistical methods and definitions will be provided in the Statistical 
Analysis Plan. The SAP will be finalized prior to unblinding to preserve the integrity of the 
statistical analysis and study conclusions. 
Categorical data will be summarized by frequency distributions (number and percentages of 
subjects) and continuous data will be summarized by descriptive statistics (mean, standard 
deviation, median, minimum, and maximum). 
All data will be provided in by-subject listings. 
All statistical analyses will be performed after the database is locked and unblinded. 
Statistical analyses will be performed using Version 9.1 or higher of SAS.  
9.4. 
Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee 
There is no planned interim analysis, adaptive design, or Data Monitoring Committee in this 
study. 
9.5. 
Selection of Subjects to be Included in the Analyses 
The following populations will be used in this study:  
 The Modified Intent-To-Treat (mITT) population:  as all randomized subjects who 
received at least 1 dose of study drug. 


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 The Efficacy Population:  all subjects in the mITT population who complete at least 
12 months of tesevatinib or placebo treatment and have a centrally read MRI at 
baseline and after 12 months of treatment. 
9.6. 
Subject Disposition 
Subjects in each analysis set, as well as subjects who complete the study, and subjects who 
prematurely discontinue from the study will be summarized by treatment group using 
descriptive statistics. In addition, for subjects who prematurely discontinue from the study, 
the reasons for discontinuation will be summarized by treatment group. 
9.7. 
Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the mITT population.  
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups at baseline. Continuous variables such as subject age, weight and height will 
be summarized using number of observations, mean, standard deviation, median, minimum, 
and maximum values. Categorical variables such as subject sex and race will be summarized 
using number of observations and percentages for each category.  
Medical history will be summarized by treatment group using the number of observations and 
percentages of subjects reporting each category. 
9.8. 
Investigational Product Exposure  
Summary statistics for the duration of exposure to investigational product will be presented 
by treatment group. In addition, the number of dose interruptions will be provided in 
by-subject listings. 
9.9. 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the World Health Organization drug 
dictionary. Prior and concomitant medications will be listed and summarized by preferred 
drug name and treatment group. 
9.10. 
Efficacy Analyses 
All efficacy analyses will be based on the Efficacy Population. 
The primary efficacy endpoint will be the change from baseline in htTKV at Month 12. An 
analysis of covariance model including treatment group as a factor and the baseline htTKV as 
a covariate will be used for efficacy analyses. The Type I error rate will be set at an alpha 
level of 0.05. Additional efficacy endpoints include change from baseline in htTKV at Months 
18, 24, and 30 days post-dose. 
In addition, the change in eGFR at the Month 12, 18, 24, and 30-days post-treatment time 
points will be evaluated. 


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9.11. 
Safety Analyses 
Safety analyses will be based on the mITT Population. 
Treatment-emergent adverse events (TEAE) will be coded using the Medical Dictionary for 
Regulatory Activities (Version 19.0 or higher). The number of events, incidence, and 
percentage of TEAEs will be presented by system organ class and by preferred term for each 
treatment group. Treatment-emergent adverse events will be further summarized by severity 
and relationship to investigational product. Adverse events related to investigational product, 
AEs leading to withdrawal, SAEs, and deaths will be summarized/listed. 
Clinical laboratory tests (including serum creatinine, cystatin C, and eGFR), vital signs, and 
ECG findings will be summarized by treatment group and visit. Potentially clinically 
important findings will also be summarized or listed. 
Physical examination, echocardiogram and ocular evaluation findings will be provided in 
listings. 
9.12. 
Sample Size Calculation and Power Considerations 
Based on the results presented in Caroli, et.al.1 it is anticipated that the mean change from 
baseline in htTKV at 12 months will be 83.6 (± 90.0) mL in the placebo group. Assuming the 
mean change from baseline in htTKV at 12 months is 26.4 mL for the tesevatinib group, 
40 subjects per group would yield approximately 80% power to detect a difference between 
treatment groups based on a 2-sided t-test with a Type I error rate of 0.05. Ten additional 
subjects per group will be added (ie, for a total of 50 subjects per group) to adjust for drop-
outs and differences in analysis methodologies (eg, the htTKV data will be log-transformed). 


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10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, International 
Council for Harmonisation (ICH), and local ethical and legal requirements.  
10.1. 
Sponsor’s Responsibilities 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations and ICH Good Clinical Practice (GCP) 
Guideline E6 (1996). 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the Sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
inter/national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The Sponsor ensures that Local Regulatory Authority requirements are met before the start of 
the study. The Sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any Regulatory Authority approvals required prior 
to release of investigational product for shipment to the site. 
Public Posting of Study Information 
The Sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating Investigators’ 
names and contact information.  
Study Suspension, Termination, and Completion 
The Sponsor may suspend or terminate the study or part of the study at any time for any 
reason. If the study is suspended or terminated, the Sponsor will ensure that applicable 
regulatory agencies and IRBs are notified as appropriate. Additionally, the discontinuation of 
a registered clinical study which has been posted to a designated public website will be 
updated accordingly. 
10.2. 
Investigator’s Responsibilities 
Good Clinical Practice Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996) and applicable regulatory requirements and guidelines. 
It is the Investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 


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Investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the 
Investigator has delegated significant study-related tasks. Curriculum vitae for Investigators 
and sub-investigators are provided to the study Sponsor (or designee) before starting the 
study. 
If a potential research subject has a primary care physician, the Investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A Coordinating Principal Investigator is appointed to review the final Clinical Study Report 
for multi-site studies. Agreement with the final Clinical Study Report is documented by the 
signed and dated signature of the Coordinating Principal Investigator, in compliance with 
Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995).  
Protocol Adherence and Investigator Agreement 
The Investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The Investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an Investigator Agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the Investigator suspends or terminates the study at their site, the Investigator will promptly 
inform the Sponsor and the IRB and provide them with a detailed written explanation. The 
Investigator will also return all investigational product, containers, and other study materials 
to the Sponsor. Upon study completion, the Investigator will provide the Sponsor, IRB, and 
regulatory agency with final reports and summaries as required by national regulations. 
Communication with local IRBs, to ensure accurate and timely information is provided at all 
phases during the study, may be done by the Sponsor, applicable contract research 
organization, Investigator, or by the Coordinating Principle Investigator, according to national 
provisions and will be documented in the Investigator Agreement. 
Documentation and Retention of Records 
10.2.1.1. Case Report Forms 
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the Investigator or designee as stated in the site delegation log. 
Corrections to data will be made according to the Code of Federal Regulations (CFR) 21 
Part 11, Electronic Records; Electronic Signatures. If corrections are made after review and 
sign-off by the Investigator, he/she must be aware of the changes and provide written 
acknowledgement. 
All data sent to the Sponsor must be endorsed by the Investigator.  


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The CRA/Study Monitor will verify the contents against the source data per the Monitoring 
Plan. If the data are unclear or contradictory, queries will be sent for corrections or 
verification of data. 
10.2.1.2. Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but is not limited to: 
subject’s medical file and original clinical laboratory reports. 
All key data must be recorded in the subject’s medical records. 
The Investigator must permit authorized representatives of the Sponsor, the respective 
national, local, or foreign regulatory authorities, the IRB, and auditors to inspect facilities and 
to have direct access to original source records relevant to this study, regardless of media. 
The CRA/Study Monitor (and auditors, IRB or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the Sponsor or its representatives, national or local 
regulatory authorities, or the IRB having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc).  
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US Food 
and Drug Administration [FDA] or an auditor).  
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the Sponsor.  
10.2.1.3. Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), other regulatory authorities, the 
Sponsor or its representatives, and the IRB for each site. 
10.2.1.4. Financial Disclosure 
The Investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the value of the compensation for conducting the study could be 
influenced by the outcome of the study. The following information is collected:  any 
significant payments from the Sponsor or subsidiaries such as a grant to fund ongoing 
research, compensation in the form of equipment, retainer for ongoing consultation or 
honoraria; any proprietary interest in investigational product; any significant equity interest in 
the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
In consideration of participation in the study, the Sponsor pays the Investigator or nominated 
payee the sums set out in the payment schedule attached to the Investigator agreement. 
10.3. 
Ethical Considerations 


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Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from all study 
subjects prior to any study related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or 
the subject’s legally-authorized representative as applicable is requested to sign the Subject 
Informed Consent Form or a certified translation, if applicable after the subject has received 
and read (or been read) the written subject information and received an explanation of what 
the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed consent 
documentation (ie, a complete set of subject information sheets and fully executed signature 
pages) must be given to the subject or the subject’s legally-authorized representative as 
applicable. Signed consent forms must remain in each subject’s study file and must be 
available for verification at any time. 
The Principal Investigator provides the Sponsor with a copy of the consent form which was 
reviewed by the IRB and which received their favorable opinion/approval. A copy of the 
IRB’s written favorable opinion/approval of these documents must be provided to the 
Sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, 
Sponsor or Coordinating Principal Investigator) is responsible for this action. Additionally, if 
the IRB requires modification of the sample Subject Information and Consent document 
provided by the Sponsor, the documentation supporting this requirement must be provided to 
the Sponsor. 
Institutional Review Board or Independent Ethics Committee 
It is the responsibility of the Investigator to submit this protocol, the informed consent 
document (approved by the Sponsor or their designee), relevant supporting information and 
all types of subject recruitment information to the IRB for review, and all must be approved 
prior to site initiation. 
Responsibility for coordinating with IRBs is defined in the Investigator Agreement. 
Prior to implementing changes in the study, the Sponsor and the IRB must approve any 
revisions of any revised informed consent documents and amendments to the protocol unless 
there is a subject safety issue. 
Investigational product supplies will not be released until the Sponsor has received written 
IRB approval of and copies of revised documents. 
The Investigator is responsible for keeping the IRB apprised of the progress of the study and 
of any changes made to the protocol, but in any case, at least once a year. The Investigator 
must also keep the local IRB informed of any serious and significant AEs. 
10.4. 
Privacy and Confidentiality 


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All sites and laboratories or entities providing support for this study, must, where applicable, 
comply with the Health Insurance Portability and Accountability Act of 1996 (HIPAA). A site 
that is not a Covered Entity as defined by HIPAA, must provide documentation of this fact to 
the Sponsor. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the Sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the Sponsor; third parties with whom the Sponsor may develop, 
register, or market drug name; national or local regulatory authorities; and the IRB(s) that 
gave approval for the study to proceed. The Sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects' identities. 
Subjects are assigned a unique identifying number. However, their initials and date of birth 
may also be collected and used to assist the Sponsor to verify the accuracy of the data, for 
example, to confirm that laboratory results have been assigned to the correct subject.  
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purpose of any such transfer would 
include: to support regulatory submissions, to conduct new data analyses to publish or present 
the study results, or to answer questions asked by regulatory or health authorities. 
10.5. 
Publication Policy 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the Sponsor in advance of submission. The 
review is aimed at protecting the Sponsor’s proprietary information existing either at the date 
of the commencement of the study or generated during the study and to provide comments 
based on information from other studies that may not yet be available to the investigator. 
In the event that Kadmon coordinates a publication or presentation of study results from all 
study sites, the participation of investigator or other representatives of study site as a named 
author shall be determined in accordance with Kadmon policy and generally accepted 
standards for authorship. 


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11. 
REFERENCES 
1. 
Caroli A, Perico N, Perna A, et al. Effect of longacting somatostatin analogue on 
kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): 
a randomised, placebo-controlled, multicentre trial. Lancet. 2013;382(9903):1485-
1495. 
2. 
Wilson PD. Polycystic kidney disease. N. Engl. J. Med. 2004;350(2):151-164. 
3. 
Chapman AB. Approaches to testing new treatments in autosomal dominant 
polycystic kidney disease: insights from the CRISP and HALT-PKD studies. Clin. J. 
Am. Soc. Nephrol. 2008;3(4):1197-1204. 
4. 
Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. 
Lancet. 2007;369(9569):1287-1301. 
5. 
Torres VE. Treatment strategies and clinical trial design in ADPKD. Adv. Chronic 
Kidney Dis. 2010;17(2):190-204. 
6. 
Belibi FA, Reif G, Wallace DP, et al. Cyclic AMP promotes growth and secretion in 
human polycystic kidney epithelial cells. Kidney Int. 2004;66(3):964-973. 
7. 
Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic 
kidney disease. N. Engl. J. Med. 2006;354(20):2122-2130. 
8. 
Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. N. 
Engl. J. Med. 2008;359(14):1477-1485. 
9. 
Lacouture ME, Anadkat MJ, Bensadoun RJ, et al. Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. 
Support. Care Cancer. 2011;19(8):1079-1095. 
10. 
Kiyohara Y, Yamazaki N, Kishi A. Erlotinib-related skin toxicities: treatment 
strategies in patients with metastatic non-small cell lung cancer. J. Am. Acad. 
Dermatol. 2013;69(3):463-472. 
11. 
Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and 
prolongation of the QT interval. J. Clin. Oncol. 2007;25(22):3362-3371. 
12. 
Fridericia LS. The duration of systole in the electrocardiogram of normal subjects and 
of patients with heart disease. Acta Med. Scand. 1920(53):469-486. 
 


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12. 
APPENDICES 


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APPENDIX 1 
CONCOMITANT DRUGS THAT INHIBIT CYP3A4 
AND SHOULD NOT BE ADMINISTERED 
Use of drugs that are moderate or strong inhibitors of the CYP3A4 family of enzymes is 
prohibited in patients who are receiving study drug.  
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with study drug. 
 
Moderate or Strong CYP3A4 Inhibitors 
Drug Type 
Drug Name 
Human immunodeficiency virus antivirals 
indinavir 
 
nelfinavir 
 
ritonavir 
 
saquinavir 
Antifungals 
itraconazole 
 
fluconazole  
 
ketoconazole  
Antibiotics 
clarithromycin 
 
erythromycin 
 
telithromycin 
Antidepressants 
nefazodone 
Calcium-channel blockers 
diltiazem  
 
verapamil  
Others 
aprepitant 
 
grapefruit juice 
Source:  http://medicine.iupui.edu/clinpharm/ddis/main-table/ 


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APPENDIX 2 
CONCOMITANT MEDICATIONS ASSOCIATED WITH 
A RISK OF QTC(F) INTERVAL PROLONGATION 
AND/OR TORSADES DE POINTES 
Use of these drugs should be avoided in subjects who are receiving study drug. Subjects who 
require treatment with these drugs should have study drug held for up to 21 days while 
receiving the treatment and should be closely monitored for QTcF prolongation and potential 
AEs. This list is not comprehensive and all concomitant medications should be evaluated for 
potential contribution to QTcF prolongation. Refer to the following web site whenever a 
potential concomitant medication is needed for additional listings and information: 
https://crediblemeds.org/index.php?rf=US 
 
Drug Type 
Drug Name 
Anti-anginal 
bepridil 
Anti-arrhythmic 
amiodarone, disopyramide, dofetilide, ibutilide, 
procainamide, quinidine, sotalol 
Antibiotic 
clarithromycin, erythromycin, azithromycin, 
sparfloxacin, gatifloxacin, moxifloxacin, 
troleandomycin 
Anticancer 
arsenic trioxide 
Anti-infective/pneumocystis pneumonia 
pentamidine 
Antimalarial 
chloroquine, halofantrine 
Antinausea 
domperidone, droperidol 
Antipsychotic 
haloperidol, mesoridazine, thioridazine 
Antipsychotic/anti-emetic 
chlorpromazine 
Antipsychotic/Tourette’s tics 
pimozide 
Gastrointestinal stimulant/heartburn 
cisapride 
Opiate agonist/pain control/narcotic 
dependence 
levomethadyl, methadone 
Reference:  http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm 
 


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APPENDIX 3 
TOPICAL STEROID POTENCY CHART 
The following potency chart categorizes brand name topical steroid medications along with 
the name of the corresponding generic drug. The medications are listed in order of their 
potency. Please note that the percentage of ingredient in the medication does not necessarily 
correlate with the strength of the steroid. The list may not be comprehensive. 
Brand Name 
Generic Name 
Class 1 – Superpotent 
Clobex Lotion/Spray/Shampoo, 0.05% 
Clobetasol propionate 
Cordran Tape, 0.05% 
Flurandrenolide 
Cormax Cream/Solution, 0.05% 
Clobetasol propionate 
Diprolene Ointment, 0.05% 
Augmented betamethasone 
Olux E Foam, 0.05% 
Clobetasol propionate 
Olux Foam, 0.05% 
Clobetasol propionate 
Psorcon Ointment, 0.05%  
Psorcon Ointment, 0.05%  
Psorcon E Ointment, 0.05%  
Psorcon E Ointment, 0.05%  
Temovate Cream/Ointment/Solution, 0.05% 
Clobetasol propionate 
Ultravate Cream/Ointment, 0.05% 
Halobetasol propionate 
Ultravate Lotion, 0.05% 
Halobetasol propionate 
Vanos Cream, 0.1% 
Fluocinonide 
Class 2 - Potent 
Diprolene Cream AF, 0.05% 
Augmented betamethasone 
Elocon Ointment, 0.1% 
Mometasone furoate 
Florone Ointment, 0.05% 
Diflorasone diacetate 
Halog Ointment/Cream, 0.1% 
Halcinonide 
Lidex Cream/Gel/Ointment, 0.05% 
Fluocinonide 
Psorcon E Cream, 0.05% 
Diflorasone diacetate 
Topicort Cream/Ointment, 0.25% 
Desoximetasone 
Topicort Gel, 0.05% 
Desoximetasone 
Class 3 – Upper Mid-Strength 
Cutivate Ointment, 0.005% 
Fluticasone propionate 
Lidex-E Cream, 0.05% 
Fluocinonide 
Luxiq Foam, 0.12% 
Betamethasone valerate 


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Brand Name 
Generic Name 
Class 4 – Mid-Strength  
Cordran Ointment, 0.05% 
Flurandrenolide 
Elocon Cream/Lotion, 0.1% 
Mometasone furoate 
Kenalog Cream/Spray, 0.1% 
Triamcinolone acetonide 
Synalar Ointment, 0.025% 
Fluocinolone acetonide 
Topicort LP Cream, 0.05% 
Desoximetasone 
Topicort LP Ointment, 0.05% 
Desoximetasone 
Westcort Ointment, 0.2% 
Hydrocortisone Valerate 
Class 5 - Lower Mid-Strength 
Capex Shampoo, 0.01% 
Fluocinolone acetonide 
Cordran Cream/Lotion 
Flurandrenolide 
Cutivate Cream/Lotion, 0.05% 
Fluticasone propionate 
Dermatop Cream, 0.1% 
Prednicarbate 
DesOwen Lotion, 0.05% 
Desonide 
Locoid Cream/Lotion/Ointment/Solution, 0.1% 
Hydrocortisone 
Pandel Cream, 0.1% 
Hydrocortisone 
Synalar Cream, 0.025/ 
Fluocinolone acetonide 
Westcort Cream, 0.2% 
Hydrocortisone valerate 
Class 6 – Mild 
Aclovate Cream/Ointment, 0.05% 
Alclometasone dipropionate 
Derma-Smoothe/FS Oil, 0.01% 
Fluocinolone acetonide 
Desonate Gel, 0.05% 
Desonide 
Synalar Solution, 0.01% 
Fluocinolone acetonide 
Verdeso Foam, 0.05% 
Desonide 
Class 7 - Least Potent  
Cetacort Lotion, 0.5%/1% 
Hydrocortisone 
Cortaid Cream/Spray/Ointment, 1% 
Hydrocortisone 
Hytone Cream/Lotion, 1%/2.5% 
Hydrocortisone 
Micort-HC Cream, 2%/2.5% 
Hydrocortisone 
Nutracort Lotion, 1%/2.5% 
Hydrocortisone 
Synacort Cream, 1%/2.5% 
Hydrocortisone 


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Abstracted from:  National Psoriasis Foundation. Topical treatments for Psoriasis. 2013. 
https://www.psoriasis.org/about-psoriasis/treatments/topicals/steroids/potency-chart (accessed 15 February 2017) 

SAP_001.pdf: 
Kadmon Corporation 
KD019-211
    Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022 
      Page 1 of 27 
STATISTICAL ANALYSIS PLAN 
A Double-blind Randomized Parallel Group Study of the 
Efficacy and Safety of Tesevatinib in Subjects with Autosomal 
Dominant Polycystic Kidney Disease 
Protocol Number: KD019-211 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
Version 1.0 
11-APR-2022
NCT03203642


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KD019-211
    Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022 
      Page 2 of 27 
SIGNATURE PAGE 
Date 
Date 


Kadmon Corporation 
KD019-211
    Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022 
      Page 3 of 27 
DOCUMENT HISTORY 
Version 
Author 
Description 
 1.0 
Original signed version 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022  
 
 
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Table of Contents 
1 
INTRODUCTION .............................................................................................. 9 
2 
STUDY SUMMARY ......................................................................................... 10 
2.1 
Study Objectives .......................................................................................... 10 
2.1.1 
Primary Objectives................................................................................ 10 
2.1.2 
Secondary Objectives............................................................................ 10 
2.2 
Study Design ................................................................................................ 10 
2.3 
Visit Schedule and Study Assessment ......................................................... 11 
2.4 
Efficacy Assessments ................................................................................... 11 
2.4.1 
Height-Adjusted Total Kidney Volume ................................................ 11 
2.4.2 
Estimated Glomerular Filtration Rate ................................................... 11 
3 
STATISTICAL METHODS ............................................................................ 13 
3.1 
General Methods .......................................................................................... 13 
3.1.1 
Computing Environment ....................................................................... 13 
3.1.2 
Sample Size Justification and power calculations: ............................... 13 
3.2 
General Considerations ................................................................................ 13 
3.2.2 
Study Day.............................................................................................. 14 
3.2.3 
Baseline ................................................................................................. 14 
3.2.4 
Handling of Incomplete or Missing Data .............................................. 14 
3.3 
Analysis Populations .................................................................................... 16 
3.4 
Subject Disposition and Evaluability ........................................................... 16 
3.5 
Protocol Deviations ...................................................................................... 16 
3.6 
Demographics and Baseline Characteristics ................................................ 17 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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3.6.1 
Demographics ....................................................................................... 17 
3.6.2 
Medical History .................................................................................... 17 
3.7 
Prior and Concomitant Medications ............................................................. 17 
3.8 
Treatment Exposure ..................................................................................... 17 
3.9 
Efficacy Analyses ......................................................................................... 18 
3.9.1 
htTKV Logarithmic Transformation ..................................................... 18 
3.9.2 
Primary Endpoint Analysis ................................................................... 18 
3.9.3 
Secondary Endpoint Analyses:  Change from Baseline in eGFR ......... 18 
3.10 
Supplementary and Sensitivity Analyses for Primary and Secondary 
Endpoints ................................................................................................................ 19 
3.10.1 htTKV Longitudinal Analysis............................................................... 19 
3.10.2 eGFR Longitudinal Analysis ................................................................ 20 
3.11 
Subgroup Analyses ................................................................................... 20 
3.12 
Multiplicity ............................................................................................... 20 
3.13 
Safety Analysis ......................................................................................... 20 
3.13.1 Adverse Events ..................................................................................... 21 
3.13.2 Clinical Laboratory Evaluation ............................................................. 21 
3.13.3 Vital Signs ............................................................................................. 22 
3.13.4 ECG....................................................................................................... 22 
3.13.5 Echocardiogram .................................................................................... 22 
3.13.6 Physical Examination............................................................................ 22 
3.14 
Interim Analysis ....................................................................................... 23 
3.15 
Mayo Classification Formula ................................................................... 23 
4 
LIST OF TABLES, FIGURES, AND LISTINGS .......................................... 26 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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5 
REFERENCES .................................................................................................. 27 
  


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022  
 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Full Term 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance  
ARPKD 
autosomal recessive polycystic kidney disease 
ATC 
American therapeutic chemical (classification) 
CI 
confidence interval 
CM 
concomitant medication 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
ECG  
electrocardiogram 
EGFR 
epithelial growth factor receptor 
eGRF  
estimated glomerular filtration rate 
htTKV 
height-adjusted total kidney volume 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation  
ITT 
intent-to-treat  
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat  
mL 
milliliters 
MMRM  
mixed model repeated measures 
MRI 
magnetic resonance imaging  
ms 
millisecond 
PKD 
polycystic kidney disease 
PT 
preferred term 
QD 
once daily 
QTcF 
corrected QT interval using Fridericia's formula 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022  
 
 
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Abbreviation 
Full Term 
TLFs 
tables, listings, and figures 
 
 
 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022  
 
 
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1 INTRODUCTION 
Polycystic kidney disease (PKD) is the most common inherited kidney disease in the 
United States, occurring in approximately 1 in every 1,000 live births. It affects more 
than 600,000 people in the United States and 12 million worldwide. It is the third 
most common single cause of kidney failure. Polycystic kidney disease is 
characterized by the growth of numerous renal cysts, which cause abnormalities in 
both structure and function of the kidneys. Cysts also develop in other organs, 
particularly in the liver. Other manifestations of PKD include high blood pressure, 
urinary tract infections, kidney stones, hematuria, and aneurysms. Pain in the back, 
abdomen, and pelvis affects many PKD patients. There are 2 types of PKD, 
autosomal dominant (ADPKD) and autosomal recessive (ARPKD). In ADPKD, the 
mutation in either the PKD1 or PKD2 gene results in the abnormal, uncontrolled 
growth of renal tubular epithelial cells. Epithelial growth factor receptor (EGFR) is 
overexpressed and mislocated from the basolateral to the luminal surface of renal 
tubular cells. Epithelial growth factor receptor ligands are secreted by tubular cells 
and are found in human PKD cyst fluids. The combination of EGFR mislocation and 
ligand secretion establishes an autocrine loop resulting in persistent renal tubular cell 
proliferation. Chronic proliferation results in renal cyst formation. The cysts then 
cause a structural distortion of the renal architecture, impeding normal nephron 
function. Cyst enlargement results in a massive increase in kidney volume and a 
progressive impairment of renal function. Associated clinical symptoms include 
hypertension, recurrent flank pain, hematuria, and recurrent pyelonephritis. Currently, 
there are no disease-modifying therapies for ADPKD; all existing treatment strategies 
are palliative and aimed at controlling symptoms.  
This Statistical Analysis Plan (SAP) describes detailed statistical procedures to be 
used for study KD019-211 as specified in the protocol (Version 2.0, 
31-August-2018): A Double-blind Randomized Parallel Group Study of the Efficacy 
and Safety of Tesevatinib in Subjects with Autosomal Dominant Polycystic Kidney 
Disease. 
The SAP was written in accordance with the recommendations outlined in the 
International Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance 
for Industry: Statistical Principles for Clinical Trials” and the most recent ICH-E3 
Guideline, entitled “Guidance for Industry: Structure and Content of Clinical Study 
Reports.”  


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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2 STUDY SUMMARY 
2.1 Study Objectives  
2.1.1 Primary Objectives 
The primary objective of this study is to evaluate the change from baseline in height-
adjusted total kidney volume (htTKV) as measured by magnetic resonance imaging 
(MRI) at Months 12, 18, 24, and 30 days post-dose in patients with ADPKD treated 
with tesevatinib or placebo. 
2.1.2  Secondary Objectives  
The secondary objectives of the study are to: 
• Evaluate the safety and tolerability of tesevatinib50 mg QD in patients with 
ADPKD 
• Evaluate the change in estimated glomerular filtration rate (eGFR) using the 
modification of diet in renal disease-4 (MDRD) formula at the Month 12, 18, 24, 
and 30 days post-dose time points 
2.2 Study Design 
This is a Phase 2b, multicenter, double-blind, randomized, parallel group study to 
evaluate the change from baseline in htTKV as measured by MRI in subjects with 
ADPKD treated with tesevatinib or placebo. Male and female subjects with ADPKD, 
18 to 60 years of age and with an eGFR ≥ 30 mL/min/1.73 m2 and ≤ 80 
mL/min/1.73 m2 will be enrolled. Up to 100 male and female subjects will be 
randomized 1:1 to receive 50 mg of tesevatinib once daily (QD) or placebo. The 
study will be conducted at approximately 25-30 sites in the United States. 
Subjects will be screened up to 28 days before initiation of treatment with tesevatinib 
or placebo (certain screening assessments may be conducted up to 42 days prior to 
dosing). Screening assessments will include medical and PKD history, physical 
examination, vital signs, electrocardiograms (ECGs), clinical laboratory evaluation 
(including hematology, serum chemistry, coagulation, thyroid stimulating hormone, 
urinalysis, and pregnancy), ocular examination, echocardiogram, and MRI. 
Calculation of htTKV at screening for eligibility determination may be performed by 
a local radiologist. 
Starting on Day 1, subjects will receive 50 mg QD of tesevatinib or placebo for up to 
24 months. During the Early Treatment Period (Days 1 to 28), subjects will report to 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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the study site on Days 1, 14, and 28; subjects will be followed every 28 days from 
Months 2 to 12 and every other month from Months 12 to 24. Safety assessments will 
be performed at regular intervals throughout the study and will include physical 
examinations, vital signs, ECGs, clinical laboratory evaluations, ocular examination, 
and echocardiograms. Magnetic resonance imaging to determine the change from 
baseline in htTKV will be performed at Months 12, 18, and 24. Entry into the study 
will be based on local MRI readings, but central MRI readings and htTKV calculation 
will be performed at baseline and during the study.  
All subjects will undergo an end-of-study evaluation approximately 30 days after the 
last dose of study drug. 
2.3 Visit Schedule and Study Assessment 
The flow chart of visit schedule and study assessments is given in Table 2 of the 
KD019-211 Protocol. 
2.4 Efficacy Assessments 
2.4.1 Height-Adjusted Total Kidney Volume 
htTKV will be assessed by MRI at Months 12, 18, 24, and 30 days post-dose. htTKV, 
reported in milliliters (mL), is calculated using total kidney volume obtained from 
MRI divided by height in meter.  
2.4.2 Estimated Glomerular Filtration Rate 
eGFR will be assessed using the MDRD-4 formula as presented in Table 1. As 
indicated in Table 2 of the study protocol serum creatinine will be assessed at the 
Screening, Day 1, Day 14, Day 28, then monthly until Month 12, then every 2 months 
until Month 24; and 30 days from last dose.  
 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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Table 1: 4-Variable Modification of Diet in Renal Disease (MDRD-4) Formula 
High Level Formula for Black or African-American Males: 
eGFR = 175 × (Scr-1.154) × (Age-0.203) × 1.212 
High Level Formula for Males NOT Black or African-American (any other option): 
eGFR = 175 × (Scr-1.154) × (Age-0.203) 
High Level Formula for Black or African-American Females: 
eGFR = 175 × (Scr-1.154) × (Age-0.203) × 1.212 × 0.742 
High Level Formula for Females NOT Black or African-American (any other option): 
eGFR = 175 × (Scr-1.154) × (Age-0.203) × 0.742 
  Note: Age is shown in years. Scr = serum creatinine 
 
 


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KD019-211                                                                                           Statistical Analysis Plan 
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3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical programming and data analyses will be performed using SAS 
Version 9.4 on a Windows platform. 
3.1.2 Sample Size Justification and power calculations: 
Based on the results presented in Caroli, et.al.1 it is anticipated that the mean change 
from baseline in htTKV at 12 months will be 83.6 (± 90.0) mL in the placebo group. 
Assuming the mean change from baseline in htTKV at 12 months is 26.4 mL for the 
tesevatinib group, 40 subjects per group would yield approximately 80% power to 
detect a difference between treatment groups based on a 2-sided t-test with a Type I 
error rate of 0.05. Ten additional subjects per group will be added (i.e., for a total of 
50 subjects per group) to adjust for dropouts and differences in analysis 
methodologies (e.g., the htTKV data will be log-transformed). 
3.2 General Considerations  
General considerations for descriptive statistics and presentation for continuous and 
categorical data are given below.  
3.2.1.1 Continuous Variables 
Continuous data will be described using descriptive statistics: number of observations 
(n), mean, standard deviation, median, minimum, and maximum.  
Means, medians, standard deviations, and confidence intervals (CIs) will be reported 
to one decimal place more than the data reported on the case report form (CRF) or by 
the vendor. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the vendor. P-values will be reported to 4 decimal 
places. 
3.2.1.2 Binary Endpoint and Other Categorical Variables 
For endpoints with two possible outcomes (i.e., dichotomous endpoints) such as 
alive/otherwise or response/otherwise within specific periods, the 95% confidence 
interval will be calculated with Clopper-Pearson method. For other categorical 
variables, the counts and percent of each category within a parameter will be 


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KD019-211                                                                                           Statistical Analysis Plan 
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calculated for observed data only. The denominator for all percentages, unless 
otherwise specified, will be the number of subjects in the treatment group or in the 
specified analysis population. 
3.2.2 Study Day 
The Study Day for all assessments prior to the first study drug administration is 
calculated as the difference between the date of the event or measurement (e.g., 
adverse event [AE] onset date, assessment date, sample collection date) and the start 
date of study treatment. The day before the start of study treatment is Study Day -1. 
The Study Day for all post-assessments after the first study drug administration is 
calculated as the difference between the date of the event or measurement (e.g., AE 
onset date, assessment date, sample collection date) and the start date of study 
treatment plus one day. The first day of study treatment is Study Day 1. 
3.2.3 Baseline 
Baseline value is defined as the valid and last non-missing value obtained within 
28 days prior to subject receiving the first study medication, unless otherwise stated 
under the related assessment section. Baseline can be the day before the first study 
medication or on the same day as the first study medication if a pre-dose assessment 
is available. Subjects without data on a parameter before the first study medication 
will have a missing baseline for this parameter.  
3.2.4 Handling of Incomplete or Missing Data 
Missing data will not be imputed in general and will be reported as missing in all 
listings. For categorical variables, patients with missing data are not included in 
calculations of percentages unless otherwise specified.  
Missing start and end dates for AE and concomitant medication (CM)  
The assumption will be the worst or most conservative judgment when imputing AE 
and CM start and end dates. The purpose of imputing a start date is to help define 
whether the AE/CM started while taking study drug. 
For a partial or missing start date: 
• If the day is missing, the first day of the month will be imputed. If the missing day 
is the same as the month of first dose of study drug, then the first dose date will be 
imputed. 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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• If the day and month are missing, the first day of January will be imputed. If the 
year is the same as the first dose date, then the first dose date will be imputed. 
• If the date is completely missing, the first dose date will be imputed. If the end 
date suggests it could have started prior to this, the first day of January of the 
same year as the end date will be imputed. 
• When imputing a start date, the start date will ensure that the new imputed date is 
sensible, i.e., is prior to the end date of the AE or CM. 
For a partial or missing end date: 
• If the day is missing, the last day of the month or the last assessment date, 
whichever is earlier, will be imputed. 
• If the day and month are missing, the 31st of December or the last assessment 
date, whichever is earlier, will be imputed 
• If the date is completely missing, there will be a need to look at whether the 
AE/CM is still ongoing before imputing a date. If the ongoing flag is missing, 
then it will be assumed that AE is still present, or CM is still being taken (i.e., do 
not impute a date). If the AE/CM has stopped, then the last assessment date will 
be imputed. 
These data imputations are for categorization purpose only and will not be used in the 
listings. 
If the assessment of the relationship of the AE to tesevatinib is missing, then it will be 
assumed that the AE is related to tesevatinib, and the AE considered as such in the 
frequency tables of possibly related AEs. No imputation should be done at the data 
level. 
Missing event dates  
Event date will be imputed only when day is missing, and the purpose of imputing an 
event date is to most conservatively calculate time to event.  
If the day is missing, the first (mid, last) day of the month will be imputed for 
undesired (neutral, desired) event. If the missing day is the same as the month of first 
dose of study drug, then the first dose date will be imputed for undesired event. 
These data imputations are for time to event calculation only and will not be used in 
the listings. 


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3.3 Analysis Populations 
The following are the set of analysis populations.  
Screened Population: All subjects who sign the Informed consent form (ICF) will be 
included in the Screened Population.  
Safety Population: The Safety Population is defined as all subjects who receive at 
least 1 dose of study medication. Subjects will be analyzed according to the study 
drug they actually received. 
Intent-to-treat (ITT) Population: The ITT population is defined as all randomized 
subjects. Subjects will be analyzed according to the study medication to which they 
were randomized.  
Modified Intent-to-treat (mITT) Population: The mITT Population is defined as all 
subjects who receive at least 1 dose of study medication. The mITT Population will 
be used for tables of demography and baseline characteristics. Subjects will be 
analyzed according to the study medication to which they were randomized. 
Efficacy Population: The Efficacy Population is defined as all subjects in the mITT 
population who complete at least 12 months of tesevatinib or placebo treatment and 
have a centrally read MRI at baseline and after 12 months of treatment. Subjects will 
be analyzed according to the study drug they actually received. This will be the 
primary population for efficacy analyses.  
3.4 Subject Disposition and Evaluability 
The analysis populations defined in Section 3.3 and the number of subjects 
discontinuing from the study and the primary reason for discontinuation will be 
summarized.  
3.5 Protocol Deviations 
All protocol deviations will be identified and classified as major or minor before 
clinical database lock and will be presented in a listing. 
Major Deviation: Protocol deviation that may impact the accuracy, and/or reliability 
of the study data or that may impact subject rights, safety, or well-being. 
Minor Deviation: Protocol deviation that does not impact the accuracy, and/or 
reliability of the study data or subject rights, safety, or well-being. 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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3.6 Demographics and Baseline Characteristics 
3.6.1 Demographics 
Descriptive summaries of demographic and baseline characteristics will be presented 
by treatment group and overall, for the mITT population. Demographics and baseline 
characteristics will be reviewed to assess the comparability of the treatment groups at 
baseline. Continuous variables such as subject age, weight and height will be 
summarized using number of observations, mean, standard deviation, median, 
minimum, and maximum values. Categorical variables such as subject sex and race 
will be summarized using number of observations and percentages for each category. 
3.6.2 Medical History 
Medical history will be summarized by primary System Organ Class (SOC) and 
Preferred Term (PT) for each treatment group. Medical history will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1 (or higher) 
terminology.  
3.7 Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (MAR2017B2). Prior medications are defined as those medications that 
began and stopped before the start of study treatment. Concomitant medications are 
defined as medications taken after the start of study treatment and during the study 
period, including those began before but ongoing at the start of study treatment. If a 
medication start date is partially or fully missing and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that the medication is 
concomitant. 
Number and percentage of incidence of prior and concomitant medications will be 
summarized according to Anatomical Therapeutic Class (ATC) and preferred drug 
name. 
3.8 Treatment Exposure 
Summary statistics for the duration of exposure to investigational product will be 
presented by treatment group. In addition, the number of dose interruptions will be 
provided in by-subject listings. The duration of exposure is defined as: 
 
Duration of exposure (days) = (Date of last dose – Date of Study Day 1) + 1. 


Kadmon Corporation 
 
 
KD019-211                                                                                           Statistical Analysis Plan 
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3.9 Efficacy Analyses 
Listings for all efficacy data will be presented. Results will be presented by Treatment 
Group. The Efficacy Population will be the primary analysis population for efficacy 
analyses, with the mITT Population being used for sensitivity and supplemental 
analyses. 
3.9.1 htTKV Logarithmic Transformation 
To reduce heterogeneity, a logarithmic transformation (log10) will be applied to the 
htTKV data prior to the analysis of covariance (ANCOVA) analyses (ie, defined in 
Sections 3.9.2) and mixed model repeated measures (MMRM) analyses (ie, defined in 
Section 3.10.1). The log10 transformation will apply to both the baseline and post-
baseline htTKV assessments . 
3.9.2 Primary Endpoint Analysis 
The primary efficacy endpoint is the change from baseline in htTKV at Month 12. An 
ANCOVA model including treatment group as a factor and the baseline htTKV (log10 
transformed) as a covariate will be used for efficacy analyses. The dependent variable 
is the log10 transformed change from baseline (ie, log10(Month 12 htTKV) - 
log10(Baseline htTKV)).  
The 2-sided Type I error rate will be set at an alpha level of 0.05.  
 
3.9.3 Secondary Endpoint Analyses:  Change from Baseline in eGFR 
A secondary endpoint is the change from baseline in eGFR at months 12, 18, 24, and 
30 days post-dose using the MDRD-4 formula (see Table 1).  
For the 30 days post-dose endpoint, the change in eGFR from baseline to post-
treatment follow-up is annualized (divided) by each subjects’ treatment duration (in 
years). This normalization is necessary, otherwise the treatment group having more 
dropouts or earlier dropouts may bias the results.  
At each timepoint (ie, months 12, 18, 24, and 30 days post-dose) and analysis of 
covariance (ANCOVA) model will be used to evaluate treatment effect. The 
ANCOVA model has eGFR as the dependent variable, treatment group as the factor, 
and baseline eGFR, patient age, and baseline htTKV as covariates.  


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3.10 Supplementary and Sensitivity Analyses for Primary and 
Secondary Endpoints 
The following are supplementary and sensitivity analyses for the primary and 
secondary endpoints: 
• The primary and secondary efficacy endpoints will be performed on the mITT 
population. 
• The htTKV at Months 18, 24, and 30 days post-dose will be analyzed in the 
manner as described in Section 3.9.2. 
• A longitudinal analysis of htTKV (as described in Section 3.10.1) 
• A longitudinal analysis of eGFR  (as described in Section 3.10.23.10.1) 
3.10.1 htTKV Longitudinal Analysis 
An MMRM analysis will be performed on the htTKV data. The following is the 
MMRM model: 
Yij = β1 + β2×Groupi + β3×tij + β4×tij×Groupi + b1i + b2i×tij + eij 
Where:  
Yij 
is the log10(htTKV) values for subject i at visit j (ie, at baseline; months 12, 
18, and 24; and 30-days post-dose)  
Groupi 
is the treatment group indicator for Subject i (=0 if placebo, =1 if KD019) 
tij 
is the time (in years) from baseline of the htTKV assessment 
β1 
is the intercept for the placebo group 
β2 
is the intercept increment for the KD019 group (ie, β1 + β2 is the intercept for 
the KD019 group) 
β3 
is the slope for the placebo group 
β4 
is the slope increment for the KD019 group (ie, β2 + β4 is the slope for the 
KD019 group) 
b1i  
Is the random intercept term for subject i 
b2i 
Is the random slope term for subject i 
eij 
Is the error term for subject i, visit j. 
Note: the random effects, b1i and b2i are assumed to be normally distributed with mean 0 and 
unknown variance covariance structure (ie, an unstructured 2×2 covariance matrix will be 
modelled). The error terms in the model, eij, are assumed mutually independent and normally 
distributed; and they are also assumed to be independent of the random effects, b1i and b2i. 
This model will test for a difference in slopes between placebo and KD019 (ie, testing 
the fixed effect parameter β4).  


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The following is the corresponding sample SAS Proc Mixed code for this MMRM 
model: 
Table 2: Sample SAS Code of Longitudinal MMRM Analyses 
** Sample SAS Code for MMRM **; 
Proc Mixed Data=XXX; 
  Class Trt subject; 
  Model  log_htTKV = treatment time treatment*time/s 
  Random intercept time / type=un subj=subject; 
Run;  
  
3.10.2 eGFR Longitudinal Analysis 
The slope of eGFR change will be analyzed by an MMRM analysis. 
The MMRM model will be the same as the model described in Section 3.10.1 with 
the dependent variable being the subjects eGFR values. The model will include the 
baseline and all post-baseline eGFR assessments.  
3.11 Subgroup Analyses 
• Summary statistics and the ANCOVA analysis for htTKV described in 
Section 3.9.2 will be performed for each of the Mayo Classification groups 
(ie, Class 1A, 1B, 1C, 1D, and 1E). This will be done for the Month 12, 18, 
24, and 30 days post-dose treatment visits.  
The formulas for the Mayo classification groups are derived from the methods 
in Irazabel (2015)2 and are presented in Section 3.15. 
• Summary statistics and the ANCOVA analysis for eGFR described in Section 
3.9.3 will be performed for each of the Mayo Classification groups (ie, Class 
1A, 1B, 1C, 1D, and 1E). This will be done for the Month 12, 18, 24, and 30 
days post-dose treatment visits.  
3.12 Multiplicity 
The primary efficacy endpoint will be tested at the 2-sided 0.05 level. The secondary 
efficacy endpoints (ie, eGFR at months 12, 18, 24, and 30 days post-dose) will not be 
controlled for multiplicity for this Phase 2 study. 
3.13 Safety Analysis 
Safety assessments will include AEs, serious adverse events (SAEs), vital sign 
measurements, clinical laboratory evaluations (hematology and chemistry), and 


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electrocardiograms (ECGs). Unscheduled visits for safety assessments will not be 
presented in summary tables but will be in listings. All safety analyses will be 
performed using the Safety Population.  
3.13.1 Adverse Events 
AEs will be coded using the MedDRA dictionary (Version 20.0). Treatment-emergent 
AEs (TEAEs) are any AE occurring or worsening in severity after the first 
administration of study medication. All AEs (including SAEs) will be graded using 
the 5-point Common Terminology Criteria for Adverse Events (CTCAE) V5.0 scale 
(mild, moderate, severe, life-threatening, or death). Causality with tesevatinib will be 
classified as: definitely related; probably related; possibly related; unlikely related; or 
not related. Definitely related, probably related and possibly related will be combined 
to related, unlikely related and not related will be combined to unrelated in some 
safety analyses.  
The number and percentage of patients who experienced at least one TEAE as well as 
the number and percentage of patients who experienced AEs of each specific system 
organ class (SOC) and preferred term (PT) will be presented. For the presentation of 
AE incidences, the SOCs and the PTs within each SOC will be presented by 
decreasing total frequency. Tabulation by maximum severity and relationship to 
tesevatinib will also be included by treatment group. 
The TEAEs, Grade ≥ 3 TEAEs, SAEs, and TEAEs leading to dose 
modification/discontinuation will be summarized by treatment arm, SOC, and PT. 
These analyses will be repeated for events considered related (definitely 
related/probably related/possibly related) to tesevatinib.  
Subject listings will be provided for SAEs, AEs resulting in study drug 
discontinuation, and deaths. 
Adverse events will also be presented in listings. Time to onset and duration of AEs 
will be included in listings, along with action taken and outcome. 
3.13.2 Clinical Laboratory Evaluation 
The summary statistics (including number, mean, standard deviation, median, 
minimum, and maximum) of all laboratory variables and changes from baseline will 
be calculated for each visit or study assessment by treatment group. For parameters of 
white blood cell counts, neutrophils (absolute count), lymphocytes (absolute count), 


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monocytes (absolute count), hemoglobin, platelets, ALP, ALT, aspartate 
aminotransaminase, gamma glutamyl transferase, total bilirubin, glomerular filtration 
rate, plots of mean/mean changes from baseline with the corresponding standard error 
will be displayed. 
For shift tables, laboratory results will be classified using the common terminology 
criteria for adverse events (CTCAE) Version 5.0. All graded laboratory parameters 
will be summarized separately for hematology and biochemistry. Corresponding shift 
tables comparing baseline to the worst post-baseline grade within the treatment period 
will be provided. 
3.13.3 Vital Signs 
Descriptive statistics for vital signs (weight, temperature, blood pressure, pulse rate, 
and respiratory rate) values and the change from baseline will be presented for each 
scheduled assessment time point.  
3.13.4 ECG 
Descriptive statistics for ECG parameters (i.e., PR interval, QRS interval, and QTcF 
interval) at each time point with triplicate ECGs will be presented for the values and 
change from baseline scores. (QTcF is the QT interval using Fridericia’s correction 
which is calculated by QTcF = QT/(RR(1/3)).)  
The number and percentage of subjects with observed QTcF values that satisfy the 
following conditions will be presented by treatment group and study visit and 
categorized as: ≤ 450 ms; > 450 to 480 ms; > 480 to 500 ms; and > 500 ms. 
The number and percentage of subjects having change from baseline QTcF values 
that satisfy the following conditions will be presented by treatment group and study 
visit and categorized as: ≤ 0 ms; > 0 to ≤ 30 ms; > 30 to ≤ 60 ms; and > 60 ms. 
3.13.5 Echocardiogram 
The results of the echocardiogram (ie, normal, abnormal, and abnormal clinically 
significant) will be summarized by treatment group for each valve (ie, aortic, mitral, 
tricuspid, and pulmonic) at each scheduled assessment timepoint.  
3.13.6 Physical Examination 
Significant abnormal physical exam findings were reported as adverse events.  


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3.14 Interim Analysis 
There is no interim analysis for this study.  
3.15 Mayo Classification Formula 
Table 3 lists the Mayo Classifications (ie, 1A, 1B, 1C, 1D, and 1E) htTKV criteria for 
a given age as presented in Irazabel (2015)2; supplemental Table S2.  
For classes 1A, 1B, 1C, and 1D the upper limits of htTKV are presented, for class 1E, 
the minimal value is presented (ie, as such the values in Table 3 for the 1D and 1E 
columns are equivalent).  
For example, a 40 year old with an htTKV of 650 would have a classification of 1C. 
Figure 1 provides an illustration of the Mayo Classification categories, as copied from 
“Figure 3” of Irazabel (2015)2.  
Table 3: Mayo Classification HtTKV Limits for Age 
Age 
(years) 
1A* 
1B* 
1C* 
1D* 
1E† 
15 
188 
234 
290 
359 
359 
16 
190 
241 
303 
381 
381 
17 
193 
248 
317 
404 
404 
18 
196 
255 
331 
428 
428 
19 
199 
263 
346 
454 
454 
20 
202 
271 
362 
481 
481 
21 
205 
279 
378 
510 
510 
22 
208 
287 
395 
541 
541 
23 
211 
296 
413 
573 
573 
24 
214 
305 
431 
607 
607 
25 
218 
314 
451 
644 
644 
26 
221 
323 
471 
682 
682 
27 
224 
333 
492 
723 
723 
28 
228 
343 
514 
767 
767 
29 
231 
353 
538 
813 
813 
30 
234 
364 
562 
862 
862 
31 
238 
375 
587 
913 
913 
32 
242 
386 
613 
968 
968 
33 
245 
398 
641 
1026 
1026 
34 
249 
410 
670 
1088 
1088 
35 
253 
422 
700 
1153 
1153 
36 
256 
435 
732 
1222 
1222 
37 
260 
448 
765 
1295 
1295 


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38 
264 
461 
799 
1373 
1373 
39 
268 
475 
835 
1456 
1456 
40 
272 
489 
872 
1543 
1543 
41 
276 
504 
912 
1635 
1635 
42 
280 
519 
953 
1734 
1734 
43 
285 
535 
996 
1838 
1838 
44 
289 
551 
1040 
1948 
1948 
45 
293 
567 
1087 
2065 
2065 
46 
298 
584 
1136 
2189 
2189 
47 
302 
602 
1187 
2320 
2320 
48 
307 
620 
1241 
2459 
2459 
49 
311 
638 
1297 
2607 
2607 
50 
316 
658 
1355 
2763 
2763 
51 
321 
677 
1416 
2929 
2929 
52 
325 
698 
1480 
3105 
3105 
53 
330 
719 
1546 
3291 
3291 
54 
335 
740 
1616 
3488 
3488 
55 
340 
762 
1688 
3698 
3698 
56 
345 
785 
1764 
3919 
3919 
57 
350 
809 
1844 
4155 
4155 
58 
356 
833 
1927 
4404 
4404 
59 
361 
858 
2014 
4668 
4668 
60 
366 
884 
2104 
4948 
4948 
61 
372 
910 
2199 
5245 
5245 
62 
378 
938 
2298 
5560 
5560 
63 
383 
966 
2401 
5893 
5893 
64 
389 
995 
2509 
6247 
6247 
65 
395 
1024 
2622 
6622 
6622 
66 
401 
1055 
2740 
7019 
7019 
67 
407 
1087 
2863 
7440 
7440 
68 
413 
1119 
2992 
7887 
7887 
69 
419 
1153 
3127 
8360 
8360 
70 
425 
1188 
3268 
8861 
8861 
71 
432 
1223 
3415 
9393 
9393 
72 
438 
1260 
3568 
9957 
9957 
73 
445 
1298 
3729 
10554 
10554 
74 
451 
1337 
3897 
11187 
11187 
75 
458 
1377 
4072 
11859 
11859 
76 
465 
1418 
4255 
12570 
12570 
77 
472 
1461 
4447 
13324 
13324 
78 
479 
1505 
4647 
14124 
14124 
79 
486 
1550 
4856 
14971 
14971 


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80 
494 
1596 
5075 
15869 
15869 
*Upper limits shown for classes A, B, C and D. 
†Minimal values shown for Class 1E 
 
Figure 1: Illustration of Mayo Classification 
 


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KD019-211                                                                                           Statistical Analysis Plan 
SAP Version 1.0:11-Apr-2022  
 
 
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4 LIST OF TABLES, FIGURES, AND LISTINGS 
The list of TLFs and corresponding shells will be presented in a separate document.  
 
 
 


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KD019-211                                                                                           Statistical Analysis Plan 
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5 REFERENCES 
1. Caroli A, Perico N, Perna A, et al. Effect of longacting somatostatin analogue 
on kidney and cyst growth in autosomal dominant polycystic kidney disease 
(ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet. 
2013;382(9903):1485-1495.  
2. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of 
autosomal dominant polycystic kidney disease: a simple model for selecting 
patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-172. 
doi:10.1681/ASN.2013101138