Clinical trial NCT04042623
Conditions: IgA Nephropathy
Keywords: IgAN AXL inhibitor Berger's Disease Proteinuria Kidney Disease
Sponsor: Aravive, Inc.
Start date: 2019-11-27; Completion date: 2020-08-01
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label Phase 2a clinical study designed to evaluate the safety and efficacy of AVB-S6-500 in patients with IgA Nephropathy (IgAN). Approximately 24 patients will be enrolled. Several dose levels of AVB-S6-500 may be evaluated.

Detailed description:

Arms: arm 1: Patients will receive AVB-S6-500 by intravenous infusion every 2 weeks for total of 6 doses.
Interventions: intervention 1: AVB-S6-500
Intervention descriptions: intervention 1: AVB-S6-500 is experimental drug

Protocol documents:
Prot_000.pdf: 
Aravive, Inc. 
AVB500-IGA-001 
CLINICAL STUDY PROTOCOL 
Protocol v3.0 
An Open-Label Phase 2a Study to Evaluate the Safety and Efficacy 
of AVB-S6-500 in Patients with IgA Nephropathy 
PROTOCOL NUMBER: AVB500-IGA-001 
NCT04042623
Sponsor: 
CmTent Protocol: 
Version and Date: 
Proprietaiy Notice: 
Ethics Statement: 
Confidential 
Aravive, Inc 
3730 Kirby Drive, Ste 1200 
Houston, Texas 77098 
USA 
3.0 
08 Oct 2019 
The concepts and infonnation contained in this document or 
generated dming the study are considered proprietaiy and may not 
be disclosed in whole or in part without the expressed, written 
consent of Aravive, Inc. 
The study will be conducted according to the International 
Conference on Hannonisation tripaitite guideline E6(R2): Good 
Clinical Practice. 
Page 1 
08 Oct 2019 




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Investigator Protocol Agreement Page 
 
I agree to conduct the study as outlined in the protocol entitled “An Open-Label Phase 2a 
Study to Evaluate the Safety and Efficacy of AVB-S6-500 in Patients with IgA Nephropathy” 
in accordance with the guidelines and all applicable government regulations including US 
Title 21 of the Code of Federal Regulations Part 54, the current requirements of ICH E6(R2) 
and local regulations. I have read and understand all sections of the protocol, including 
Section 4, Investigator’s Obligations. 
 
 
 
 
 
 
 
Principal Investigator’s Name 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 


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Table of Contents 
SIGNATURE PAGE .................................................................................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ...........................................................3 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF FIGURES ...................................................................................................................6 
PROTOCOL SYNOPSIS...........................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................12 
1. 
INTRODUCTION .................................................................................................14 
1.1 
IgA Nephropathy Overview and Treatment .................................................14 
1.2 
Study Rationale .............................................................................................14 
1.2.1 
The Role of GAS6-AXL Signaling in IgA Nephropathy ....................14 
1.2.2 
AVB-S6-500 Targets GAS6 ................................................................16 
1.2.3 
AVB-S6-500 Non-Clinical Data ..........................................................17 
1.2.4 
AVB-S6-500 Clinical Data ..................................................................19 
2. 
STUDY OBJECTIVES ..........................................................................................20 
2.1 
Primary Objectives ........................................................................................20 
2.2 
Secondary Objectives ....................................................................................20 
3. 
INVESTIGATIONAL PLAN ................................................................................20 
3.1 
Study Design .................................................................................................20 
3.1.1 
Safety Evaluation for AVB-S6-500 Dosing Regimen .........................21 
3.1.2 
PK Evaluation of AVB-S6-500 Dosing Regimen ...............................22 
3.2 
Selection of Study Population .......................................................................22 
3.2.1 
Inclusion Criteria .................................................................................23 
3.2.2 
Exclusion Criteria ................................................................................23 
3.3 
Prohibited Medications .................................................................................24 
3.4 
Individual AVB-S6-500 Dose Discontinuation Rule ...................................24 
3.5 
Withdrawal of Patients from the Study .........................................................24 
3.5.1 
Reasons for Withdrawal .......................................................................24 
3.5.2 
Handling of Withdrawals .....................................................................25 
3.5.3 
Replacements .......................................................................................25 
3.6 
Early Termination of the Study.....................................................................25 
3.7 
Study Procedures ..........................................................................................26 
3.7.1 
Screening Phase ...................................................................................26 
3.7.2 
Treatment Phase ...................................................................................27 
3.7.2.1 
Treatment Visits ..........................................................................27 
3.7.2.2 
End of Treatment Visit................................................................27 
3.7.3 
Post-Treatment Phase...........................................................................28 
3.7.3.1 
Follow-Up ...................................................................................28 
3.7.4 
Safety Assessments ..............................................................................28 


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3.7.4.1 
Adverse Events ...........................................................................28 
3.7.4.1.1 
Definitions.............................................................................28 
3.7.4.1.2 
Eliciting and Documenting Adverse Events .........................29 
3.7.4.1.3 
Reporting Adverse Events ....................................................30 
3.7.4.1.4 
Reporting Serious Adverse Events .......................................30 
3.7.4.1.5 
Assessment of Severity .........................................................30 
3.7.4.1.6 
Assessment of Causality of SAEs .........................................31 
3.7.4.2 
Electrocardiograms .....................................................................32 
3.7.4.3 
Physical Examinations ................................................................32 
3.7.4.4 
Vital Signs Measurements ..........................................................32 
3.7.4.5 
Laboratory Analyses ...................................................................32 
3.7.4.6 
Anti-drug Antibodies (ADA) Assessment ..................................33 
3.7.4.7 
Pregnancy ....................................................................................33 
3.7.5 
Pharmacokinetic Assessments .............................................................34 
3.7.5.1 
Collection, Handling, and Shipment of Pharmacokinetic, 
Pharmacodynamic, and Anti-drug Antibody Samples ...............35 
3.8 
Treatments.....................................................................................................36 
3.8.1 
Method of Assigning Patients to Treatment Groups ............................36 
3.8.2 
Treatments Administered .....................................................................36 
3.8.3 
Identity of Investigational Product .......................................................36 
3.8.4 
Management of Clinical Supplies ........................................................37 
3.8.4.1 
Study Drug Packaging and Labeling ..........................................37 
3.8.4.2 
Test Article Accountability .........................................................37 
3.8.5 
Blinding................................................................................................37 
3.8.6 
Prior and Concomitant Therapy ...........................................................37 
3.8.6.1 
Medications Prohibited/Restricted in Combination with 
AVB-S6-500 ...............................................................................37 
3.8.7 
Sample Size Calculations .....................................................................37 
3.8.8 
Analysis Sets ........................................................................................38 
3.9 
Statistical Analysis ........................................................................................38 
3.9.1 
Exploratory Efficacy Analyses ............................................................38 
3.9.2 
Pharmacokinetic Analyses ...................................................................39 
3.9.3 
Pharmacodynamic and Anti-drug Antibody Analyses ........................39 
3.9.4 
Safety Analyses ....................................................................................40 
3.9.4.1 
Adverse Events ...........................................................................40 
3.10 
Data Quality Assurance ................................................................................40 
4. 
INVESTIGATOR’S OBLIGATIONS ...................................................................40 
4.1 
Confidentiality ..............................................................................................41 
4.2 
Institutional Review ......................................................................................41 
4.3 
Subject Consent ............................................................................................41 
4.4 
Study Reporting Requirements .....................................................................42 
4.5 
Financial Disclosure and Obligations ...........................................................42 


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4.6 
Investigator Documentation ..........................................................................42 
4.7 
Study Conduct ...............................................................................................43 
4.8 
Data Collection .............................................................................................43 
4.8.1 
Case Report Forms Completion ...........................................................43 
4.9 
Adherence to Protocol...................................................................................43 
4.10 
Reporting Adverse Events ............................................................................44 
4.11 
Investigator’s Final Report ...........................................................................44 
4.12 
Records Retention .........................................................................................44 
4.13 
Publications ...................................................................................................44 
5. 
STUDY MANAGEMENT ....................................................................................44 
5.1 
Monitoring ....................................................................................................44 
5.1.1 
Monitoring of the Study .......................................................................44 
5.1.2 
Inspection of Records ..........................................................................45 
5.2 
Management of Protocol Amendments and Deviations ...............................45 
5.2.1 
Modification of the Protocol ................................................................45 
5.2.2 
Protocol Violations and Deviations .....................................................45 
5.3 
Final Report ..................................................................................................46 
6. 
REFERENCES ......................................................................................................46 
7. 
APPENDICES .......................................................................................................47 
7.1 
Appendix 1: Time and Events Schedule .......................................................47 
 
List of Tables 
Table 1-1: 
AVB-S6-500 Exposures from Preclinical Pharmacology and Toxicology 
Studies Relative to Actual Exposures in FIH Study ..................................19 
Table 1-2: 
AVB-S6-500 PK Parameters in Single Ascending Dose Cohorts 
Calculated using Noncompartmental Analysis (AVB500-HV-001) .........20 
Table 3-1 
Dose Levels of AVB-S6-500 That May be Evaluated ...............................22 
Table 3-2: 
Blood Sample Collection for Pharmacokinetic, Pharmacodynamic, and/or 
ADA Analyses ...........................................................................................35 
Table 3-3: 
Composition of AVB-S6-500 Drug Product in Vials ................................37 
Table 7-1: 
Time and Events Schedule .........................................................................48 
 
List of Figures 
Figure 1-1: 
Correlation of GAS6 Expression with Prognostic Factors ........................15 
Figure 1-2: 
Effects of Proteinuria on Survival from Renal Failure ..............................16 
Figure 3-1 
Study Schema.............................................................................................21 




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Safety: 
Safety assessment will include evaluation of adverse events (AEs), clinical laboratory results, vital sign 
measurements, 12-lead ECG measurements, and physical examinations. AEs will be coded using the 
MedDRA dictionary and concomitant medications using the WHO Drug dictionary.  
Efficacy: 
Efficacy will be assessed primarily by effect on urine protein excretion (UPE), effect on estimated 
glomerular filtration rate (eGFR), and effect on urine albumin/creatinine ratio (uACR).  
Pharmacokinetics (PK) and Pharmacodynamics (PD): 
Blood samples for serum pharmacokinetics (AVB-S6-500) and pharmacodynamics (GAS6) analysis 
will be collected prior to every dose of AVB-S6-500 (within approximately 45 minutes prior to 
dosing), on Day 1 at 1 hr (±30 minutes) post-dose, and at EOT.  
 
STUDY POPULATION: 
Up to approximately 24 patients will be enrolled in this study.  
NUMBER OF SITES: 
Patients will be enrolled at approximately 4 sites in the United States and Ukraine 
CRITERIA FOR INCLUSION AND EXCLUSION 
Inclusion Criteria: 
Subjects who meet all listed inclusion criteria may be eligible for enrollment: 
1. Male or female age 18 years or older 
2. Diagnosis of biopsy-proven IgAN (biopsy to be taken within 1 year of screening) 
3. Proteinuria ≥ 1g to 3 g/24 hr as measured at the 24-hr urine collection  
4. Estimated Glomerular Filtration Rate (eGFR) has been stable (±15%) for at least 3 months 
prior to screening and ≥ 45 mL/min per 1.73 m2 using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula  
5. Patients who have been on a steady dose of ACE inhibitors or ARB for at least 3 months and 
throughout screening and who are not expected to have their dose adjusted during the study are 
allowed on study (patients who are not on ACEi/ARB due to inability to tolerate these 
therapies are also allowed). Patients may be on other anti-hypertension medications in addition 
to ACEi or ARB and these medications should be at a stable dose for at least 3 months prior to 
Screening.)  
6. Systolic blood pressure (BP) ≤ 150 mmHg and diastolic BP ≤ 100 mmHg 
7. If a sexually-active patient, must agree to use a reliable method of birth control from at least 
4 weeks prior to first dose of study drug, during the study and for 1 month following 
completion of therapy. A reliable method of birth control is defined as one of the following: 
oral or injectable contraceptives, intrauterine device, contraceptive implants, tubal ligation, 
hysterectomy, or a double-barrier method (diaphragm with spermicidal foam or jelly, or a 
condom) or vasectomy 
 
Exclusion Criteria: 
Subjects who meet any of the following criteria are not eligible for enrollment: 




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DURATION OF TREATMENT:  
Patients will be treated with a dose of AVB-S6-500, 
 
All patients will undergo an End of Treatment Visit approximately 2 weeks after the 
last dose and a follow up visit approximately 28 days after their last dose of study drug (± 5 days). 
SAFETY ASSESSMENTS: 
Safety assessments will include the monitoring of AEs, clinical laboratory evaluations (hematology, 
and serum chemistry), vital sign measurements (pulse and blood pressure), respiratory rate and body 
temperature, physical examination findings, 12-lead ECG and anti-drug antibodies (ADA).  
STATISTICAL METHODS: 
No formal sample size estimate has been made as the study is an exploratory study that has no 
inferential statistical analysis. However, the number of participating patients in each part of the present 
study is common in early clinical studies and considered sufficient to evaluate to study objectives. 
Safety: 
Adverse event data will be summarized by preferred term and primary system organ class.  
Efficacy: 
This is an exploratory study to understand the impact AVB-S6-500 has on IgAN. The effect of 
AVB-S6-500 may be analyzed on the following, as well as additional endpoints:  
1. Change from baseline (last value in screening) to End of Treatment in 24-hour urine protein 
excretion (UPE) in g/day. 
2. Change from baseline (last value in screening) to End of Treatment in 24-hour urine protein 
excretion (UPE) in g/day in the subset of patients with baseline high proteinuria (defined as 
24-hour UPE ≥ 2 g/day). 
3. Proportion of patients with urinary protein equivalent of < 1 g/24 hours at End of Treatment. 
4. Proportion of patients who had at least a decrease of 0.5 g/day proteinuria from baseline (last 
value during screening) to End of Treatment. 
5. Change from baseline (last value during screening) to End of Treatment in urine 
albumin/creatinine ratios (uACRs). 
6. Change from baseline (last value during screening) to End of Treatment in estimated 
glomerular filtration rate (eGFR). 
 
PK/PD: 
Individual serum AVB-S6-500 concentrations and noncompartmental analysis (NCA) parameters will 
be tabulated and descriptive statistics will be presented for both serum concentrations and resulting 
NCA parameters as appropriate. GAS6 serum levels will be determined as described above and will be 
combined with AVB-S6-500 exposure data (Cmax, Ctrough and AUC) to graphically evaluate possible 
exposure-response relationships over the dose levels administered. 
 
ADA: 
Anti-drug antibody data will be summarized as patients with pre-existing ADA and no increase in titer, 
pre-existing ADA with increase in titer post dose, and patients with negative ADA at baseline and 
positive for ADA during treatment. 
 


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Exploratory: 
Free serum GAS6 levels may also be analyzed in context of any ADA to investigate the potential to 
develop neutralizing antibodies. 
 


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List of Abbreviations and Definition of Terms 
Abbreviation 
Definition  
ACE 
Angiotensin-converting enzyme inhibitors 
ADA 
Anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARB 
Angiotensin-receptor blockers 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AVB 
AVB-S6-500 
AXL 
AXL receptor tyrosine kinase 
BLQ 
Below the limit of quantitation 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic kidney disease -Epidemiology collaboration equation 
CFR 
Code of Federal Regulations 
CL/F 
apparent oral clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRA 
clinical research associate 
CRO 
contract research organization 
CRF 
case report form 
DEC 
Dose Escalation Committee 
DLT 
Dose-limiting toxicity 
ECG 
electrocardiogram 
EOT 
End of treatment 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
fM 
femtomolar  
g 
Gram 
GAS6 
Growth arrested specific protein-6 (PD marker) 
HIV 
human immunodeficiency virus 
Hr 
Hours 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgAN 
Immunoglobulin A nephropathy 
IEC 
independent ethics committee 


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Abbreviation 
Definition  
IRB 
institutional review board 
i.v 
Intravenous 
kg 
Kilogram (s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram (s) 
min 
Minute (s) 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PVG 
pharmacovigilance 
Q2W 
Every two weeks 
SAE 
serious adverse event 
SIR 
standard infusion reactions  
uACR 
urine albumin/creatinine ratio 
ULN 
upper limit of normal 
UPE 
Urine protein electrophoresis  
UTI 
Urinary tract infection 
WHO 
World Health Organization 


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1. Introduction 
1.1 
IgA Nephropathy Overview and Treatment 
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, 
exhibiting a variable clinical and pathological course, which significantly contributes to the 
global burden of chronic kidney disease and end-stage renal disease (Penfold 2018). Patients 
may present at any age, but there is a peak incidence in the second and third decades of life. 
There is approximately a 2:1 male-to-female predominance in North American and Western 
European populations, although the sexes are equally affected among populations in East Asia. 
IgAN is an autoimmune disease where IgA1 with galactose-deficient O-glycans and anti-glycan 
autoantibodies form complexes that deposit in the glomerular mesangium. These immune 
complexes are nephritogenic, contributing directly to glomerular inflammation and mesangial 
proliferation. In almost all IgAN biopsies, mesangial proliferation and prominent IgA 
depositions are observed by light microscopy and immunofluorescence microscopy. 
Approximately 15–20% of patients diagnosed with IgAN will develop end stage renal disease 
within 10 years, and about 25–30% of patients will develop end stage renal disease by 20 years.  
There is no cure for IgA nephropathy and no definite way of knowing what course the disease 
will take. Treatment with a number of medications can slow the progress of the disease and help 
manage signs and symptoms such as high blood pressure, protein in the urine (proteinuria), and 
swelling (edema) in the hands and feet.  
1.2 
Study Rationale 
1.2.1 
The Role of GAS6-AXL Signaling in IgA Nephropathy 
Within the kidney, AXL and GAS6 are expressed in vascular smooth muscle cells (VSMCs), 
glomerular mesangial cells and tubular cells. The basal expression of GAS6/AXL is low in 
normal kidney. However, its expression can be upregulated in several murine models of chronic 
kidney disease including: glomerulonephritis induced by Thy1.1 antibody and nephrotoxic 
nephritis. Patients with chronic kidney disease have elevated plasma GAS6 levels 
(Lee et al. 2012) and Aravive has found that serum GAS6 levels are significantly increased in 
IgAN patients compared to age-matched controls (Study PHARM-012).  
GAS6 is known to play a role in mesangial proliferation (and resulting proteinuria) and fibrosis. 
Renal biopsies demonstrate evidence of GAS6 pathway activation and the GAS6 expression 
correlates to severity of the disease (Figure 1-1). Proteinuria is a known predictor of survival 
from this renal disease (Figure 1-2) and, as such, is a recognized endpoint by FDA for 
development of therapies to treat IgAN. 


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Figure 1-1: 
Correlation of GAS6 Expression with Prognostic Factors 
 
GAS6 stained area in human IgA nephropathy correlated with (A) Oxford mesangial hypercellularity score and 
(B) urine protein excretion. N = 28. Oxford M score, Oxford mesangial hypercellularity score.  
Source: Nagai 2013 
 
















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3.2.1 
Inclusion Criteria 
Eligible patients must meet the following inclusion criteria. Unless otherwise specified the 
criteria below apply to all patients.  
1. Male or female age 18 years or older 
2. Diagnosis of biopsy-proven IgAN (biopsy to be taken within 1 year of screening) 
3. Proteinuria ≥ 1g to 3g/24hr as measured by 24 hr urine collection  
4. Estimated Glomerular Filtration Rate (eGFR) has been stable (±15%) for at least 
3 months prior to screening and ≥ 45 mL/min per 1.73 m2 using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) formula  
5. Patients who have been on a steady dose of ACE inhibitors or ARB for at least 3 months 
and throughout screening and who are not expected to have their dose adjusted during the 
study are allowed on study (patients who are not on ACEi/ARB due to inability to 
tolerate these therapies are also allowed). Patients may be on other anti-hypertension 
medications in addition to ACEi or ARB and these medications should be at a stable dose 
for at least 3 months prior to Screening.) 
6. Systolic BP ≤ 150 mmHg and diastolic BP ≤ 100 mmHg 
7. If a sexually-active patient, must agree to use a reliable method of birth control from at 
least 4 weeks prior to first dose of study drug, during the study and for 1 month following 
completion of therapy. A reliable method of birth control is defined as one of the 
following: oral or injectable contraceptives, intrauterine device, contraceptive implants, 
tubal ligation, hysterectomy, or a double-barrier method (diaphragm with spermicidal 
foam or jelly, or a condom) or vasectomy. 
 
3.2.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study.  
1. Patients with chronic UTIs (defined as ≥ 2 episodes in a 6-month period or ≥ 4 over 
1 year prior to Screening) or taking prophylactic antibiotics to prevent recurrent UTIs 
2. Treatment with systemic immunosuppressive medications (including corticosteroids) 
within 8 weeks of the first dose of the study drug 
3. Rapidly progressing nephropathy defined as falling GFR (≥ 15%) over past 3 months 
prior to screening 
4. Clinical or biological evidence of diabetes mellitus, systemic lupus erythematosus, IgA 
vasculitis (Henoch-Schonlein purpura), secondary IgAN, or other renal disease 
5. Have a hemoglobin < 9.0 g/dL 
6. History or clinical evidence of cirrhosis or liver disease with serum alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x upper limit of normal  
7. Organ transplant recipient (including bone marrow) or a planned transplant during the 
study 


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8. Have a diagnosis of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C 
infection, or positive serology at screening 
9. Recent active infection requiring hospitalization or i.v. treatment within 30 days prior to 
the first dose of study drug  
10. Received transfusion, plasmapheresis or plasma exchange, IV immunoglobulin (IVIg) 
within 90 days prior to screening 
11. Malignancy within the past 5 years. (Those with history of malignancy greater than 
5 years ago should provide evidence of remission or cure.) Exceptions are squamous cell 
carcinoma of skin, basal cell carcinoma of skin, and cervical carcinoma in situ which 
have been excised and are considered cured 
12. Females who are nursing, pregnant, or intending to become pregnant during the time of 
the study, or who have a positive pregnancy test at baseline (if the subject is a female of 
child-bearing potential). A female is considered to be of child-bearing potential unless 
she is permanently sterilized or post-menopausal for at least 12 months with no menses 
and no alternative medical cause  
13. Exposure to an investigational drug or device within 90 days or 5 half-lives (whichever is 
longer) prior to the first dose of study drug 
14. Known sensitivity to any of the products to be administered during dosing 
15. Subject will not be available for follow-up assessment 
16. Subject has any kind of disorder that compromises the ability of the subject to give 
written informed consent and/or to comply with study procedures 
17. Prior exposure to AVB-S6-500 
 
3.3 
Prohibited Medications 
There are no prohibited medications beyond those specified in the inclusion/exclusion criteria. 
AVB-S6-500 is a protein and not expected to have the typical drug interactions involving 
cytochrome P450s. 
3.4 
Individual AVB-S6-500 Dose Discontinuation Rule 
Patients who experience a definitely, probably, or possibly drug-related SAE or a definitely, 
probably, or possibly drug-related clinically significant, nonserious AE, which in the opinion of 
the Investigator warrants discontinuation of participation in the study for that subject’s 
well-being may not be re-dosed with AVB-S6-500. Also, any patient who experiences a DLT 
should not be re-dosed with AVB-S6-500. 
3.5 
Withdrawal of Patients from the Study 
3.5.1 
Reasons for Withdrawal 
All patients have the right to withdraw from the study at any time, for any reason, without 
prejudice. Patients will be discontinued from the study for any of the following reasons: 


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• 
Unacceptable toxicity  
• 
Withdrawal of consent for treatment by subject 
• 
The sponsor terminates the study 
• 
The subject is pregnant 
• 
The Investigator decides it is in the subject’s best interest to discontinue treatment and/or 
participation in the study. Reasons may include the following: 
o The subject is not adherent to the protocol 
• 
A medication is begun that may have the ability to alter responses to study drug: Patients 
who initiate treatment with oral or parenteral corticosteroids, immunosuppressant or 
whose dose antihypertensive therapy is increased or initiated after screening must be 
withdrawn from study.  
 
3.5.2 
Handling of Withdrawals 
If a subject withdraws consent, the investigator should make a reasonable attempt to document 
the specific reason why consent is being withdrawn in the medical record and eCRF. Any subject 
who discontinues from the study early, should be encouraged to still participate in the End of 
Treatment and Follow-Up Visits. 
If possible, before the subject withdraws consent or the subject is withdrawn by the investigator, 
every effort should be made to complete and report the follow-up assessments listed for the End 
of Treatment and Follow-Up Visits, as thoroughly as possible. The investigator should notify the 
sponsor of the subject’s withdrawal within 48 hours. 
If a subject is lost to follow-up and cannot be reached by telephone, a certified letter should be 
sent to the subject (or the subject’s legally authorized representative, if appropriate) requesting 
contact with the investigator. 
At any point, the investigator may discontinue the subject’s study participation at his/her 
discretion and ensure the subject receives appropriate medical care if necessary. The investigator 
may also consult the Medical Monitor. 
3.5.3 
Replacements 
Patients who don’t complete all planned doses of AVB-S6-500 and an End of Treatment Visit 
may be replaced. All subjects will be assigned a unique identifier. 
3.6 
Early Termination of the Study 
The Sponsor reserves the right to terminate the study at any time with appropriate notification. 
Reasons for terminating the study may include but are not limited to the following: 
• 
Potential health hazard to subjects, as indicated by the incidence or severity of AEs in 
this or other studies 
• 
Unsatisfactory subject enrollment 
• 
Inaccurate or incomplete data recording 


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• 
Administrative reasons 
 
In addition, the regulatory agency or the site’s IRB has the authority to stop the study. 
3.7 
Study Procedures 
This study consists of a Screening Phase (Section 3.7.1), a Treatment Phase (Section 3.7.2) 
including an End of Treatment Visit, and a Post-treatment Phase that includes a Follow-Up Visit 
(Section 3.7.3). Patients will receive AVB-S6-500 in an open-label design during the Treatment 
Phase and will undergo procedures and assessments including regular safety and efficacy 
evaluations during the entire conduct of the study.  
The actual sampling times of blood draws for PK/PD/ADA testing will be documented; 
deviations from the suggested sampling times will not be considered protocol violations. 
As with administration of any injectable drug, patients should be monitored for infusion 
reactions during and for up to an hour after administration of AVB-S6-500. General guidance on 
management of infusion reactions is provided from UpToDate clinical database (LaCasce 2018): 
Intravenous infusion reactions may affect any organ system in the body. The most common signs 
and symptoms of standard infusion reactions (SIR) to injectable drugs are: 
• 
Fever and/or shaking chills 
• 
Flushing and/or itching 
• 
Alterations in heart rate and blood pressure 
• 
Dyspnea or chest discomfort 
• 
Back or abdominal pain 
• 
Nausea, vomiting, and/or diarrhea 
• 
Various types of skin rashes 
 
Infusion of AVB-S6-500 should be stopped for any patient experiencing an SIR. The patient 
should be treated symptomatically to resolve the SIR, which could include administration of 
histamine blockers, corticosteroids, antipyretics, or Demerol (for rigors). Patients should not be 
re-challenged with AVB-S6-500 if they experience an infusion reaction. 
3.7.1 
Screening Phase 
After providing consent to participate, patients will undergo a screening visit. Screening 
assessments must occur within 28 days preceding the first dose of study drug for determination 
of subject’s overall eligibility for the study. 
A screen failure log will be maintained by the investigator. 
Screening assessments will include: 
• 
Demography, including sex, date of birth and race 
• 
Height and weight will be recorded 


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• 
Medical history 
• 
Physical examination, excluding rectal and pelvic examinations and breast examinations 
• 
Confirmation of IgAN diagnosis via renal biopsy within 12 months of first dose of study 
drug  
• 
Vital signs: pulse, blood pressure, respiratory rate, and body temperature 
• 
Complete laboratory evaluation, including hematology and serum chemistry 
• 
Review of inclusion/exclusion criteria 
• 
Serum pregnancy test (for all female patients of childbearing potential) 
• 
12-lead ECG 
• 
Collection of independent urine sample for albumin/creatinine ratio analysis 
• 
Patient will be provided materials for 24-hour urine collection (protein) 
• 
Prior medications: all medications taken or received within 14 days prior to the first dose 
of the study drug must be recorded 
• 
Estimated GFR per CKD-EPI formula 
 
The Screening visits will include the assessments shown in the Time and Events Schedule 
(Table 7-1). Hematology and clinical chemistry samples will be collected and analyzed in local 
laboratories. 
3.7.2 
Treatment Phase 
3.7.2.1 
Treatment Visits 
AVB-S6-500 will be administered 
 
 Patients will be treated with a dose of AVB-S6-500 on Day 1 and Q2W thereafter, 
totaling 6 doses. During the Treatment Phase, subject will undergo procedures and assessments 
including regular evaluations for safety and efficacy as described in the Time and Events 
Schedule (Table 7-1). When the 12-lead ECG and blood collection assessments are scheduled for 
the same time point, the ECG should be taken prior to blood collection. Blood samples for 
analysis of AVB-S6-500 concentration, GAS6 (the PD marker), and anti-drug antibodies will be 
collected from patients as outlined in the Time and Events Schedule (Table 7-1). ADA samples 
will be taken at Day 1 and at the Follow Up visit.  
Concomitant medications and AEs will also be collected from the time of first dose of study drug 
through the end of study participation, as indicated in the Time and Events Schedule (Table 7-1).  
3.7.2.2 
End of Treatment Visit 
At the end of treatment or at early withdrawal from treatment or the study, all patients should 
complete an End of Treatment (EOT) Visit, as outlined in the Time and Events Schedule 
(Table 7-1). 
The following assessments will be done at the EOT Visit: 
• 
Physical examination, excluding rectal and pelvic examinations and breast examinations 
• 
Pregnancy Test 


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• 
12 -lead ECG 
• 
Vital signs: pulse, blood pressure, respiratory rate, and body temperature 
• 
Collection of blood samples for PK/PD analysis 
• 
Complete laboratory evaluations, including hematology and chemistry 
• 
Collection of blood samples for GFR evaluation 
• 
Collection of independent urine sample for uACR assessment 
• 
Patient will be provided materials for 24-hour urine collection for evaluation of protein, 
to be completed within the visit window 
• 
Collection of AE/SAE information 
• 
Concomitant medication usage 
 
3.7.3 
Post-Treatment Phase 
3.7.3.1 
Follow-Up  
All patients should complete the follow-up visit as outlined in the Time and Events Schedule 
(Table 7-1).  
The following assessments will be done at the Follow-up Visit: 
• 
Physical examination, excluding rectal and pelvic examinations and breast examinations 
• 
Pregnancy Test 
• 
Vital signs: pulse, blood pressure, respiratory rate, and body temperature 
• 
12 -lead ECG 
• 
Complete laboratory evaluations, including hematology and chemistry 
• 
Concomitant medication usage 
• 
Collection of blood samples for ADA evaluation 
• 
Collection of AE/SAE information 
 
3.7.4 
Safety Assessments 
Safety evaluations will include the monitoring of AEs, 12-lead ECGs, physical examination 
findings, vital signs measurements, clinical laboratory assessments, concomitant medications, 
and pregnancy tests results for females of childbearing potentials.  
Adverse events will be followed by the investigator as specified in Section 3.7.4.1. 
3.7.4.1 
Adverse Events 
3.7.4.1.1 Definitions 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study medication or their clinical significance. 
Adverse Event: An AE is any untoward medical occurrence in a study patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship to study 


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medication. Patients will be instructed to contact the Investigator or Sub-investigator at any time 
after informed consent if any symptoms develop. Medical events occurring after informed 
consent but before the first dose of study drug will not be captured in the safety database, 
however the Investigator will be responsible for ensuring the safety of the subject in these 
instances. Medical events occurring after informed consent but before the first dose of study drug 
may either cause the subject to be ineligible for the study based on inclusion/exclusion 
requirements or will become part of the medical history for those patients who remain eligible to 
continue in the study. Likewise, any medical condition that is present at the time the patient is 
screened but does not deteriorate should be captured on the patient’s medical history but should 
not be reported as an AE; however, if it deteriorates at any time during the study after first dose 
of study drug it should be reported as an AE. 
An AE is defined as any event not present before exposure to study medication or any event 
already present that worsens in either intensity or frequency after exposure to study medication. 
Serious Adverse Event (SAE): An SAE is an event that: 
Results in death 
Is immediately life threatening 
Requires inpatient hospitalization for greater than 24 hours or prolongs existing hospitalization  
Results in persistent or significant disability and/or incapacity, or  
Is a congenital anomaly/birth defect 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one 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. 
Adverse events and SAEs must be reported in detail in the appropriate CRF (electronic) page. 
Adverse events (serious and nonserious) must be followed until the event resolves or is otherwise 
explained, stabilizes, or the patient is stable or lost to follow-up. Information to be collected is 
described in Section 3.7.4.1.3. Adverse events and serious adverse events will be captured from 
the time the patient receives the first dose of study drug through the follow-up visit. 
3.7.4.1.2 Eliciting and Documenting Adverse Events 
At every study visit starting with Day 1, patients will be asked a standard question to elicit 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant medication 
regimens (both prescription and over the counter medications). 




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Severe: These events interrupt a patient’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
A “severe” AE need not be “serious” in nature and a “serious” AE need not, by definition, be 
“severe”. Changes in the severity of an AE should be documented to allow for an assessment of 
the duration of the event at each level of intensity to be performed. 
3.7.4.1.6 Assessment of Causality of SAEs 
Investigator assessment of an SAE’s relationship to study drug will be part of the documentation 
process, as this is necessary to assess whether or not an SAE becomes classified as an expedited 
IND Safety Report. Thus, all SAEs must have a documented causality assessment; however, the 
Investigator’s assessment of causality is not required for nonserious AEs. 
It is the sponsor’s responsibility to assess the causality of an SAE and determine whether it meets 
the criteria for a suspected unexpected serious adverse reaction (SUSAR) requiring regulatory 
reporting responsibility. For investigator assessment of SAE causality, the relationship or 
association of the study drug in causing or contributing to the SAE will be characterized using 
the following classification and criteria: 
Definite: SAEs that, after careful medical evaluation, are considered definitely related to the drug 
treatment, and other conditions (concurrent illness, progression/expression of disease state, or 
concurrent medication reaction) do not appear to explain the event. 
Probable: SAEs that, after careful medical evaluation, are considered with a high degree of 
certainty to be related to the study drug. The following characteristics will apply: 
• 
A reasonable temporal relationship exists between the event and exposure to the study 
drug, and 
• 
The event is a known reaction to the study drug that can be explained by an alternative 
cause commonly occurring in the population or individual, or 
• 
The event is not a known reaction to the study drug but cannot be reasonably explained 
by an alternative cause. 
 
Possible: SAEs that, after careful medical evaluation, do not meet the criteria for a definite or 
probable relationship to the study drug, but for which a connection cannot be ruled out with 
certainty. The following characteristics will apply: 
• 
The event occurs after exposure to the study drug, and 
• 
There is a reasonable temporal relationship to the study drug, but the event is not a 
known reaction to the study drug and could be explained by a commonly occurring 
alternative cause, or 
• 
In the absence of a reasonable temporal relationship, the event cannot be explained by an 
alternative cause. 
 


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Unlikely: SAEs that, after careful medical evaluation, do not meet the criteria for a possible or 
probable relationship to the study drug and for which a connection is unlikely. The following 
characteristics will apply: 
• 
The event does not follow a reasonable temporal sequence from study drug dosing, or 
• 
The event may have been produced by environmental factors, and 
• 
There is no apparent pattern of response to the study drug. 
 
Not related: SAEs in this category will have either of the following characteristics: 
• 
The event occurs before exposure to the study drug, or 
• 
The event does not have a reasonable temporal relationship to study drug and can be 
explained by a commonly occurring alternative cause. 
 
Events classified as definite, probably, or possible will be considered related to drug for 
reporting purposes. 
3.7.4.2 
Electrocardiograms 
For all patients enrolled in the study, a standard 12-lead ECG will be conducted with the patient 
in a supine position at times indicated in the Time and Events Schedule. The investigator or 
designee will be responsible for reviewing the ECG for any abnormalities and to determine the 
clinical significance of the results. These assessments will be recorded on the eCRF. Additional 
assessments can be done at any time if clinically indicated or as per investigator discretion. 
3.7.4.3 
Physical Examinations 
A complete physical examination of all body systems (excluding rectal and pelvic examinations 
and breast examinations) will be performed at Screening visit, at the End-of-Treatment (or Early 
Withdrawal), and Follow-Up visit. A brief physical exam (symptom directed) will be performed 
at Days 1, 15, 29, 43, 57, and 71. Additional assessments can be done at any time if clinically 
indicated or as per investigator discretion. 
3.7.4.4 
Vital Signs Measurements 
Vital sign measurements include temperature, respiratory rate, pulse rate, and systolic and 
diastolic blood pressure and will be collected at times indicated in the Time and Events 
Schedule. When scheduled to occur at the same time point as the collection of clinical laboratory 
blood samples, vital sign measurements should be obtained before blood sample collection if 
possible. For vital sign measurements, patients may be either in a semi-recumbent or seated 
position and measurements will be collected after a 5-minute rest period. Additional assessments 
can be done at any time if clinically indicated or as per investigator discretion. 
3.7.4.5 
Laboratory Analyses 
Clinical laboratory tests will be performed by local laboratories. Blood samples for hematology 
and chemistry will be prepared using standard procedures. All patients will have samples of 


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blood (approximately 16 mL for safety labs and 6 mL for PK/PD/ADA analysis) and urine 
collected at times shown in the Time and Events Schedule.  
The blood samples collected for clinical laboratory assessments per schedule will be used for the 
following tests: 
Hematology: hemoglobin, hematocrit, platelet count, red blood cell count, mean corpuscular 
volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white 
blood cell count with differential 
Serum chemistry: albumin, alkaline phosphatase, ALT, amylase, AST, blood urea nitrogen (or 
urea), calcium (albumin corrected), chloride, creatinine, glucose (Screening only), lactate 
dehydrogenase, lipase, magnesium, phosphorus, potassium, sodium, total bilirubin, total protein, 
thyroid stimulating hormone (Screening only), and uric acid  
Serology: human immunodeficiency virus (HIV), hepatitis B, hepatitis C 
Additional assessments can be done at any time if clinically indicated or as per investigator 
discretion. 
Urine for albumin/creatinine ratio: At least 40 mL urine should be collected from the patient 
24-hour urine collections will be obtained at times shown in the Time and Events Schedule. A 
24-hour urine collection is done by collecting urine in a special container over a full 24-hour 
period. The container must be labelled and kept refrigerated until the urine is returned to the 
clinic. Urine must be returned to the clinic within the next 24 hours following completion of 
collection. 
In addition, female patients of childbearing potential will have a serum pregnancy test at 
screening and urine pregnancy test (or a serum pregnancy test if preferred at the discretion of the 
investigator or if required by local regulations) will be performed at other time points.  
3.7.4.6 
Anti-drug Antibodies (ADA) Assessment 
Each subject will have blood samples (6 mL) collected at the Day 1 prior to dosing and at the 
Follow-Up visit for analysis of the presence of ADA.  
3.7.4.7 
Pregnancy 
Any pregnancy that occurs after the first dose of the study drug or within 30 days of the last dose 
of the study drug must be reported using a Pregnancy Notification Form. To ensure subject 
safety, each pregnancy must be reported to PVG as soon as possible after learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child and reported on the Pregnancy Outcome Form. 
Pregnancy complications and elective terminations for medical reasons must be reported as an 
AE or SAE. Spontaneous abortions must be reported as an SAE. Any subject who becomes 
pregnant will be discontinued from the study. 












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3.9.2 
Pharmacokinetic Analyses 
PK parameters will be calculated using a validated version of PhoenixTM WinNonlin® 7.0 or 
later. Summary tables and/or figures will be generated using a validated version of PhoenixTM 
WinNonlin® 7.0 or later. Tables, listings, and figures will be generated using R v3.3.3 (or 
higher).  
PK parameters for AVB-S6-500 will be calculated from concentration profiles calculated relative 
to the end of AVB-S6-500 IV infusion. The actual PK sampling time will be used in all 
calculations. The actual dose administered, and the actual infusion duration time will be used to 
calculate the PK parameters. No negative actual times will be included in the calculation of PK 
parameters. Blood samples for AVB-S6-500 measurements that were taken prior to the start of 
infusion of the study medication will be assigned to time 0 hours for the calculation of PK 
parameters. Cmax and Cmin values from subsequent doses will also be tabulated and reported. 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. If actual sampling times are not available, 
nominal times may be used. 
Concentration values of AVB-S6-500 that are reported as BLQ will be set to zero for PK and 
statistical analyses. There will be no substitutions made to accommodate missing data points.  
Visual inspection of AVB-S6-500 concentration-time profiles will be performed to determine 
dataset integrity. Patients with observations that are deviating from the mean by ±3 standard 
deviations (SD) and, thus, are different from 99.73% of the rest of the observations for the same 
treatment group, will be reviewed for inclusion/exclusion from the descriptive statistics. If 
deemed necessary, a sensitivity analysis will be performed (i.e., outputs will be generated with 
and without deviating profiles).  
Patients with incomplete dosing information (e.g., missing dosing record) will be reviewed for 
inclusion/exclusion into the PK analysis set to determine the disposition of these patients. 
Nominally, patients who received a dose of AVB-S6-500 with no major protocol deviations and 
with sufficient AVB-S6-500 sample data to assess PK parameters for each individual 
concentration-time profile of AVB-S6-500 will be included in the analysis. 
3.9.3 
Pharmacodynamic and Anti-drug Antibody Analyses 
ADA data will be summarized as patients with pre-existing ADA (based on baseline value) and 
no increase in titer, pre-existing ADA with increase in titer post dose, negative ADA at baseline 
and no ADA during treatment, and patients with negative ADA at baseline and positive for ADA 
during treatment. The circulating concentration of free serum GAS6 will be analyzed and 
described in tabular and graphical formats. Analysis of the serum free GAS6 concentrations in 
the context of ADA may be included to assist with identification of any neutralizing antibody 
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3.9.4 
Safety Analyses 
All safety endpoints will be summarized by treatment group using the safety analysis set. 
Descriptive statistics will be tabulated for both categorical (number of patients, %) and 
continuous (number of patients, mean, standard deviation, minimum, median, and maximum) 
safety variables including, but not limited to AEs, clinical laboratory parameters, ECGs, vital 
sign measurements, and concomitant medications. 
3.9.4.1 
Adverse Events 
Adverse events will be coded using the most updated version of MedDRA. Data will be 
summarized using the preferred term and primary system organ class. The coded events will be 
summarized in subsets of all AEs. All nonserious AEs will be summarized by severity for each 
treatment group. Patients who have discontinued due to an AE or who experienced an SAE will 
be tabulated by treatment group. 
Serious AEs and treatment-related SAEs will be summarized and listed. 
3.10 Data Quality Assurance 
Steps to be taken to ensure the accuracy and reliability of data include the selection of a qualified 
investigator and appropriate study center, review of protocol procedures with the investigator 
and associated personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, preparation, and shipment of blood and plasma 
samples. 
The eCRFs will be provided to the clinical contact and the CRA will review them with site 
personnel. The investigator, or designee, will enter study data required by the protocol into an 
electronic data eCRF system. The clinical research associates will visit each study site, at a 
frequency documented in the monitoring plan, to review eCRF for completeness and accuracy. 
Any discrepancies found between source documents and completed CRF (electronic) will be 
entered as a discrepancy in the EDC system by the clinical research associate. Appropriate study 
site personnel should then address those discrepancies in the EDC system. Uniform procedures 
for CRF (electronic) correction (queries) will be discussed during the study site initiation visits, 
and will be documented in the study operations manual. 
4. Investigator’s Obligations 
The following administrative items are meant to guide the Investigator (Principal Investigator or 
Subinvestigator) in the conduct of the study but may be subject to change based on industry and 
government standard operating procedures (SOPs), working practice documents, or guidelines. 
Changes will be reported to the IRB/IEC but will not result in protocol amendments. 


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4.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be deidentified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient, except as necessary for monitoring and auditing by the Sponsor, its designee, or 
the local regulatory authorities, or ethics committees. 
The Principal Investigator or Subinvestigator and all employees and coworkers involved with 
this study may not disclose or use for any purpose other than performance of the study, any data, 
record, or other unpublished, confidential information disclosed to those individuals for the 
purpose of the study. Prior written agreement from the sponsor or its designee must be obtained 
for the disclosure of any said confidential information to other parties. 
4.2 
Institutional Review 
Federal regulations and the International Conference on Harmonisation (ICH) guidelines require 
that approval be obtained from an IRB/IEC before participation of human patients in research 
studies. Before study onset, the protocol, informed consent form, advertisements to be used for 
the recruitment of study patients and any other written information regarding this study to be 
provided to the patient must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with the ICH harmonised tripartite guideline E6(R2): 
Good Clinical Practice will be maintained by the study site and will be available for review by 
the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title and/or protocol number, and the date 
approval and/or favorable opinion was granted. 
The Principal Investigator or Subinvestigator is responsible for obtaining continued review of the 
clinical research at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
Principal Investigator or Subinvestigator must supply the sponsor or its designee with written 
documentation of continued review of the clinical research. 
4.3 
Subject Consent 
A written informed consent shall be obtained from each patient before the patient enters the 
study or before any unusual or nonroutine procedure that involves risk to the patient is 
performed. An ICF will be provided by the sponsor to investigative sites. If any institution-
specific modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the sponsor and/or its designee, if appropriate before IRB/IEC 
submission. Once reviewed, the consent will be submitted by the Investigator to the IRB/IEC for 
review and approval before the start of the study. If the informed consent form is revised during 
the course of the study, all active participating patients should sign the revised form, if 
applicable, especially if the rights, well-being, and the safety of the patient are impacted by the 
revision. 


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Before enrollment, each prospective subject will be given a full explanation of the study and be 
allowed to read the approved informed consent form. Once the Investigator or designee is 
assured that the patient understands the implications of participating in the study, the subject will 
be asked to give consent to participate in the study by signing the informed consent form. 
The Investigator or designee shall retain the signed original ICFs and provide a copy of the 
signed original to the subject.  
4.4 
Study Reporting Requirements 
By participating in this study, the Principal Investigator or Subinvestigator agrees to submit 
reports of SAEs according to the timeline and method outlined in the protocol. In addition, the 
Principal Investigator or Subinvestigator agrees to submit annual reports to his/her IRB/IEC as 
appropriate. 
4.5 
Financial Disclosure and Obligations 
Principal Investigators or Subinvestigators are required to provide financial disclosure 
information to allow the sponsor to submit the complete and accurate certification or disclosure 
statements required under 21 Code of Federal Regulations (CFR) 54. In addition, the Investigator 
(Principal Investigator or any Subinvestigators) must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year after the completion of the study. 
Neither the sponsor nor CRO is financially responsible for further testing/treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the sponsor nor CRO is financially responsible for further 
treatment of the patient’s disease. 
4.6 
Investigator Documentation 
Before beginning the study, the Principal Investigator will be asked to comply with ICH 
E6(R2) 8.2 and 21 CFR (Parts 50, 54, 56, and 312) by providing essential documents, including 
but not limited to the following: 
• 
An original signed Investigator Protocol Agreement Page of the protocol. 
• 
An IRB/IEC approved informed consent, samples of site advertisements for recruitment 
for this study (if applicable), and any other written information regarding this study that 
is to be provided to the patient. 
• 
IRB/IEC approval. 
• 
Form Food and Drug Administration (FDA) 1572, fully executed, and all updates on a 
new fully executed Form FDA 1572. 
• 
Curriculum vitae for the Principal Investigator and each Subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. They will be signed 
and dated by the Principal Investigators and Subinvestigators at study start-up, indicating 
that they are accurate and current. 
• 
Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 


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Investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
 
4.7 
Study Conduct 
The Principal Investigator agrees that the study will be conducted according to the principles of 
the ICH E6(R2). The Principal Investigator will conduct all aspects of this study in accordance 
with all national, state, and local laws or regulations. 
4.8 
Data Collection 
4.8.1 
Case Report Forms Completion 
Case report forms are provided for each subject in electronic format.  
Electronic data capture (EDC) will be used for this study. The study data will be transcribed by 
study personnel from the source documents onto an eCRF. The electronic file will be considered 
the CRF. Worksheets may be used for the capture of some data to facilitate completion of the 
eCRF. Any such worksheets will become part of the patients’ source documentation. All data 
relating to the study must be recorded in the eCRF approved by the sponsor. Designated site 
personnel must complete eCRFs as soon as possible after a subject visit but preferably within 
approximately 48 hours of completing the subject’s visits, and the forms should be available for 
review at the next scheduled monitoring visit. 
The investigator is responsible for approval of the entered/corrected data.  
All eCRF entries, corrections, and alterations must be made by authorized study site personnel. If 
necessary, queries will be generated in the EDC tool. An authorized member of the 
investigational staff must adjust the eCRF (if applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways: 
1. Site personnel can make corrections in the EDC tool at their own initiative or as a 
response to an auto query (generated by the EDC tool), 
2. The clinical research associate (CRA) can generate a query (field data collection form) 
for resolution by the investigational staff, or 
3. The clinical data manager can generate a query for resolution by the investigational staff 
 
4.9 
Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with the 
ICH E6(R2) guidelines and applicable government regulations. 


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4.10 Reporting Adverse Events 
By participating in this study, the Principal Investigator or Subinvestigator agrees to submit 
reports of SAEs according to the timeline and method outlined in the protocol 
(Section 3.7.4.1.4). In addition, the Principal Investigator or Subinvestigator agrees to submit 
annual reports to his/her IRB/IEC as appropriate.  
4.11 Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform his/her 
institution of study completion; the Investigator/institution should provide the IRB/IEC with a 
summary of the study’s outcome. 
4.12 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study medication. These documents should be 
retained for a longer period, if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the Principal 
Investigator or Subinvestigator/institution as to when these documents no longer need to be 
retained. 
4.13 Publications 
After completion of the study, study data may be considered for reporting at a scientific meeting 
or for publication in a scientific journal. In these cases, the sponsor will be responsible for these 
activities and will work with the Investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The sponsor has final approval authority over all such issues. 
Data are the property of the sponsor and cannot be published without prior authorization from 
the sponsor, but data and publication thereof will not be unduly withheld. 
5. Study Management 
5.1 
Monitoring 
5.1.1 
Monitoring of the Study 
The clinical research associate (CRA), as a representative of the sponsor will visit the Principal 
Investigator or Subinvestigator and study facility at periodic intervals, in addition to maintaining 
necessary telephone and letter contact. The monitor will maintain current personal knowledge of 
the study through observation, review of study records and source documentation, and discussion 
of the conduct of the study with the Principal Investigator or Subinvestigator and study site 
personnel. 


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All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and current standard operating procedures. 
5.1.2 
Inspection of Records 
Principal Investigators or Subinvestigators and institutions involved in the study will permit 
study-related monitoring, audits, IRB/IEC review, and regulatory inspections by providing direct 
access to all study records. In the event of an audit, the Principal Investigator or Subinvestigator 
agrees to allow the sponsor, representatives of the sponsor, the FDA, or other regulatory agency 
access to all study records. 
The Principal Investigator or Subinvestigator should promptly notify the sponsor and CRO of 
any audits scheduled by any regulatory authorities and promptly forward copies of any audit 
reports received to the sponsor. 
5.2 
Management of Protocol Amendments and Deviations 
5.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the patient, must be reviewed and approved by the sponsor or its designee. 
Amendments to the protocol must be submitted in writing to the Principal Investigator’s or 
Subinvestigator’s IRB/IEC for approval before patients are enrolled into an amended protocol. 
5.2.2 
Protocol Violations and Deviations 
The Principal Investigator or Subinvestigator or designee must document and explain in the 
patient’s source documentation any deviation from the approved protocol. The Principal 
Investigator or Subinvestigator may implement a deviation from, or a change of the protocol to 
eliminate an immediate hazard to study patients without prior IRB/IEC approval. As soon as 
possible after such an occurrence, the implemented deviation or change, the reasons for it, and 
any proposed protocol amendments should be submitted to the IRB/IEC for review and approval, 
to the sponsor for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the sponsor and the IRB/IEC and agreed to by the 
Principal Investigator or Subinvestigator. Deviations usually have an impact on individual 
patients or a small group of patients and do not involve inclusion/exclusion or primary endpoint 
criteria. A protocol violation occurs when there is nonadherence to the protocol that results in a 
significant, additional risk to the patient, when the patient or Principal Investigator or 
Subinvestigator has failed to adhere to significant protocol requirements (e.g. inclusion/exclusion 
criteria) and the patient was enrolled without prior sponsor approval, or when there is 
nonadherence to FDA regulations and/or ICH E6(R2) guidelines. 
Protocol violations and deviations will be documented by the clinical research associate 
throughout the course of monitoring visits. Investigators should notify their IRB/IEC of all 
protocol violations and deviations in a timely manner. 


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5.3 
Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study report is prepared and provided to the regulatory agencies as required by the 
applicable regulatory requirements. The sponsor will also ensure that the clinical study report in 
marketing applications meet the standards of the harmonised tripartite guideline E3: Structure 
and Content of Clinical Study Reports. 
6. References 
Dirks N. and Meibohm B.(2010) Population of Therapeutic Monoclonal Antibodies. 49 (10) 
633-659. 
LaCasce A., Castells M., Burstein H., et al. (2018) Infusion-related reactions to therapeutic 
monoclonal antibodies used for cancer therapy. UpToDate. 
Lee I. J., Hilliard, B., Swami, A., Madara, J.C., Rao, S., et al. (2012). Growth arrest-specific gene 
6 (Gas6) levels are elevated in patients with chronic renal failure. Nephrol. Dial. Transplant. 27, 
4166–72. 
Nagai K., Miyosh M., Kake T., et al. (2013) Dual Involvement of Growth Arrest-Specific Gene 6 
in the Early Phase of Human IgA Nephropathy. PloS One 8 (6), e66759. 
Penfold R.S, Prendecki M., McAdoo S., Tam F.W.K. (2018). Primary IgA Nephropathy: Current 
Challenges and Future Prospects. International Journal of Nephrology and Renovascular 
Disease/ 11, 137-148 
Reich H. N., et al., (2007). Remission of Proteinuria Improves Prognosis in IgA Nephropathy. J 
Am Soc Nephrol 18, 3177–83. 
Rojko J.L., et al (2014). Formation, Clearance, Deposition, Pathogenicity, and Identification of 
Biopharmaceutical-related Immune Complexes: Review and Case StudiesToxicologic Pathology, 
42: 725-764 
Yanagita M, Ishimoto Y, et al., (2002) Essential role of Gas6 for Glomerular Injury in 
Nephrotoxic Nephritis, J. Clin. Invest., 110:239-246. 
Zhen, Y., Lee, I.J., Finkelman, F.D., Shao, W.H. (2018). Targeted inhibition of Axl receptor 
tyrosine kinase ameliorates anti-GBM induced lupus-like nephritis. Journal of Autoimmunity 93, 
37–44. 


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7. Appendices 
7.1 
Appendix 1: 
Time and Events Schedule 
 







SAP_001.pdf: 
Aravive, Inc. 
AVB500-IGA-001 
STATISTICAL ANALYSIS PLAN 
For
An Open-Label Phase 2a Study to Evaluate the Safety and Efficacy 
of AVB-S6-500 in Patients with IgA Nephropathy 
PROTOCOL NUMBER: AVB500-IGA-001 
NCT04042623
Sponsor: 
Document Date:
Confidential 
Aravive, Inc 
3730 Kirby Drive, Ste 1200 
Houston, Texas 77098 
USA 
20 October 2021
Page 1 
20 October 2021 
Aravive, Inc. certifies that Statistical Analysis Plan was not drafted, since the study was terminated after 
only one patient was enrolled in the study AVB500-IGA-001. This subject received a single dose of the 
study drug and did not complete the study. No outcome measures were analyzed and there are no plans to 
conducted any analyses in the future.