An Open Label Phase 1 Study to Compare the Safety and Tolerability of the AKST1210 Column at Different Blood-Flow Rates in Patients With End-Stage Renal Disease (ESRD) Undergoing Hemodialysis (HD)
Phase: NA
Conditions: End-Stage Renal Disease
Sponsor: Alkahest, Inc.

 
 
CONFIDENTIAL STATEMENT 
The information contained in this document and all information provided as related to this clinical study are the 
confidential and proprietary information of the Sponsor and except as may be required by federal, state, or local 
laws or regulations may not be disclosed to others without prior written permission of the Sponsor. The principal 
investigator may, however, disclose such information to supervised individuals working on the clinical study, 
provided such individuals agree to maintain the confidentiality of such information. 
 
AN OPEN LABEL PHASE 1 STUDY TO COMPARE THE SAFETY AND 
TOLERABILITY OF THE 
 COLUMN AT                                                     
DIFFERENT BLOOD-FLOW RATES IN PATIENTS WITH                                                  
END-STAGE RENAL DISEASE UNDERGOING HEMODIALYSIS  
Protocol Number: 
AKST1210-101 
Clinical Phase: 
1 
Sponsor: 
Alkahest, Inc. 
125 Shoreway Road, Suite D 
San Carlos, CA 94070 
Study Agent: 
 β2 microglobulin (b2M) apheresis column (also 
known as AKST1210)  
Indications: 
End-stage renal disease with cognitive impairment 
 
in patients on hemodialysis 
Authorized Representative: 
  
 
 
 
 
Version Number: 
2.1 
Version Date: 
13MAY2021 
Replaces Version(s): 
2.0, 12APR2021 
NCT: NCT04985383

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 2 of 80 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
LIST OF DEFINITIONS .................................................................................................................8 
PROTOCOL APPROVAL PAGE ...................................................................................................9 
STATEMENT OF COMPLIANCE ...............................................................................................10 
PROTOCOL SUMMARY .............................................................................................................11 
SCHEMATIC OF STUDY DESIGN ............................................................................................14 
1. 
KEY ROLES ........................................................................................................................15 
1.1. 
Authorized Representative (Signatory) / Responsible Party .............................................15 
1.2. 
Study Organization ............................................................................................................15 
2. 
INTRODUCTION ................................................................................................................16 
 
 
 
 
 
 
 
 
3. 
OBJECTIVES AND PURPOSE ..........................................................................................22 
4. 
STUDY DESIGN AND ENDPOINTS ................................................................................23 
4.1. 
Description of the Study Design ........................................................................................23 
4.2. 
Study Endpoints .................................................................................................................24 
4.2.1. 
Primary Endpoints .......................................................................................................24 
4.2.2. 
Secondary Endpoints ...................................................................................................24 
5. 
STUDY ENROLLMENT AND WITHDRAWAL ..............................................................25 
5.1. 
Inclusion Criteria ...............................................................................................................25 
5.2. 
Exclusion Criteria ..............................................................................................................25 
5.3. 
Strategies for Recruitment and Retention ..........................................................................26 
5.4. 
Subject Withdrawal/Discontinuation .................................................................................27 
5.4.1. 
Reasons for Withdrawal/Discontinuation ....................................................................27 
5.4.2. 
Handling of Participant Withdrawals/Discontinuation ................................................27 
5.5. 
Premature Termination or Suspension of Study ................................................................28 
6. 
STUDY DEVICE .................................................................................................................29 
6.1. 
Study Device Description ..................................................................................................29 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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6.1.2. 
Description, Appearance, Packaging, and Labeling ....................................................29 
6.1.3. 
Product Storage ............................................................................................................31 
6.1.4. 
Preparation ...................................................................................................................31 
6.1.5. 
Column Size Escalation and Administration ...............................................................31 
6.1.6. 
Duration of Therapy .....................................................................................................31 
6.2. 
Study Device Accountability .............................................................................................32 
7. 
STUDY PROCEDURES AND SCHEDULE ......................................................................33 
7.1. 
Study Procedures/Evaluations ...........................................................................................33 
7.1.1. 
Study Specific Procedures ...........................................................................................33 
7.2. 
Laboratory Procedures/Evaluations ...................................................................................36 
7.3. 
Study Schedule...................................................................................................................37 
7.3.1. 
Screening/Run-in .........................................................................................................37 
7.3.2. 
Treatment .....................................................................................................................37 
7.3.3. 
End of Treatment/End of Study Visits .........................................................................37 
7.3.4. 
Early Withdrawal .........................................................................................................37 
7.4. 
Concomitant Medications ..................................................................................................37 
7.5. 
Prohibited Medications, Treatments, and Procedures........................................................37 
8. 
ASSESSMENT OF SAFETY ..............................................................................................38 
8.1. 
Specification of Safety Parameters ....................................................................................38 
8.1.1. 
Definition of Adverse Event, Procedure-Related Adverse Event, and Adverse 
Device Effect ...............................................................................................................38 
8.1.2. 
Definition of Serious Adverse Event and Serious Adverse Device Effect ..................38 
8.2. 
Classification of An Adverse Event ...................................................................................39 
8.2.1. 
Severity of Event..........................................................................................................39 
8.2.2. 
Relationship to Study Device.......................................................................................39 
8.2.3. 
Expectedness of Adverse Device Effects ....................................................................40 
8.3. 
Time Period/Frequency for Event Assessment/Follow-up ................................................40 
8.3.1. 
Post-Study Safety Assessment .....................................................................................40 
8.4. 
Reporting Procedures .........................................................................................................41 
8.4.1. 
Adverse Event Reporting .............................................................................................41 
8.4.2. 
Serious and Unanticipated Adverse Events/Effects Reporting ....................................41 
8.4.3. 
Reporting of Pregnancy ...............................................................................................43 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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8.5. 
Study Halting Rules ...........................................................................................................43 
8.6. 
Safety Oversight.................................................................................................................44 
9. 
CLINICAL MONITORING ................................................................................................45 
10. 
STATISTICAL CONSIDERATIONS .................................................................................46 
10.1. Statistical Design Model and Analytical Plans ..................................................................46 
10.2. Statistical Hypotheses ........................................................................................................46 
10.3. Analysis Datasets ...............................................................................................................46 
10.4. Description of Statistical Methods .....................................................................................47 
10.4.1. 
General Approach ........................................................................................................47 
10.4.2. 
Analysis of the Primary Endpoint ................................................................................47 
10.4.3. 
Analysis of the Secondary Endpoints ..........................................................................47 
10.4.4. 
Adherence and Retention Analyses .............................................................................48 
10.5. Sample Size ........................................................................................................................48 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .............49 
12. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................50 
12.1. Ethical Standard .................................................................................................................50 
12.2. Institutional Review Board ................................................................................................50 
12.3. Informed Consent Process .................................................................................................50 
12.3.1. 
Consent Forms .............................................................................................................50 
12.3.2. 
Consent Procedures and Documentation .....................................................................50 
12.4. Participant and Data Confidentiality ..................................................................................51 
12.5. Future Use of Stored Specimens ........................................................................................52 
13. 
DATA HANDLING AND RECORD KEEPING ................................................................53 
13.1. Data Collection and Management Responsibilities ...........................................................53 
13.1.1. 
Investigator Responsibilities ........................................................................................53 
13.1.2. 
Study Files ...................................................................................................................54 
13.2. Study Records Retention....................................................................................................54 
13.3. Protocol Deviations ............................................................................................................55 
13.4. Publication and Data Sharing Policy .................................................................................56 
14. 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY .......................58 
15. 
SCHEDULE OF EVENTS ...................................................................................................59 
15.1. Screening (Weeks -5 to -2)/Run-in (Week -1)/Treatment Period (Weeks 1 and 2) ..........59 
15.2. Treatment Period (Weeks 3 to 6) /End of Study (Week 7) ................................................60 
15.3. Schedule of Laboratory Tests ............................................................................................61 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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16. 
REFERENCES .....................................................................................................................64 
17. 
APPENDICES ......................................................................................................................66 
17.1. Escalation, De-escalation, and Discontinuation Rules for Treatment with the 
 Column .............................................................................................................67 
17.1.1. 
Escalation Rules ...........................................................................................................67 
17.1.2. 
De-escalation Rules .....................................................................................................69 
17.1.3. 
Discontinuation Rules ..................................................................................................70 
18. 
REVISION HISTORY .........................................................................................................71 
18.1. Summary of Changes .........................................................................................................71 
 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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LIST OF ABBREVIATIONS 
ACT 
Activated clotting time 
ACTH 
Adrenocorticotropic hormone 
ADE 
Adverse device effect 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
b2M  
Beta 2-microglobulin, β2-microglobulin 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CH50 
Total hemolytic complement 
CK 
Creatine kinase 
CMP 
Clinical Monitoring Plan 
HCO3 
Bicarbonate 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
DBP 
Diastolic blood pressure 
 
 
ECG 
Electrocardiogram 
ENT 
Ear, nose, throat 
EOS 
End of Study 
EOT 
End of Treatment 
ESA 
Erythropoiesis-stimulating agents  
ESRD 
End-stage renal disease 
ESRD-CI 
End-stage renal disease with cognitive impairment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C antibody 
HD 
Hemodialysis 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HIV Ab 
Human immunodeficiency virus antibody 
ICH 
International Conference on Harmonisation 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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ICH E6 R2 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use Guidance for Industry, Good Clinical Practice: Consolidated Guidance, 
Revision 2 
IDE 
Investigational Device Exemption 
IDH 
Intradialytic hypotension/hypotensive event 
IGFBP1 
Insulin-like growth factor protein 1 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
Kt/V 
Fractional urea clearance 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
PRAE 
Procedure-related adverse event 
PT 
Preferred Term; prothrombin time 
PT/INR 
Prothrombin time/international normalized ratio 
PVG 
Pharmacovigilance 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia's correction formula 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical Analytical Plan 
SBP 
Systolic blood pressure 
SC5b-9 
Soluble membrane attack complex 
SD 
Standard deviation 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid-stimulating hormone 
UADE 
Unanticipated adverse device effect 
UFR 
Ultrafiltration rate 
URR 
Urea reduction ratio 
US 
United States 
WOCBP 
Women of childbearing potential 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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LIST OF DEFINITIONS 
 
Intradialytic 
hypotension/hypotensive 
event (IDH) 
A systolic blood pressure (SBP) < 90 mmHg that occurs during 
hemodialysis and is confirmed by repeat measurement. 
Expected IDH Rate 
The expected number of occurrences of IDH per weekly treatment period 
derived from a subject’s Historical IDH rate (see row below and also 
Appendix 17.1). The expected IDH Rate is compared with the actual IDH 
rate and used to assess escalation, de-escalation, and discontinuation. 
 
Historical IDH Rate 
The number of occurrences of IDH as documented in a subject’s medical 
record during a recent 8-week period prior to the run-in period. Subjects 
with 7 or more IDH events during this 8-week interval will be excluded. 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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PROTOCOL APPROVAL PAGE 
 
Study Title: 
An Open Label Phase 1 Study to Compare the Safety and 
Tolerability of the 
 Column at Different                    
Blood-Flow Rates in Patients with End-Stage Renal Disease 
Undergoing Hemodialysis 
Protocol Number: 
AKST1210-101 
Version/Date:  
V2.1, 13MAY2021 
Sponsor Name and 
Address: 
Alkahest, Inc. 
125 Shoreway Road, Suite D 
San Carlos, CA 94070 
I, the undersigned, have read and approve this protocol and agree on its content. It is confirmed 
that the information and guidance given in this protocol complies with scientific principles, the 
guidelines of Good Clinical Practice, the Declaration of Helsinki in the latest relevant version, 
and applicable legal and regulatory requirements. 
 
 
 
Approved by: 
 
  
 
 
 
 
 
  
 
 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
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STATEMENT OF COMPLIANCE 
Protocol Title: 
An Open Label Phase 1 Study to Compare the Safety and Tolerablity 
of the 
 Column at Different Blood-Flow Rates in Patients 
with End-Stage Renal Disease Undergoing Hemodialysis 
Protocol Number: 
AKST1210-101 
Version/Date: 
V2.1, 13MAY2021 
By my signature, I: 
• 
Confirm that my staff and I have carefully read and understand this protocol or protocol 
amendment, have received the Investigator Brochure, and are thoroughly familiar with the 
appropriate use of the investigational agent described herein. 
• 
Agree to comply with the conduct and terms of the study specified herein and with any other 
study conduct procedures provided by the Sponsor, Alkahest, Inc., or their designee. 
• 
Agree to assume responsibility for the proper conduct of the study at this site, including 
complying with current relevant versions of the United States (US) Food and Drug 
Administration (FDA) regulations, International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines, Declaration of Helsinki, and all applicable rules, regulations, and federal, state, 
and local laws relating to the conduct of clinical studies and the protection of human subjects. 
• 
Agree not to implement deviations from or changes to the protocol or protocol amendments 
without agreement from the Sponsor and prior submission to and written approval (where 
required) from the Institutional Review Board (IRB) except when necessary to eliminate an 
immediate hazard to the subjects, or for administrative aspects of the study (where permitted 
by all applicable regulatory requirements). 
• 
Agree to onsite monitoring of all source documents by Alkahest, Inc. or designee and to 
onsite inspection of source documents by appropriate regulatory authorities, including but not 
limited to the FDA, local governing regulatory bodies, and IRB inspectors. 
 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
 
 
Print Name 
 
 
 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
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PROTOCOL SUMMARY 
 
Title: 
An Open Label Phase 1 Study to Compare the Safety and Tolerablity of the 
 Column at Different Blood-Flow Rates in Patients with End-Stage 
Renal Disease Undergoing Hemodialysis 
Objective: 
The objective of this study is to evaluate the safety and tolerability of the 
 column at blood-flow rates greater than 250 mL/min in subjects with 
end-stage renal disease (ESRD) undergoing hemodialysis (HD). The study will 
assess the safety, tolerability, and impact on HD parameters when the 
 
column is used at a blood-flow of up to 450 mL/min. 
Précis:  
This is an open-label study in 12 to 15 subjects between 40 and 75 years of age 
with ESRD on HD. The purpose of the study is to compare the safety and 
tolerability of two blood-flow rates when the b2M 
 column is used 
during HD. The 
 column was originally developed for blood-flow 
rates of 250 mL/min, and in this study it will be evaluated at both 250 mL/min 
and up to 450 mL/min. 
After screening (Visit 1), subjects will undergo HD at a lower blood-flow rate 
(250 mL/min) for a 1-week run-in period to determine the HD duration required 
to achieve adequate fractional urea clearance (Kt/V) (> 1.2). Daugirdas’ formula 
will be used to calculate Kt/V (Daugirdas 1993, Daugirdas 1995, Daugirdas and 
Schneditz 1995).  
 
The 
 column comes in 3 sizes (S-15, S-25, S-35) and each size will be 
tested at blood-flow rates of 250 mL/min and up to 450 mL/min as tolerated (see 
Appendix 17.1: Escalation, De-escalation, and Discontinuation Rules for 
Treatment with the 
 Column). Each column-size and blood-flow rate 
combination will be evaluated during 3 consecutive HD sessions before 
proceeding with the next combination, as follows: 
• 
Week -1 (Visits 2-4) 
HD run-in period (no column) at 250 mL/min to 
determine Kt/V 
• 
Week 1 (Visits 5-7) 
 column S-15 at 250 mL/min 
• 
Week 2 (Visits 8-10) 
 column S-15 at up to 450 mL/min 
• 
Week 3 (Visits 11-13) 
 column S-25 at 250 mL/min 
• 
Week 4 (Visits 14-16)  
 column S-25 at up to 450 mL/min 
• 
Week 5 (Visits 17-19) 
 column S-35 at 250 mL/min 
• 
Week 6 (Visits 20-22) 
 column S-35 at up to 450 mL/min 
• 
Week 7 (Visit 23) 
End of study (EOS), no column, HD at patient’s 
standard rate 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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The first treatment with the 
 column S-15 (150 mL) will occur mid-
week (e.g., on Wednesday for subjects on a Monday/Wednesday/Friday 
schedule and on Thursday for subjects on a Tuesday/Thursday/Saturday 
schedule). 
The escalation to the subsequent column-size and flow-rate combination will 
occur mid-week (e.g., on Wednesday for subjects on a 
Monday/Wednesday/Friday schedule and on Thursday for subjects on a 
Tuesday/Thursday/Saturday schedule).  
The duration of each HD treatment will be adjusted to ensure adequate Kt/V 
with a reduced flow rate (approximately 4-6 hours at 250 mL/min, 3-4 hours at 
up to 450 mL/min). During each week determination of HD adequacy will 
include KtV > 1.2 (calculated from measurements of blood urea) and urea 
reduction ratio (URR) (weekly URR > 65%). 
The most important known potential risk for use of the 
 column is an 
increased risk of IDH. Risk mitigations may include prophylactic administration 
of saline, supine positioning/lower limb elevation, avoidance of fasting before 
HD, avoidance of food intake during HD, use of cooled dialysate, education 
about the importance of avoiding excessive fluid gain between HD sessions 
(interdialytic weight gain), and avoiding the use of ultrafiltration rates (UFR) 
above 13 mL/kg/h. Concomitant medications, especially medications related to 
or affecting blood pressure (BP), should remain stable while on study and 
receiving HD with the 
 column. 
 
The occurrence of IDH events during each week, as outlined in Appendix 17.1: 
Escalation, De-escalation, and Discontinuation Rules for Treatment with the 
 Column, will be one factor used to determine column size/blood-flow 
rate escalation/de-escalation as well as discontinuation from the study. There is 
also a possibility that the blood-flow rate of 450 mL/min cannot be attained due 
to factors related to the dialysis circuit or other technical issues. If the blood-
flow rate of 450 mL/min cannot be attained, it can be adjusted down to enable 
continued dialysis at a blood-flow rate as high as possible. The reason(s) for the 
inability to attain a blood-flow rate of 450 mL/min must be documented.  
Endpoints:               
 
Primary Endpoints: 
• 
Safety and tolerability of each column size at each blood-flow rate. 
o Evaluation of safety and tolerability will include assessment of 
the rate and severity of all adverse events (AEs), with analyses of 
adverse device effects (ADEs), treatment-emergent AEs 
(TEAEs), number of IDH events, and changes in total and free 
hemoglobin (Hgb). 
o Tolerability will be assessed by the proportion of subjects who 
can escalate to and tolerate each column size and blood-flow-rate 
combination. 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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Secondary Endpoints 
• 
Weekly Kt/V and URR. 
• 
Total fluid balance for each column-size flow-rate combination. 
• 
Proportion of subjects who are able to achieve the dry weight goal during 
the allotted HD duration for each column size and flow rate combination. 
• 
Change in plasma b2M concentrations (before and after HD) and 
contribution of the 
 column to b2M removal at each column 
size and blood-flow rate. 
• 
Number of occurrences of visible thrombosis (clotting) in the 
 
column, dialyzer, and/or tubing. 
• 
Changes in plasma levels of complement factors, including total 
hemolytic complement (CH50), soluble membrane attack complex 
(SC5b-9), and C5a. 
• 
Changes in plasma levels of other proteins, including insulin, 
adrenocorticotropic hormone (ACTH), insulin-like growth-factor protein 
1 (IGFBP1), etc.  
Population: 
Approximately 15 subjects between 40 and 75 years of age with ESRD will be 
enrolled. Assuming a drop-out rate of 20% (unrelated to safety) enrollment will 
yield approximately 12 evaluable subjects. Ultimately, the clinical conditions to 
be treated are patients with ESRD on maintenance HD who have a diagnosis of 
 ESRD with cognitive impairment (ESRD-
CI). 
Phase: 
1 
Number of Sites: 
Up to 4, US only 
Description of 
Study Device: 
The 
 column (also known as AKST1210) is an adsorbent column 
containing porous, spherical cellulose beads with covalently linked hexadecyl 
groups as ligands. The 
 column adsorbs b2M by the combined use of 
hydrophobic interaction and the appropriate pore size on cellulose beads. The 
 column selectively binds b2M (11.8 kDa), with a positive correlation 
occurring between the amount of the b2M adsorbed and the pretreatment serum 
b2M concentration in both in vitro and clinical uses, while keeping essential 
proteins such as albumin remaining in blood circulation. 
Study Duration: 
Approximately 7 months 
Subject 
Participation: 
Approximately 12 weeks (up to 4 weeks for screening and 8 weeks on study, 
inclusive of the 1-week run-in period) 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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SCHEMATIC OF STUDY DESIGN 
 
 
For information regarding rules for de-escalation and discontinuation see Appendix 17.1. 
  
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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1. 
KEY ROLES 
1.1. 
Authorized Representative (Signatory) / Responsible Party 
 
 
 
1.2. 
Study Organization 
The name and contact information of the responsible party and individuals involved with the 
study (e.g., investigator(s), Sponsor’s medical expert and study monitor, Sponsor’s 
representative(s), laboratories, steering committees, and oversight committees (including IRBs, 
as applicable) will be maintained by the Sponsor, or their designee, and provided to the 
investigator. 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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2. 
INTRODUCTION 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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2.2. 
Potential Risks and Benefits 
 
 
 
 
 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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Page 22 of 80 
3. 
OBJECTIVES AND PURPOSE 
The objective of this study is to explore the safety and tolerability of the 
 column at 
blood-flow rates greater than 250 mL/min in subjects with ESRD undergoing HD. The proposed 
study will assess the safety, tolerability, and impact on HD parameters when the 
 
column is used at a blood-flow rates of up to 450 mL/min. Secondary objectives include 
exploration of the performance of the column by measuring b2M concentrations before and after 
HD as well as the potential impact on other plasma proteins, including complement factors. 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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4. 
STUDY DESIGN AND ENDPOINTS 
4.1. 
Description of the Study Design 
This is an open-label study in subjects between 40 and 75 years of age who have ESRD requiring 
HD. Assuming a drop-out rate (unrelated to safety and tolerability) of 20%, approximately 15 
subjects will be enrolled to obtain 12 evaluable subjects. The 
 column will be 
connected in series before (upstream) of the dialysis cartridge for the duration of each HD 
session. Only single-use dialyzers will be used during the study. 
After screening (Visit 1), subjects will undergo HD at a lower blood-flow rate (250 mL/min) for 
a 1-week run-in period to determine the HD duration required to achieve adequate Kt/V (> 1.2). 
Daugirdas’ formula will be used to calculate Kt/V (Daugirdas 1993, Daugirdas 1995, Daugirdas 
and Schneditz 1995). 
The 
 column size will be increased from S-15 (150 mL) to S-25 (250 mL) to S-35 
(350 mL), as tolerated, and blood-flow rates will be evaluated at 250 mL/min and up to 
450 mL/min as tolerated (see Appendix 17.1: Escalation, De-escalation, and Discontinuation 
Rules for Treatment with the 
 Column). Each column-size and blood-flow rate 
combination will be evaluated during 3 consecutive HD sessions (1 week) before proceeding 
with the next combination, as follows (and as shown in the Schematic of Study Design): 
 
• 
Week -1 (Visits 2-4) 
HD run-in period (no column) at 250 mL/min 
to determine Kt/V 
• 
Week 1 (Visits 5-7) 
 column S-15 at 250 mL/min 
• 
Week 2 (Visits 8-10) 
 column S-15 at up to 450 mL/min 
• 
Week 3 (Visits 11-13) 
 column S-25 at 250 mL/min 
• 
Week 4 (Visits 14-16)  
 column S-25 at up to 450 mL/min 
• 
Week 5 (Visits 17-19) 
 column S-35 at 250 mL/min 
• 
Week 6 (Visits 20-22) 
 column S-35 at up to 450 mL/min 
• 
Week 7 (Visit 23) 
EOS, no column, HD at patient’s standard rate 
 
The first treatment with the 
 column S-15 (150 mL) will occur mid-week (e.g., on 
Wednesday for subjects on a Monday/Wednesday/Friday schedule and on Thursday for subjects 
on a Tuesday/Thursday/Saturday schedule). 
The escalation to the subsequent column-size and flow-rate combination will occur mid-week 
(e.g., on Wednesday for subjects on a Monday/Wednesday/Friday schedule and on Thursday for 
subjects on a Tuesday/Thursday/Saturday schedule).  

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The duration of HD time will be adjusted for flow rate (approximately 4-6 hours for 
250 mL/min, 3-4 hours for up to 450 mL/min). During each HD session, measurements of HD 
effectiveness will include Kt/V > 1.2 (calculated from measurements of blood urea) and URR 
(weekly URR > 65%). 
The incidence of IDH events, as defined in Appendix 17.1: Escalation, De-escalation, and 
Discontinuation Rules for Treatment with the 
 Column, will be one factor used to 
determine column size/blood-flow rate escalation/de-escalation as well as discontinuation from 
the study. 
The planned duration of subject participation is approximately 12 weeks (up to 4 weeks for 
screening and 8 weeks on-study, which is inclusive of the 1-week run-in period). 
4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoints 
 
• 
Safety and tolerability of each column size and each blood-flow rate. 
o Evaluation of safety and tolerability will include assessment of the rate and 
severity of all AEs, with analyses of ADEs, TEAEs, number of IDH events, and 
changes in total and free Hgb. 
o Tolerability will be assessed by the proportion of subjects who can escalate to and 
tolerate each column size and blood-flow-rate combination. 
 
4.2.2. 
Secondary Endpoints 
 
• 
Weekly Kt/V and URR. 
• 
Total fluid balance for each column-size flow-rate combination. 
• 
Proportion of subjects who are able to achieve the dry weight goal during the allotted HD 
duration for each column size and flow rate combination. 
• 
Change in plasma b2M concentrations (before and after HD) and contribution of the 
 column to b2M removal at each column size and blood-flow rate. 
• 
Number of occurrences of visible thrombosis (clotting) in the 
 column, 
dialyzer, and/or tubing. 
• 
Changes in plasma levels of complement factors, including total CH50, SC5b-9, and C5a. 
• 
Changes in plasma levels of other proteins, including insulin, ACTH, IGFBP1, etc.  
 

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5. 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1. 
Inclusion Criteria 
1. 
Males and females aged 40 – 75 years, inclusive. 
2. 
ESRD requiring HD.  
3. 
Dialysis vintage ≥ 24 months.  
4. 
Absence of clinically-relevant residual renal function. 
5. 
Regular HD sessions done at blood-flow rates between 400 and 500 mL/min, and with 
inter-dialysis intervals of 48 hours or more. 
6. 
Stable health status for at least 4 weeks prior to screening based on medical history, and 
findings from physical examination, laboratory tests, vital signs, and ECG, as assessed by 
the investigator. 
7. 
Life expectancy > 6 months (as determined by the investigator). 
8. 
Body mass index (BMI) between 18 and 37 kg/m2, inclusive, with a minimum body 
weight of 52 kg. 
9. 
Must be on stable doses (> 4 weeks) of all treatments for concomitant diseases (e.g., 
diabetes, hypertension), but this does not apply to medications for conditions related to 
ESRD (e.g., medications for calcium and phosphate control, anemia). 
10. 
Must be able to follow the study protocol and receive the treatment in the established 
timeframe. 
11. 
Must provide a signed and dated informed consent form. 
 
5.2. 
Exclusion Criteria 
1. 
Patients for whom adequate anticoagulation cannot be achieved, such as those with 
severe anemia, severe hemorrhagic diathesis, severe gastrointestinal ulcers, or who are 
receiving anticoagulant medications for any reason other than as required for HD. Use of 
antiplatelet drugs (e.g., aspirin or clopidogrel) is allowed. 
2. 
Patients for whom extracorporeal circulation therapy is contraindicated, such as those 
with severe cardiac insufficiency, acute myocardial infarction, severe cardiac arrhythmia, 
acute seizure disorder, or severe uncontrolled hypertension. 
3. 
Patients with Kt/V < 1.2 during recent 8-week period prior to run-in. 
4. 
History of hypersensitivity to heparin, including heparin-induced thrombocytopenia. 
5. 
History of hypersensitivity to the 
 column or its components. 
6. 
Patients who are not anticipated to be able to tolerate blood-flow rates of 450 mL/min 
during HD (e.g., new vascular access that cannot be used with 14G or 15G needles). 
7. 
Patients who are at higher risk for IDH including: 
a. 
Medical records indicating the occurrence IDH (SBP < 90 mmHg) in more than 
30% of HD sessions during a recent 8-week period prior to run-in; 
b. 
Patients requiring or expected to require extensive fluid management as 
determined by the investigator; 
c. 
Presence of pre-dialysis hypotension, defined as SBP < 90 mmHg and/or diastolic 
blood pressure (DBP) < 50 mmHg, before any of the last 3 dialysis sessions prior 
to screening; 
d. 
Diagnosis of IDH in medical records; 

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e. 
Diagnosis of autonomic dysfunction; 
f. 
Patients who frequently require a UFR above 13 mL/kg/h. 
8. Patients who are pregnant or breast-feeding or who are planning to become pregnant. 
Female subjects must not be pregnant or breastfeeding. Women of childbearing potential 
(WOCBP) must have a negative serum pregnancy test at screening and prior to start of 
treatment. WOCBP and men must agree to use highly-effective contraception (Clinical 
Trial Facilitation Group 2014) prior to study entry. A woman is considered of 
childbearing potential following menarche and until becoming postmenopausal (no 
menses for at least 2 years without an alternative cause). Should a woman become 
pregnant or suspect she is pregnant while she or her male partner is participating in the 
study, she should inform her treating physician immediately. 
9. Clotting disorders. 
10. Sickle cell anemia, hereditary spherocytosis, or autoimmune hemolysis. 
11. Clinically significant abnormalities on screening ECG including QT interval corrected for 
heart rate (QTc) using Fridericia's correction formula [QTcF] of ≥ 500 ms in men and 
≥ 520 ms in women.   
12. Delirium (encephalopathy). 
13. Out of range value for complete blood count (CBC), complete metabolic panel, or 
coagulation that the investigator deems clinically significant.  
14. Thyroid stimulating hormone (TSH) below 0.2 or above 6.0 mIU/L, and/or clinically-
relevant abnormalities in T3 or T4. 
15. Hemoglobin level < 9.0 g/dL. 
16. Alanine aminotransferase (ALT) and/or aspartate transaminase (AST) > 3 times upper 
limit of normal. 
17. Uncontrolled type 2 diabetes. 
18. Concurrent or have recent participation in another interventional clinical trial. Prior 
clinical trial subjects must have discontinued investigational agents/devices at least 30 
days prior to planned first use of the 
 column. 
19. History of severe depression/suicidality requiring hospitalization in the last 6 months. 
20. Significant drug or alcohol abuse within the past 12 months.  
21. Patients planning to receive renal transplantation during the study.  
22. Patients with any other condition and/or situation the investigator believes may interfere 
with the safety of the subject during study participation, study conduct, or interpretation 
of study data. 
5.3. 
Strategies for Recruitment and Retention 
The Sponsor does not anticipate any specific challenges in meeting recruitment goals of 
enrolling and retaining a total of 12 evaluable subjects in this study. Approximately 15 subjects 
will be enrolled. Assuming a drop-out rate (unrelated to safety/tolerability) of 20%, enrollment at 
this level will yield approximately 12 evaluable subjects. Subjects will be recruited continuously 
until the planned sample size is achieved.  
The estimated duration of subject participation of approximately 12 weeks is not expected to be 
challenging to subjects. Subjects will be compensated for the additional time required for study 
participation; details will be provided in the informed consent form.  

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5.4. 
Subject Withdrawal/Discontinuation  
5.4.1. 
Reasons for Withdrawal/Discontinuation 
A subject will be withdrawn from the study for the following medical or administrative reasons: 
• 
Occurrence of an AE, including significant hemodynamic compromise, that represents an 
unacceptable risk to the subject and when continued participation in the investigational 
study is not warranted, in the judgment of the investigator, Sponsor, or medical monitor. 
The investigator must follow the subject until the AE resolves or is stable, unless the 
subject is lost to follow up. 
• 
Treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator. 
• 
Subject noncompliance, defined as refusal or inability to adhere to the trial schedule or 
procedures. 
• 
At the request of the subject (e.g., subject withdraws consent), investigator, Sponsor, or 
regulatory authority. 
• 
Pregnancy. 
• 
As subject will be discontinued if adequate dialysis is not achievable at a blood-flow rate of 
250 mL/min during run-in. 
• 
A subject will be discontinued if they have an SBP < 90 mmHg, confirmed by repeat 
measurement, before the start of an HD session. 
• 
A subject will be discontinued if the number of IDH events (defined as an SBP 
< 90 mmHg, confirmed by repeat measurement) during a treatment period exceeds the 
predetermined threshold of the subject’s Historical IDH Rate after de-escalation to the 
lowest column size (see Appendix 17.1).  
5.4.2. 
Handling of Participant Withdrawals/Discontinuation 
Subjects will be encouraged to complete the study and all assessments. Subjects may voluntarily 
withdraw at any time, and the investigator may discontinue individual subjects from the study at 
any time.  
Approximately 15 subjects will be enrolled with the intent of obtaining 12 evaluable subjects 
(see Section 10.3).  
Subjects who have received at least 1 HD with the 
 column but are withdrawn or 
withdraw from the study will be encouraged to complete the EOS procedures. The primary 
reason for study discontinuation will be documented on the case report form (CRF). 

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5.5. 
Premature Termination or Suspension of Study 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, the 
Sponsor and/or their representatives will arrange discontinuation procedures and notify the 
investigators, appropriate regulatory authority(ies), and IRB(s). In terminating the study, the 
Sponsor and the investigators will continue to protect the subjects’ privacy and identity as 
required by relevant statutes and regulations. 
Alkahest, Inc. has the right to terminate a study site from participating in the study at any time. 
Reasons for study or site termination may include, but are not limited to: 
• Unanticipated risk to subject safety. 
• Unsatisfactory subject enrollment. 
• Unacceptable Protocol Deviations as assessed by the Sponsor’s Program Physician. 
• Inaccurate or incomplete data entry and recording/fabricated data. 
• Investigational site non-compliance with ICH/GCP. 
• Unacceptable emergent safety profile. 
If the Sponsor were to receive withdrawal of IRB or FDA approval, or other action on the part of 
the IRB or FDA that affects the study, the Sponsor will notify the FDA and/or all reviewing 
IRBs, and all participating investigators, within 5 days of the IRB or FDA decision. 
 

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6. 
STUDY DEVICE 
6.1. 
Study Device Description 
 
 
  
  
 
 
 
 
6.1.2. 
Description, Appearance, Packaging, and Labeling 
6.1.2.1. 
Device Description and Appearance 
The 
 b2M apheresis column is an investigational device and may only be used for 
subjects who have been enrolled in the AKST1210-101 study and who are under the supervision 
of an appropriately qualified investigator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2. Description of the 
 Column Model Sizes 
Model 
Column Capacity (mL) 
Extracorporeal Volume (mL) 
S-15 
150 
65 
S-25 
250 
105 
S-35 
350 
177 
 
The 
 column is an extracorporeal column for adsorption of b2M from circulating 
blood, and it is placed in series with a hemodialyzer in an HD circuit. Figure 3 depicts the 
connection of the 
 column in the HD blood circuit.  
Figure 3. 
 Column in the Hemodialysis Blood Circuit 
 
 
 

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6.1.2.2. 
Packaging and Labeling 
The 
 
 column will be used and will not be modified in any way except 
for the addition of an Investigational Use label on the immediate package of the device with the 
appropriate investigational statement per 21 CFR 812.5(a): “CAUTION - Investigational device. 
Limited by Federal (or United States) law to investigational use." An example of label text is 
provided below. 
6.1.3. 
Product Storage 
The 
 column should be handled with care during transportation and storage. The 
 column should be stored at temperatures between 5 °C and 30 °C. Direct sunlight, 
high humidity, excessive vibration, and freezing conditions should be avoided. Do not drop the 
 column or strike it with a hard instrument (e.g., forceps). Do not use any 
 
column that has been damaged or frozen. 
The fluid pathway of the 
 column is sterile and nonpyrogenic. Careful aseptic handling 
techniques are necessary to maintain this condition. Do not use the device if the package, the 
bag, or the product is damaged. Remove the device from the bag just before use. 
6.1.4. 
Preparation 
The 
 column will be connected in series before (upstream of) the dialyzer for the 
duration of each HD session. Specifics of column preparation (rinsing, priming, and disposal) are 
specified in the Device Procedures Manual. 
6.1.5. 
Column Size Escalation and Administration 
For a description of the 
 column escalation and administration for this study, please see 
Section 4.1 Description of the Study Design.  
6.1.6. 
Duration of Therapy 
The treatment period for each subject is approximately 6 weeks. The total duration of subject 
participation is expected to be approximately 8 to 12 weeks. 

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6.2. 
Study Device Accountability 
Under the supervision of the investigator, qualified personnel are responsible for ensuring 
adequate accountability of all used and unused 
 columns. This includes 
acknowledgment of receipt of each shipment of 
 columns (quantity and condition), 
subject dispensing records, and destruction of used columns. 
 column dispensing 
records will document quantities received and quantities dispensed to subjects including the date 
dispensed, size of column (S-15, S-25, or S-35), lot number, subject’s study identifier, initials of 
the individual responsible for dispensing, and initials of the dialysis nurse, or other qualified 
medical professional, administering the column. Device accountability will be monitored by a 
clinical research associate (CRA). 
Accountability records must be maintained and readily available for inspection by 
representatives of Alkahest, Inc., or their designee, and are open to inspection by regulatory 
authorities at any time. Accounts of any 
 column accidentally wasted or intentionally 
disposed of must be maintained.  
All unused 
 columns should be kept securely at the site until otherwise instructed. All 
unused containers of 
 columns at the site should not be returned or destroyed without 
prior written approval from the Sponsor, and authorized destruction must be performed in 
accordance with the site’s or hospital’s administrative policy (or equivalent), and/or relevant US 
regulations. The site’s procedure(s) for disposal/destruction will be evaluated by the Sponsor or 
an authorized representative in order to ensure that it complies with study requirements. A copy 
of the site’s device disposal policy should be maintained or referenced in the investigator’s study 
file. 

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7. 
STUDY PROCEDURES AND SCHEDULE 
7.1. 
Study Procedures/Evaluations 
7.1.1. 
Study Specific Procedures 
7.1.1.1. 
Screening and Run-in Procedures 
 
During the screening visit, the following procedures will be performed: 
• 
Informed consent 
• 
Evaluation of inclusion/exclusion criteria 
• 
Demographics 
• 
Medical history and review of medications 
• 
Assessment of HD history during a recent 8-week period, including blood-flow rates, 
vascular access, and IDH  
• 
Physical examination, including measurements of height, weight, and BMI 
• 
Vital signs 
• 
12-lead ECG  
• 
Screening laboratory tests (including pregnancy test for WOCBP only) 
• 
Concomitant medication review 
• 
AEs should be collected and evaluated after the subject signs the Informed Consent; 
events that occur before signing of the Informed Consent should not be recorded as AEs 
 
During the run-in period, the following procedures will be performed: 
• 
HD (at maximum flow rate of 250 mL/min) 
• 
Vital signs 
• 
Targeted physical examination, including weight measurement before and after HD 
• 
b2M/proteomic samples collected  
• 
Laboratory tests (including pregnancy test for WOCBP only) 
• 
Kt/V assessment 
• 
Concomitant medication review 
• 
AE evaluation/collection 
 
Detailed descriptions of each of these procedures are provided in the sections immediately 
following. Information pertaining to the schedule of events during screening/run-in is provided 
in Section 15.1. 
7.1.1.1.1. 
Demographics 
Demographic information such as the subject’s education level, ethnicity, and race will be 
collected. 
7.1.1.1.2. 
Medical History and Review of Medications 
The investigator or designee will obtain a detailed medical history through interview with the 
subject during screening. The medical history should focus on recent history. Additionally, the 
medical history should include: 

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• 
A detailed history of ESRD and HD in the last 6 months, including complications with 
vascular access, compliance with dietary and fluid restrictions, ability to maintain 
adequate levels, tolerability of HD, occurrence of IDH, blood-flow rates used, etc. 
• 
Current/past illnesses and conditions 
• 
Current symptoms of any active medical condition 
• 
Surgeries and procedures 
• 
Allergies 
The investigator or designee should obtain a complete list of the subject’s current medications, 
including over-the-counter drugs, herbal supplements, and/or vitamins, as well as those taken by 
the subject in the past 3 months and any regimen changes in the last 3 months. Any additions, 
discontinuation, or dosage changes in medication during the course of the study will be recorded. 
7.1.1.1.3. 
Physical Examination 
A complete physical examination will be performed at screening to assess the following organ 
systems: skin, ENT (ears, nose, and throat), head, eyes, lungs, heart, abdomen, musculoskeletal, 
extremities, and neurologic and lymphatic systems. Physical examination assessments performed 
within 3 months of the screening visit need not be repeated. Height will be measured at 
screening; weight will be measured at screening and BMI calculated. Weight will be measured  
throughout the study both prior to and after HD. 
7.1.1.1.4. 
12-Lead ECG 
A 12-lead ECG will be performed after the subject has rested quietly for at least 5 minutes in a 
supine position. In some cases, it may be appropriate to repeat abnormal ECGs to rule out 
technical factors contributing to ECG artifacts or abnormality. It is important that leads are 
placed in the same positions each time for consistency. The overall conclusion with the 
interpretation of the ECGs will be recorded on the appropriate CRF. The interpretation of the 
ECGs will be recorded as normal, abnormal but not clinically significant, or abnormal and 
clinically significant. QTc will be calculated using Fridericia’s correction formula. 
7.1.1.1.5. 
Laboratory Evaluations 
Blood samples will be collected and analyzed throughout the study. Blood will be drawn by a 
qualified medical provider. Laboratory evaluations will be completed by a central laboratory. 
Samples for screening laboratory evaluations should be collected either on a non-dialysis day or 
prior to HD. For additional information, refer to Section 15.3 Schedule of Laboratory Tests. 
7.1.1.1.6. 
Hemodialysis 
Beginning at run-in, HD will be conducted 3 times weekly at different blood-flow rates (see 
Section 4.1). The following key dialysis parameters will be captured during each HD treatment: 
arterial, venous, and transmembrane pressures every 30 minutes (from the HD machine; mmHg), 
mean and maximum blood flow rate (mL/min), reasons for changes in blood-flow rate, dialysis 
time (min), and type of dialyzer. Adequate safety precautions should be employed prior to and 
throughout HD, particularly for subjects who are at risk for developing IDH. Refer to Table 1 in 

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Section 2.2.1 for risks associated with the 
 column as well as proposed mitigation 
strategies. 
7.1.1.1.7. 
Heparinization 
The 
 column requires anticoagulation to prevent clotting, and the different column 
sizes generally require different amounts of heparin. Subjects will undergo heparinization 
according to institutional practices at the start of, and throughout, each HD session when the 
 column is used. The dose of heparin should be determined by the investigator based 
on each patient’s individual requirements, the state of the dialysis circuit, and laboratory tests. 
Additional guidance is provided in the Device Procedures Manual.  
7.1.1.2. 
Procedures to Assess Safety 
Subjects enrolled in the trial will be monitored closely to assess safety and tolerability of the 
 column. Study-specific procedures that will be used for this purpose are summarized 
below. Information regarding the timing and frequency of these procedures is provided in 
Section 15:  
• 
Review of AEs 
• 
Vital signs 
• 
Adequacy of dialysis 
• 
Assessment of fluid status 
• 
Targeted physical examination, weight measurements 
• 
Laboratory assessments 
7.1.1.2.1. 
Review of Adverse Events 
Adverse events (AEs) will be reviewed, documented, and reported as required at each visit 
beginning at screening. For definitions, guidance, and additional information regarding AEs, 
please see Section 8. 
7.1.1.2.2. 
Monitoring of Vital Signs 
Vital signs monitoring will occur at every visit. Seated/reclined blood pressure (BP) will be 
recorded before each dialysis session, approximately every 30 minutes during dialysis, and at the 
end of the session. Other vital signs will be captured at the beginning and end of each visit; these 
include heart rate (beats per minute [bpm]), respiratory rate (breaths per minute), and body 
temperature. Vital signs will be measured after the subject has been seated/reclined for ~5 
minutes.  
Subjects will be monitored for IDH (see Definitions). Beginning at run-in, should the number of 
occurrences of IDH exceed a predetermined threshold based on the subject’s Expected IDH Rate, 
then the subject will be discontinued or de-escalated to a previously tolerated, smaller column 
size at blood-flow rates up to 450 mL/min (Appendix 17.1). 

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7.1.1.2.3. 
Assessment of Fluid Status 
Fluid status will be assessed during each HD treatment according to institutional standards of 
care. This will include body weight and assessment of pulmonary and dependent (pedal) edema 
and could include the following: pre and post HD bioimpedance, lung ultrasound monitoring of 
Kerley B-lines (Lichtenstein 2017), and continuous hematocrit monitoring during HD as deemed 
appropriate by the investigator/HD staff (Rodriguez 2005). Data will be collected concerning the 
performance of these procedures, as appropriate, and the outcomes assessed. 
7.1.1.2.4. 
Targeted Physical Examination 
A targeted physical examination (i.e., a re-examination of any abnormalities noted previously or 
new signs and symptoms that warrant clinical assessment) will be performed as needed (see 
Section 15). Weight will be assessed before and after HD at every visit. 
7.1.1.2.5. 
Laboratory Evaluations 
Blood samples will be collected and analyzed according to the schedule of laboratory tests 
(Section 15.3). Blood will be drawn by a qualified medical provider. Clinical laboratory 
evaluations will be processed by a central laboratory. Sites may collect and process these locally 
at the discretion of the investigator for ad-hoc safety monitoring and/or to guide heparin dosing. 
7.1.1.2.6. 
Pregnancy Testing 
Serum pregnancy testing will be performed in WOCBP in accordance with the Schedule of 
Events (see Section 15). 
7.1.1.3. 
Procedures to Assess Device Performance 
In addition to safety and tolerability, device performance will be assessed per the secondary 
endpoints defined in the study, including evaluation of change in plasma b2M concentrations 
(before and after HD) and contribution of the 
 column to b2M removal at each column 
size and blood-flow rate, number of occurrences of visible thrombosis (clotting) in the 
 
column, dialyzer, and/or tubing, changes in plasma levels of complement factors, including total 
, as well as changes in plasma levels of other proteins, including 
 
. 
7.1.1.3.1. 
 
7.2. 
Laboratory Procedures/Evaluations 
Blood samples will be collected for laboratory evaluations in accordance with Section 15.3 
Schedule of Laboratory Tests. Screening and clinical laboratory evaluations will be processed by 
a central laboratory. Sites may collect and process laboratory evaluations locally at the discretion 
of the investigator for ad-hoc safety monitoring and/or to guide heparin dosing. 
The investigator is responsible for determining and documenting whether out of range laboratory 
values are clinically significant. All clinically significant values will be recorded as AEs in the 

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CRF and followed until determined to be stable or resolved, unless the subject is lost to follow 
up. Once resolved, the appropriate CRF page(s) will be updated. 
7.3. 
Study Schedule 
7.3.1. 
Screening/Run-in 
For a complete list of screening and run-in procedures and assessments, please see Section 15.1. 
7.3.2. 
Treatment 
For a complete list of treatment procedures and assessments, please see Section 15.1. and Section 
15.2. 
7.3.3. 
End of Treatment/End of Study Visits 
For a complete list of end of treatment (EOT) and EOS procedures, please see Section 15.2. 
7.3.4. 
Early Withdrawal 
In the event of early withdrawal or discontinuation of a subject who has received at least 1 HD 
treatment with the 
 column, the EOS procedures will be performed unless the subject 
has withdrawn consent (also see Section 5.4). 
7.4. 
Concomitant Medications 
 
Concomitant medications taken by the subject during study participation will be recorded. For 
this protocol, a prescription medication is defined as a medication that can be prescribed only by 
a properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant 
prescription medications, over-the-counter medications, and non-prescription medications. 
7.5. 
Prohibited Medications, Treatments, and Procedures 
The following concomitant medications, treatments, and procedures are prohibited: 
• 
Anticoagulants other than those administered during HD. Use of antiplatelet drugs (e.g., 
aspirin or clopidogrel) is allowed. 
• 
Anti-seizure medications for a seizure disorder. 
• 
Concurrent or recent participation in another investigational clinical trial. Prior clinical 
trial subjects must have discontinued investigational agents at least 30 days prior to 
screening. 
• 
Renal transplantation surgery. 
 

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8. 
ASSESSMENT OF SAFETY 
8.1. 
Specification of Safety Parameters 
8.1.1. 
Definition of Adverse Event, Procedure-Related Adverse Event, and Adverse 
Device Effect 
Per the International Organization for Standardization (ISO) 14155:2011 an AE is any untoward 
medical occurrence, unintended disease or injury, or untoward clinical signs (including 
laboratory findings) in subjects, users, or other persons, whether or not related to the 
investigational medical device. 
• Note 1: This definition includes events related to the investigational medical device.  
• Note 2: This definition includes events related to the procedures involved. 
• Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices.   
 
In relation to Note 2 above, a sub-classification of an AE is a procedure-related AE (PRAE). A 
PRAE is an AE that most likely occurs as a result of HD or related procedures, irrespective of 
the investigational medical device. Examples of a PRAE in HD include vascular access site 
complications, including access hemorrhage and venous needle dislodgement; disruption or 
contamination of the dialysis water system; venous air embolism; sepsis; cardiac complications 
including arrhythmia, angina, and cardiac arrest; electrolyte imbalances including hypokalemia 
and hyperkalemia, etc. In cases where relatedness is unclear, a conservative stance is to consider 
the event as related to the investigational medical device. 
 
Per ISO 14155:2011, an ADE is an AE that is assessed as related to the use of an investigational 
medical device: 
• Note 1: This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device. 
• Note 2: This definition includes any event resulting from use error or from intentional 
misuse of the investigational medical device.   
8.1.2. 
Definition of Serious Adverse Event and Serious Adverse Device Effect 
Per ISO 14155:2011 a serious adverse event (SAE) is an AE that: 
a. 
Leads to death. 
b. 
Leads to serious deterioration in the health of the subject, that either results in: 
• 
A life-threatening illness or injury, or 
• 
A permanent impairment of a body structure or a body function, or  
• 
Inpatient or prolonged hospitalization, or 
• 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or body function.  

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c. 
Leads to fetal distress, fetal death, or a congenital abnormality or birth defect. 
Per ISO 14155:2011 a serious adverse device effect (SADE) is an ADE that results in any of the 
consequences characteristic of a SAE. 
All SAEs should be reported in the timeframe outlined in Section 8.4. 
8.2. 
Classification of An Adverse Event 
8.2.1. 
Severity of Event 
Each AE/ADE must be assessed for its seriousness and severity. Severity will be assessed by the 
investigator or designee using the following definitions: 
 
SEVERITY 
DEFINITION 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVERE 
Incapacitating with inability to work or do usual activity 
Outcome will be assessed using the following categories: recovered/resolved, not recovered/not 
resolved, recovered/resolved with sequelae, fatal, or unknown. 
8.2.2. 
Relationship to Study Device 
Investigators are required to assess the relatedness (i.e., whether there is reasonable possibility 
that the study device caused the event) using the following definitions: 
• 
Unrelated: another cause of the AE is more plausible, including AEs that commonly occur 
during HD (e.g. procedure-related AEs); a temporal sequence cannot be established with the 
onset of the AE and administration of the study device; or a causal relationship is considered 
biologically implausible. 
• 
Possibly Related: There is a clinically plausible time sequence between onset of the AE and 
administration of the study device, but the AE could also be attributed to concurrent or 
underlying disease, or the use of other devices or procedures. Possibly related should be used 
when the study device is one or several biologically plausible AE causes. 
• 
Definitely Related: The AE is clearly related to use of the study device. 
If either the investigator or the Sponsor considers the event related, then the event will be 
considered related for reporting purposes and will therefore be an ADE or SADE. 

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8.2.3. 
Expectedness of Adverse Device Effects 
8.2.3.1. 
Unanticipated Adverse Device Effect 
Per 21 CFR 812.3(s) an unanticipated adverse device effect (UADE), “means any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.” 
The investigator is required to make an initial assessment of whether an SADE is considered 
anticipated according to the known risks and associated device effects identified in Section 2.2.1 
and the Investigator’s Brochure. If an SADE is considered unanticipated by the investigator, it 
must be reported to the Sponsor or designee according to the timeframes outlined in Section 
8.4.2.1. Once received, the Sponsor or designee will be responsible for making the final 
determination of whether the device effect is unanticipated for subsequent reporting to FDA.  
8.3. 
Time Period/Frequency for Event Assessment/Follow-up 
At very clinic visit, subjects will be assessed for AEs and SAEs. All AEs and SAEs will be 
monitored and recorded by trained and knowledgeable personnel to protect subjects from harm. 
At the beginning of each visit, after the subject has had an opportunity to spontaneously mention 
any problems that may have occurred during the preceding interdialytic interval, the investigator 
should inquire about any possible interdialytic AEs by asking a non-leading question such as the 
following: 
1. “How are you feeling?” 
2. “Have you had any changes since your last assessment/visit?” 
3. “Have you taken any new medicines since your last assessment/visit?” 
During and for a period after each HD session, participating subjects will be closely monitored 
by qualified healthcare personnel who are trained in HD and who have experience in the types of 
AEs that typically occur during HD. Any events that occur during or after HD (before the subject 
leaves the clinic), will be assessed by the HD personnel (e.g. hemodialysis technician or nurse) 
and discussed as appropriate with the investigator or designee. 
8.3.1. 
Post-Study Safety Assessment 
The investigator is not obligated to actively seek safety information in former study subjects, but 
the investigator is encouraged to notify Alkahest, Inc. or their designee of any AE/ADE or 
SAE/SADE occurring within 30 days after a subject completes the study (or has their last visit) 
that the investigator judges may be reasonably related to study treatment or study participation. 

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8.4. 
Reporting Procedures 
8.4.1. 
Adverse Event Reporting 
All subjects who have given informed consent will be evaluated for AEs. All AEs that occur 
after initiation of treatment with the 
 column will be considered TEAEs. Subjects with 
TEAEs must be followed until the AE/ADE is resolved or is stable, unless the subject is lost to 
follow up. 
Each AE/ADE must be described as follows: the date of onset, date of resolution, severity (mild, 
moderate, severe), frequency of the event (single episode, intermittent, continuous), action taken 
with study device (no action taken, device discontinued), outcome, relationship to study device* 
(unrelated, possibly related, definitely related), and seriousness criteria. Each AE/ADE must be 
recorded separately. 
*Note: Assessment of the relationship to study device will be made only when the AE occurs 
after the subject has initiated at least one (1) treatment with the 
 column. An AE 
occurring before the subject’s exposure to the 
 column will always be labeled as 
“unrelated.” 
Any AE/ADE or SAE/SADE occurring during the study must be documented in the subject’s 
source documentation and as an AE/ADE in the CRF. All SAE/SADEs should be reported to the 
Sponsor according to the reporting timeframes specified in Section 8.4.2.1. 
The investigator should attempt to establish a diagnosis of the event (that meets the definition of 
an AE/ADE or SAE/SADE) based on signs, symptoms, and/or other clinical information. In such 
cases, the diagnosis should be documented as the AE/ADE and/or SAE/SADE and not the 
individual signs or symptoms. The diagnosis will become the basis for the verbatim term as 
reported by the investigator. If no diagnosis is known and clinical signs and symptoms are not 
present, the abnormal finding should be recorded. 
In addition to the investigator’s own description of the AE/ADE, each AE/ADE will be encoded 
according to the Medical Dictionary for Regulatory Activities (MedDRA). The investigator will 
take all appropriate and necessary therapeutic measures required for resolution of and AE/ADE. 
Any medication necessary for the treatment of an AE/ADE must be recorded on the concomitant 
medication CRF.  
8.4.2. 
Serious and Unanticipated Adverse Events/Effects Reporting 
8.4.2.1. 
Timeframes for Reporting 
As per 21 CFR 812.150 an investigator shall submit to the Sponsor and to the reviewing IRB a 
report of any UADE (see Section 8.2.3.1) occurring during an investigation as soon as possible 
after the investigator first learns of the effect. Prompt notification of the Sponsor, and/or the 
Sponsor’s representatives, and promptly providing requested follow-up information regarding 
such events is essential so that ethical and regulatory responsibilities and legal obligations can be 
satisfied. Investigators are responsible for reporting all SAEs (including SADEs and UADEs) 
according to the following timeframes:  

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• 
Initial notification (e.g., a completed SAE Report Form) and relevant source documents, 
if applicable, must be completed and faxed or emailed to 
 
within 24 hours of observation or learning of the event. 
 
 
 
 
 
 
• 
Follow-up information must be sent to the 
 within 24 hours of receipt of 
information by the investigational site.  
All applicable events (including UADEs) must be reported to the IRB as soon as possible but in 
no event later than 10 working days after becoming aware of the event.  
In addition to the IRB, the Sponsor will notify the FDA and all participating investigators in a 
safety report of potentially serious, unanticipated risks from clinical trials as soon as possible 
after the Sponsor receives the safety information and determines that the information qualifies 
for reporting: 
• 
No later than 7 working days for events that are life threatening (in the opinion of the 
investigator or the Sponsor) or that involve death as an outcome. 
• 
No later than 10 working days for all other UADEs. 
Sites acting under their local IRB should submit all applicable events, unanticipated problems, 
and safety reports to their local IRB, if applicable. All safety reporting deviations should also be 
submitted to their local IRB, if applicable. 
8.4.2.2. 
SAE/SADE/UADE Information to Report 
The SAE Report Form must be completed and faxed or emailed according to the timeframes 
specified above. The submission should include copies of relevant source documents/medical 
records, if applicable. At a minimum, the SAE Report Form must contain the subject number, 
verbatim term, onset date, relationship to study device, and a brief narrative of the event. Please 
note that relationship to study device as well as the reported verbatim term are very 
important and should be included in the initial report as it may impact expedited regulatory 
reporting requirements for the event. The date of discovery by the site staff should be 
documented in the source documents. 
A separate SAE Report Form should be used to report each SAE. However, if at the time of 
initial reporting, multiple SAEs are present that are temporally and/or clinically related, they may 
be reported on the same SAE Report Form. 
The investigator must record all relevant information regarding an SAE/SADE/UADE in the 
applicable sections of the report form, and the form must be signed by the investigator or his/her 
designee before transmittal to the Contract Research Organization (CRO) (see Section 8.4.2.1). It 

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is very important that the investigator provide his/her assessment of relationship to the study 
device as well as an applicable diagnosis at the time of the initial SAE report. It is not acceptable 
for the investigator to send photocopies of the subject’s medical records in lieu of completion of 
the appropriate SAE Report Form. However, there may be instances when copies of medical 
records for certain cases are requested by the CRO and/or the Sponsor. If medical records are 
submitted to the CRO, then all subject personal identifiers must be completely and thoroughly 
redacted prior to submission. 
 
A blank SAE Report Form and instructions for reporting will be provided to the site and will be 
maintained in the investigator’s study file.  
 
If new information about an SAE/SADE/UADE is received or corrections to data are needed, the 
investigator should complete a new SAE Report Form and check the “follow-up” box on the 
form. This follow-up SAE Report Form should be submitted within 24 hours of learning of the 
information. 
  
The SAE/SADE/UADE pages of the CRF should also be completed as thoroughly as possible.  
8.4.3. 
Reporting of Pregnancy 
While pregnancy itself is not considered an AE, pregnancy occurring in a clinical study must be 
followed to collect information regarding the experiences of gestation and pregnancy with study 
device exposure. The investigator must report any pregnancy that occurs in a female study 
subject or female partner of a male subject subsequent to first exposure to the study device until 
EOS, or within 3 months following a subject’s last use of the device in the event of early 
termination. All pregnancies will be reported to the IRB, Sponsor, and CRO. In the event of a 
pregnancy, treatment will be discontinued, and the subject will undergo continued safety follow-
up through pregnancy outcome. 
Any pregnancy must be followed by the investigator until delivery or to the end of pregnancy. 
Any anomalies, complications, abnormal outcomes, or birth defect(s) observed in the child must 
be reported as an SAE within 24 hours of the investigator or study personnel’s first knowledge. 
8.5. 
Study Halting Rules 
 
If any of the following safety events occur, a Safety Evaluation Meeting (defined below) will be 
triggered: 
• Three or more SAEs (including SADEs and UADEs) that are assessed as possibly or 
definitely related to the study device by an investigator and confirmed as such by the 
Sponsor (see Section 8.2.2). 
• An overall pattern of symptomatic, clinical, or laboratory events associated with the 
study device that the Sponsor’s Program Physician or designee consider a serious 
potential safety concern (e.g., suspicious overall pattern). 
Events that are not considered “device related” and will not contribute to the count of definitely-
related SAEs that would trigger a Safety Evaluation Meeting. 
 

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Safety Evaluation Meeting 
 
If safety events of potential concern occur during the trial (i.e., 3 related events or a suspicious 
overall pattern, as defined above) a Safety Evaluation Meeting will be triggered, and the study 
may be temporarily halted based on the observations. The Sponsor will inform investigators and 
the appropriate Regulatory Authorities in the event of any temporary halt in the study at any 
time during the conduct of the study. The purpose of the meeting is for investigators, the 
Sponsor, and the CRO Medical Monitor(s) to discuss and evaluate the safety of the subjects 
using available aggregated safety data.  
 
Attendants at the Safety Evaluation Meeting will include the Program Physician of Alkahest (or 
his/her designee), the CRO medical monitor(s), and available active investigators participating 
in the trial. After sufficient data review, the Sponsor will choose one of the following courses of 
action: 
1. Continue the study with no change to protocol. 
2. Halt use of the 
 column (all column sizes/blood-flow rates) and stop the study.  
3. Continue with a modified protocol design and amend the protocol as appropriate. 
8.6. 
Safety Oversight 
Safety oversight will be provided by the Sponsor’s Program Physician or his or her designee and 
the CRO’s Medical Monitor(s) in concert with the site investigators. There will be no formal 
Data Safety Monitoring Board established. As needed, Safety Evaluation Meetings will be 
convened as described in Section 8.5 to monitor the ongoing safety of the study. The Sponsor’s 
Program Physician or designee is the final authority for safety oversight in the study. 

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9. 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and wellbeing of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s). 
• 
Monitoring for this study will be performed by the study CRO in accordance with the 
Clinical Monitoring Plan (CMP). 
• 
Details of clinical site monitoring tasks and scope are documented in the study’s CMP. 
The CMP describes in detail who will conduct monitoring, at what frequency monitoring 
will be done, at what level of detail monitoring will be performed, and the distribution of 
monitoring reports. 
• 
Co-monitoring visits and/or independent audits may be conducted by the Sponsor in 
accordance with a quality oversight plan or equivalent to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the 
CMP. 

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10. 
STATISTICAL CONSIDERATIONS 
10.1. Statistical Design Model and Analytical Plans 
Data from this feasibility study will be analyzed mostly in a descriptive manner. Limited 
statistical comparison of outcomes across the various column-size and blood-flow-rate 
combinations will be performed. With the limited sample size, exact methods for binomial data 
and t-statistics for continuous data will be used in generating 95% confidence intervals for 
estimates. A statistical analysis plan (SAP) will be prepared to provide details of the analysis of 
data. Counts and percentages of safety events will be reported separately for each combination. 
Similarly, continuous safety data will be summarized by combination.  
No formal statistical comparison of the safety data will be performed. The rate of IDH in the 
general ESRD population, using the Nadir 90 definition, is 10%, based on a study in over 10,000 
US patients undergoing HD (Flythe 2015). With 12 subjects there will be an approximate 70% 
probability of detecting at least 1 event in each week. Descriptive statistics will be utilized for 
trial conduct: screen failures, enrollment, withdrawal of consent, and study completion. Primary 
and secondary endpoints will be assessed at the beginning and end of each week of treatment for 
a particular column size and blood-flow rate combination. The effect of blood-flow rate will be 
assessed for a given column size as well as intrasubject and across-subject variability. The 
sample size was chosen based on clinical consideration of the study designed to test the safety 
and functionality of the 
 column operated at higher blood-flow rates. 
10.2. Statistical Hypotheses 
The primary objective of the study is to evaluate the safety and tolerability of the 
 
column when used at blood-flow rates up to 450 mL/min. The safety and tolerability will be 
assessed at each column size and blood-flow rate to enable comparisons across those variables in 
each subject (intrasubject) and across all subjects.   
10.3. Analysis Datasets 
Two (2) analysis datasets will be defined as follows: 
• 
Safety Dataset: all subjects who received at least 1 (or partial) HD treatment with the 
 column.  
• 
Evaluable Dataset: all subjects who complete blood-flow rates up to 450 mL/min for at 
least 1 column size (e.g., S-15 at 250 and up to 450 mL/min).  
The presentation of baseline characteristics will be conducted on the Safety Dataset. Comparison 
of the safety and tolerability of each column size and blood-flow rate will use both the Safety 
Dataset and Evaluable Dataset.  

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10.4. Description of Statistical Methods 
10.4.1. 
General Approach 
Using the safety dataset, all safety endpoints will be summarized serially over time using 
descriptive statistics to assess the within-subject changes and between-condition differences. 
Overall baseline and demographic data will be summarized using descriptive statistics.  
For analysis of the primary and secondary endpoints, the following will be considered:  
• 
For endpoints that are continuous in nature: 
– Number of observations, mean, median, minimum and maximum, and standard 
deviation (SD) and change from baseline values (or percent change from baseline) will 
be presented as descriptive summary. 
• 
For endpoints that are categorical in nature: 
– Frequency counts and percentages will be presented as descriptive summaries. 
Subject disposition (e.g., the number of subjects enrolled, completed, and discontinued at each 
phase) will be summarized, and medical history data will be listed. Prior and concomitant 
medications taken from screening and during the study will be categorized by World Health 
Organization classification for therapeutic class and medication name, listed and summarized by 
number and percentage of subjects.  
Final analyses are not limited to the summaries described herein. As noted above, analytical 
details and assumptions will be fully presented in the SAP. 
10.4.2. 
Analysis of the Primary Endpoint 
Safety and tolerability will be evaluated by examining the occurrence of TEAEs and AEs leading 
to de-escalation and/or discontinuation from the study and by the number of subjects who are 
able to complete each phase (i.e., a column size at both blood-flow rates).  
Summary tabulations of the reported AEs will be presented by column size after the verbatim 
terms have been coded to preferred terms (PTs) and system organ classes (SOCs) using the 
MedDRA Version 23.0 coding dictionary or higher. The summaries will include severity and 
attribution to the study device. Multiple reports of the same AE by the same subject will be 
counted only once at the highest severity and strongest attribution to the study device. 
10.4.3. 
Analysis of the Secondary Endpoints 
Actual values and changes from baseline in clinical laboratory measurements will be assessed 
and summarized. Laboratory shift tables or graphics displaying the change (number of subjects) 
relative to the reference range from baseline to each study visit may also be presented for each 
test. The investigator should exercise his or her medical and scientific judgment in deciding and 

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documenting whether an abnormal laboratory finding, or other abnormal assessment, is clinically 
significant. 
For secondary endpoints that are continuous in nature the mean, median, minimum, maximum, 
and standard deviation will be summarized. 
For secondary endpoints that are categorical in nature, the frequency counts and percentages will 
be presented as descriptive summaries. 
Per-subject extent of exposure will be listed. 
10.4.4. 
Adherence and Retention Analyses 
 
Subject adherence with the study visits schedule, visit procedures, HD procedures, and subject 
retention will be assessed. Subject adherence will be assessed for each column size and blood-
flow rate. Reasons for study discontinuation will be compared across column-sizes and blood-
flow rates and across subgroups of interest, as appropriate. 
10.5. Sample Size 
The sample size for this study was based on FDA Guidance for the Content for Premarket 
Notifications for Conventional and High Permeability Hemodialyzers (FDA 1998) which 
recommends that data be collected for a minimum of 12 subjects for a minimum of 36 
treatments. In this study, approximately 15 subjects between 40 and 75 years of age with ESRD 
will be enrolled. Assuming a drop-out rate of 20% (unrelated to safety) enrollment will yield 
approximately 12 evaluable subjects. With regard to the most important risk of 
 IDH, 
a sample of 12 subjects will provide approximately 70% probability of detecting at least 1 IDH 
event in each week (i.e., for each column size and blood-flow rate combination). This estimate is 
based on the assumption that the rate of IDH in the general ESRD population, using the Nadir 90 
definition, is 10%, based on a study in over 10,000 US patients undergoing HD (Flythe 2015).  
 

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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 R2 and regulatory and Institutional requirements for the protection of 
confidentiality of subjects. Each site will permit authorized representatives of regulatory 
agencies, the IRB, the Sponsor, or the Sponsor’s representatives to examine (and when permitted 
by applicable law, to copy) clinical records for the purposes of QA reviews, audits, and 
evaluation of the study safety, progress, and data validity. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subject’s memory aids or evaluation 
checklists, pharmacy dispensing records, recorded audio tapes of counseling sessions, recorded 
data from automated instruments, copies or transcriptions certified after verification as being 
attributable, legible, accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial. 
It is not acceptable for the CRF to be the only record of a subject’s participation in the study. 
This is to ensure that anyone who would access the subject’s medical record has adequate 
knowledge that the subject is participating in a clinical trial. Source document templates will be 
developed for this study. 

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12. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1. Ethical Standard 
The investigator will ensure this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in, 21 CFR Parts 11,50, 54, 56, 812, ICH E6 
R2, and the Declaration of Helsinki. 
12.2. Institutional Review Board 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB. Approval from the IRB must be 
obtained before starting the study and should be documented in a letter to the investigator 
specifying the protocol number, protocol version, documents reviewed, and date on which the 
committee met and granted the approval. 
All changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented subjects need to be re-consented. 
Any modifications or amendments to the protocol must also be submitted to the IRB for approval 
prior to implementation. 
If the investigator were to receive withdrawal of IRB approval, or other action on the part of the 
IRB that affects the study, the investigator will provide written notification within 5 days of the 
IRB decision to the Sponsor. If Alkahest were to receive withdrawal of IRB approval, or other 
action on the part of the IRB that affects the study, the Sponsor will provide written notification 
within 5 days of the IRB decision to the FDA and investigators. 
12.3. Informed Consent Process 
12.3.1. 
Consent Forms 
Consent forms describing in detail the study device, study procedures, and risks are given to the 
subject and written documentation of informed consent is required prior to any study-related 
procedures. 
12.3.2. 
Consent Procedures and Documentation 
It is the responsibility of the investigator or designee to obtain written informed consent from 
each subject participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study and prior to undertaking any study-related 
procedures. 
Subjects should have the opportunity to discuss the study with their family members or other 
advisors and the time to consider participation in the trial carefully. Subjects may withdraw 
consent at any time throughout the course of the trial. The rights and welfare of the subjects will 

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be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
The investigator or designee must utilize an IRB approved consent form that contains the 
elements required by ICH GCP and applicable regulatory requirements for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the subject 
and the person obtaining consent. A copy of the signed consent form will be provided to the 
subject. By signing the informed consent form, all parties agree they will complete the 
evaluations required by the study, unless they withdraw voluntarily or are terminated from the 
study for any reason. 
Investigators will be expected to maintain a screening log of all potential study candidates that 
includes limited information about the potential candidate (e.g., date of screening). 
All subjects who provide consent will be assigned a unique study number. This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to the study subject. Once a number is assigned to a subject, that number 
will remain with that study subject and will not be reused. 
If an individual’s medical chart or results of diagnostic tests performed as part of an individual’s 
regular medical care are going to be used for screening, written informed consent must be 
obtained prior to review of that information in accordance with Health Insurance Portability and 
Accountability Act. 
12.4. Participant and Data Confidentiality 
Subject confidentiality is held in strict trust by the participating investigators, their staff, the 
Sponsor, and their agents. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to subjects. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or data will be released to any unauthorized 
third party without prior written approval of the Sponsor. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
or government regulatory agencies may inspect documents and records required to be maintained 
by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this study. The clinical study site will permit access to such 
records. 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. An identification code (i.e., not names) should 
be recorded on non-local laboratory samples, requisitions, and any documents submitted to the 
CRO, Sponsor, and/or IRB. The investigator must keep a subject log showing codes, names, and 
pertinent contact information for all subjects screened and for all subjects enrolled in the trial. 
The study subject’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and/or Institutional regulations. 

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12.5. Future Use of Stored Specimens 
With the subject’s approval and as approved by local IRBs, de-identified biological samples may 
be stored at Alkahest, or designee, for future use. These samples could be used for future 
research and to improve treatment. Alkahest will also be provided with a code-link that will 
allow linking the biological specimens with the specific data from each subject, maintaining the 
masking of the identity of the study subject. Subjects may choose whether the Sponsor can store 
and use samples for further research. 
During the conduct of the study, an individual subject can choose to withdraw consent to have 
biological specimens stored for future research.  
When the study is completed, access to study data and/or samples will be managed by Alkahest. 
In the event Alkahest transfers ownership to another commercial Sponsor, ownership of the 
samples may be transferred as well. 

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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, and 
timeliness of the data reported. 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. Data entered in the 
eCRFs that are transcribed from source documents must be consistent with the source documents 
or the discrepancies must be explained. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. Black or blue ink is required to ensure 
clarity of reproduced copies. When making changes or corrections, cross out the original entry 
with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. The investigator may need to request 
previous medical records or transfer records, depending on the trial; also, current medical records 
must be available. 
The CRF must be completed in a timely manner. The investigator will review and approve the 
CRF for each study subject after all data have been entered, the CRFs have been source 
document verified, and all queries have been resolved. This also applies to records for those 
subjects who fail to complete the study. If a subject withdraws from the study, the reason must 
be noted on the CRF. If a subject is withdrawn from the study because of an AE, thorough efforts 
should be made to clearly document the outcome. 
13.1.1. 
Investigator Responsibilities 
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by an IRB), ICH GCP, and applicable regulatory requirements. The investigator is 
ultimately responsible for the conduct of all aspects of the study at the study site and verifies by 
signature the integrity of all data transmitted to the Sponsor. The term “investigator” as used in 
this protocol as well as in other study documents, refers to the investigator or authorized study 
personnel that the investigator has designated to perform certain duties. Sub-investigators or 
other authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required. 
13.1.1.1. 
Reporting Responsibilities 
 
Investigators are required to: 
• Submit AEs/ADEs/SAEs/SADEs/UADEs to the study Sponsor or designee, as per the 
reporting requirements outlined in Section 8.4. 
• Submit to their IRB a report of any UADEs, or events of subject death, occurring during 
an investigation as soon as possible but in no event later than 10 working days after the 
investigator first learns of the event. 
• Notify the study Sponsor of withdrawal of IRB approval or other action on the part of the 
IRB that affects the study as soon as possible but in no event later than 5 working days.  

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• Notify the Sponsor, Monitor, and IRB of study progress at regular intervals but in no 
event less often than yearly. 
• Notify the Sponsor/IRB of any significant deviations from the investigational plan for 
emergency purposes, as soon as possible but in no event later than 5 working days after 
deviation occurs to protect the life or physical well-being of a subject in an emergency. 
– For non-emergency purposes, obtain prior approval by Sponsor and, if deviation 
may affect scientific soundness of the trial or the rights, safety, or welfare of 
subject, also obtain approval by the IRB and FDA as an Investigational Device 
Exemption (IDE) supplement. 
• Notify the Sponsor and IRB if a subject is treated with an investigational device without 
first obtaining informed consent, within 5 working days of use of the investigational 
device.  
• Notify the Sponsor and IRB with a final study report within 3 months after termination or 
completion of study or termination of site’s participation. 
13.1.2. 
Study Files 
 
Investigators are required to maintain on file the following accurate, complete, and current 
records relating to this study: 
• All correspondence relating to the study with another investigator, an IRB involved in the 
study, Alkahest, Inc., a monitor, or FDA, including required reports. 
• Records of receipt, use, or disposition of a 
 column. 
• All clinical forms and documentation, including:  
– Records of each subject's case history and exposure to the 
 column. 
– A copy of the signed subject consent form. 
– Date and time of exposure to the 
 column. 
– All procedure and follow-up report forms, including supporting documents. 
– Records of any adverse event or device effect, including supporting documentation. 
– Records pertaining to subject deaths during the study. 
– The study protocol/amendments including documentation and rationale for any 
deviations from the clinical protocol. 
– Any other records required by Alkahest, Inc. or FDA. 
 
The investigator’s study file will contain all of these documents, as well as staff curriculum vitae 
and authorization forms, and other appropriate documents and study-specific manuals (e.g., 
Device Procedures Manual). 
13.2. Study Records Retention 
Per 21 CFR 812.140(d), an investigator or Sponsor shall maintain the records required by this 
subpart during the investigation and for a period of 2 years after the latter of the following 2 
dates: the date on which the investigation is terminated or completed, or the date that the records 
are no longer required for purposes of supporting a premarket approval application, a notice of 
completion of a product development protocol, a humanitarian device exemption application, a 
premarket notification submission, or a request for De Novo classification. 

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Before the investigator destroys any material related to the clinical study, he/she must obtain 
approval in writing from the Sponsor. 
The investigator should keep a file where the full name and address of the subject and all signed 
informed consents are included for at least 15 years after completion of the trial. Any original 
study-related information that permits verification of inclusion and exclusion criteria, including 
clinical history, a copy of all data collection logs, and documents on the use of the study device, 
must be stored for as long a time period as permitted by the center.  
Should the investigator wish to move study records to another location, arrangements must be 
made to store these in sealed containers so that they can be returned sealed to the investigator in 
case of a regulatory audit. Where source documents are required for the continued care of the 
subject, appropriate copies should be made for storage outside of the site. 
13.3. Protocol Deviations 
A Protocol Deviation is any noncompliance with the clinical trial protocol or with GCP. The 
noncompliance may be either on the part of the subject, the investigator, or the study site staff. 
When deviations occur, corrective actions are to be developed by the site and implemented 
promptly. 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
Protocol Deviations will be categorized as either Major or Minor and will be defined in the study 
specific Protocol Deviation Plan. 
 
Major Protocol Deviations are departures from the approved protocol relating to the 
conduct of the study which may significantly impact the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect the rights, safety, and/or 
wellbeing of study participants. Examples of Major Protocol Deviations include, but are 
not limited to: 
• Failure to obtain informed consent (i.e., no evidence of informed consent) 
• Enrolling subjects in violation of key eligibility criteria designed to ensure a 
specific subject population 
• A device dispensing or related error that could have affected the safety of the 
subject 
• Failure to collect data necessary to interpret the primary endpoint(s), as this may 
compromise the scientific value of the trial. 
 

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CONFIDENTIAL/PROPRIETARY 
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Major Protocol Deviations may result in data that are not deemed evaluable for analysis 
and/or may require that subjects are discontinued from the study.  
 
Note: Observations categorized as Major may include those situations where there is a 
pattern of deviation, numerous Minor observations, or other significant deviation. 
 
Minor Protocol Deviations are departures from the approved protocol relating to the 
conduct of a study that does not affect the rights, safety, and/or wellbeing of study 
participants or the study outcomes or data quality. Examples of Minor Protocol 
Deviations include, but are not limited to: 
• A protocol visit date outside of a visit window 
• An isolated case of a missed or incomplete study procedure  
• An isolated incident of a missed or incomplete study evaluation 
 
Minor Protocol Deviations would not generally preclude subject data from the per 
protocol analysis population. Observations categorized as Minor may become Major if 
not corrected. 
 
All deviations will be logged and tracked by the site and CRO. Periodic review of Protocol 
Deviations will serve an indicator of site performance. 
 
Per 21 CFR 812.150(a)(4), it is the responsibility of the site to use continuous vigilance to 
identify and report deviations promptly (within 5 working days) to the study CRO and/or 
Sponsor. All deviations must be addressed in study source documents. Notification of Protocol 
Deviations must be sent to the local IRB per their guidelines. The site investigator/study staff is 
responsible for knowing and adhering to their IRB requirements. 
13.4. Publication and Data Sharing Policy 
In compliance with the International Committee of Medical Journal Editors clinical trials 
registration policy and Section 801 of the FDA Amendments Act of 2007, this study will be 
registered by the Sponsor in ClinicalTrials.gov, a public trials registry which is sponsored by the 
National Library of Medicine. 
Notwithstanding the Sponsor’s requirements for registration and data sharing in 
ClinicalTrials.gov, any formal presentation or publication of data collected as a direct or indirect 
result of this trial will be considered as a joint publication by the investigator(s) and the Sponsor. 
In the case of multicenter studies, it is mandatory that the first publication be made based on the 
totality of data obtained from all centers, analyzed as stipulated in the protocol, and presented 
and interpreted as documented in the final Clinical Study Report. The resulting publication will 
name investigators according to the policy of the chosen journal. Where it is not permitted for all 
investigators to be included as authors, the publication will name all investigators within the 
publication. 

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Individual investigators may publish data arising from their own subjects. The investigator will 
provide the Sponsor with copies of written publications (including abstracts and posters) at least 
60 days in advance of submission. This review is to permit the Sponsor to review the 
communication for accuracy (thus avoiding potential discrepancies with submissions to 
regulatory authorities), to verify that confidential information is not inadvertently divulged 
(including patent protection), to allow adequate input or supplementary information that may not 
have been available to the investigator, and to allow establishment of co-authorship. 
Investigators participating in multicenter studies must agree not to engage in presentations based 
on data gathered individually or by a subgroup of centers before publication of the first main 
publication unless this has been agreed otherwise by all other investigators and the Sponsor. 
However, in the event that no publication of the overall results has been submitted after approval 
of the Clinical Study Report, investigators may publish results of one or more center’s subjects to 
the same review as outlined above. The Sponsor will circulate proposed multicenter publications 
to all investigators for review. 
Data will be reviewed by all participating investigators prior to publication. The study Sponsor 
will have 90 days to review all definitive publications, such as manuscripts and book chapters, 
and a minimum of 30 days to review all abstracts. 

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14. 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY 
A separate financial disclosure agreement will be made between each principal investigator and 
Alkahest, Inc. or its authorized representative before the study agent is shipped. Each 
investigator will notify Alkahest, Inc. or its authorized representative of any relevant changes 
during the conduct of the study and for 1 year after the study has been completed. Alkahest and 
the study CRO will evaluate any disclosed conflicts of interest and will establish a mechanism 
for their management. 

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CONFIDENTIAL/PROPRIETARY 
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15. 
SCHEDULE OF EVENTS 
 
15.1. Screening (Weeks -5 to -2)/Run-in (Week -1)/Treatment Period (Weeks 1 and 2) 
 
 
Screening 
Run-In Period 
Treatment Period 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Week 
Weeks -5 
to -2 
Week -1 
Week 1* 
Week 2 
Study Day(s) (± 1) 
Days -35 to 
-7 
Day   
-6 
Day   
-3 
Day   
-1 
Day 
1 
Day 
3 
Day 
6 
Day 
8 
Day 
10 
Day 
13 
Procedures 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests2 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Column size 
None 
None 
S-15 
S-15 
Hemodialysis blood-
flow rate (mL/min) 
Standard 
rate 
250  
Up to 450 
Assessment of fluid 
status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Kt/V assessment 
 
 
X 
 
 
X 
 
 
X 
 
Adverse events and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*The first treatment with the 
 column S-15 (150 mL) will occur mid-week (e.g., on Wednesday for subjects on a 
Monday/Wednesday/Friday schedule and on Thursday for subjects on a Tuesday/Thursday/Saturday schedule). 
1. For additional information, see Section 7.1.1.2.2 Monitoring of Vital Signs. 
2. For additional information, see Section 15.3 Schedule of Laboratory Tests. 
 

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CONFIDENTIAL/PROPRIETARY 
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15.2. Treatment Period (Weeks 3 to 6) /End of Study (Week 7) 
 
 
Treatment Period 
 
EOS 
Visit Number 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
(EOT) 
V23 
Study Week 
Week 3* 
Week 4 
Week 5* 
Week 6 
 
Week 7 
Study Day(s)     (± 1) 
Day 
15 
Day 
17 
Day 
20 
Day 
22 
Day 
24 
Day 
27 
Day 
29 
Day 
31 
Day 
34 
Day 
36 
Day 
38 
Day 
41 
Day 43 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests2 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Column size 
S-25 
S-35 
 
Hemodialysis blood-
flow rate (mL/min) 
250 
Up to 450 
250 
Up to 450 
 
Assessment of fluid 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Kt/V assessment 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Adverse events and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
*The escalation to the subsequent column-size and flow-rate combination of the 
 column will occur mid-week (e.g., on 
Wednesday for subjects on a Monday/Wednesday/Friday schedule and on Thursday for subjects on a Tuesday/Thursday/Saturday 
schedule). 
1. For additional information, see Section 7.1.1.2.2 Monitoring of Vital Signs. 
2. For additional information, see Section 15.3 Schedule of Laboratory Tests. 

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CONFIDENTIAL/PROPRIETARY 
Page 61 of 80
 
 
 
15.3. Schedule of Laboratory Tests 
Assessment 
Screening 
Run-in 
Treatment Period 
End of 
Study 
(EOS) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
(EOT) 
V23 
b2M/proteomics 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Serum pregnancy 
(WOCBP only) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Hematology 
 
 
 
 
 
Note: CBC, Hp, Hgb, and plasma-free Hgb should be taken AFTER HD V4-V21. 
 
 
Complete blood 
count (CBC) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Haptoglobin (Hp) 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Hemoglobin 
(Hgb) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Plasma-free Hgb 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Chemistry 
 
 
Note: BUN and Creatinine should be collected BEFORE and AFTER HD. 
Alanine 
aminotransferase 
(ALT) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Albumin 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Aspartate 
transaminase 
(AST) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Bicarbonate 
(HCO3) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin (total) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood urea 
nitrogen (BUN)  
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Calcium (Total) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Chloride (Cl) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Creatine kinase 
(CK) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine  
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Glucose 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Hemoglobin A1c 
(HbA1c) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol AKST1210-101 V2.1                                                                                                                                                                                            13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 62 of 80
 
 
Assessment 
Screening 
Run-in 
Treatment Period 
End of 
Study 
(EOS) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
(EOT) 
V23 
Lactate 
dehydrogenase 
(LDH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magnesium (Mg) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potassium (K) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Phosphate 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Protein (total) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Sodium (NA) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activated partial 
thromboplastic 
time (aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prothrombin time 
(PT/INR) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B 
surface/core 
antigen (HBsAg)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C 
antibody (HCV 
Ab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Human 
immunodeficienc
y virus antibody 
(HIV Ab, 
HIV1/HIV-2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Clinical 
Labs 
Note: All labs in the “Other Clinical Labs” 
section should be collected AFTER HD at V4. 
Note: All labs in the “Other Clinical Labs” section should be collected BEFORE and AFTER HD at V7 and V22.  
 
Adrenocorticotro
pic hormone 
(ACTH) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complement  
(total)(CH50) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complement C3 
and C4 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Complement C5a 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Gastrin 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Heparin Anti-Xa 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 

Protocol AKST1210-101 V2.1                                                                                                                                                                                            13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 63 of 80
 
 
Assessment 
Screening 
Run-in 
Treatment Period 
End of 
Study 
(EOS) 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
(EOT) 
V23 
(only for patients on low 
molecular weight heparin) 
Insulin 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Insulin-like 
growth factor-
binding protein 1 
(IGFBP1) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Osteocalcin 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Parathyroid 
hormone (PTH) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Terminal 
complement 
complex (sC5b-9) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Thyroid-
stimulating 
hormone (TSH) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 

Protocol AKST1210-101 V2.0                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 64 of 80 
 
16. 
REFERENCES 
 
 
 
 
Clinical Trial Facilitation Group.  Recommendations related to contraception and pregnancy 
testing in clinical trials. Version 2014-09-15:1-13. 
Daugirdis JT. Second generation logarithmic estimates of single-pool variable volume KtV: an 
analysis of error. J Am Soc Nephrol. 1993;4:1205-1213. 
Daugirdis JT. Simplified equations for monitoring Kt/V, PCRn, eKt/V, and ePCRn. Adv Renal 
Replace Ther. 1995;2:295-304. 
Daugirdis JT, Schneditz D. Overestimation of hemodialysis dose depends on dialysis efficiency 
by regional blood flow but not by conventional two pool urea kinetic analysis. Am Soc Art 
Intern Org. 1995;41:M719-M724. 
Flythe JE, Xue H, Lynch KE, Curhan GC, Brunelli SM. Association of mortality risk with 
various definitions of intradialytic hypotension. J Am Soc Neprhol. 2015;26:724-734. 
Food and Drug Administration (FDA) Center for Devices and Radiological Health. Guidance for 
the Content of Premarket Notifications for Hemodialysis Delivery Systems. August 7, 1998.  
 
 
Investigator’s Brochure (
 Column/AKST1210). 
Lichtenstein D: Novel approaches to ultrasonography of the lung and pleural space: where are 
we now? Breathe. 2017; 13:100–111. 
 
  
Murray AM, Bell EJ, Tupper DE, Davey CS, Pederson SL, Amiot EM, et al: The brain in kidney 
disease (BRINK) cohort study: design and baseline cognitive function. Am J Kidney Dis. 
2016;67(4):593–600.  
Rodriguez HJ, Domenici R, Diroll A, Goykhman I. Assessment of dry weight by monitoring 
changes in blood volume during hemodialysis using Crit-Line. Kidney Intl. 2005;68:854-861. 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
Alkahest, Inc. 
CONFIDENTIAL/PROPRIETARY 
Page 65 of 80 
Roumelioti ME, Trietley G,  Nolin TD, Ng YH, Zu Z, Alaini A, et al. Beta-2 microglobulin 
clearance in high-flux dialysis and convective dialysis modalities: a meta-analysis of published 
studies. Nephrol Dial Transplant. 2018;33(3):542-552. 
Sarnak M, Tighiouart H, Scott T, Lou KV, Sorensen EP, Giang LM, et al. Frequency and risk 
factors for poor cognitive performance in hemodialysis patients. Neurology. 2013;80:471–480.   
Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, et al: β2-microglobulin is a systemic 
pro-aging factor that impairs cognitive function and neurogenesis. Nat Med. 2015;21:932-937. 
Tamura MK, Vittinghoff E, Hsu C,  Tam K, Seliger SL, Sozio S,et al: Loss of executive function 
after dialysis initiation in adults with chronic kidney disease. Kidney Int. 2017;91:948–953 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 66 of 80 
17. 
APPENDICES 
 
 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 67 of 80 
17.1. Escalation, De-escalation, and Discontinuation Rules for Treatment with the 
 Column 
The purpose of the escalation rules is to ensure the safety of the subject when transitioning to a 
larger-size column. Since the main risk of 
 – IDH – is related to column size, the 
occurrence of IDH will be the main criterion used to determine the appropriateness of escalation 
to a larger column size; however, other factors will be considered when escalating, including the 
overall status of the subject, other AEs, laboratory abnormalities, adequacy of HD, etc.   
The following definitions are relevant to evaluating whether to escalate, de-escalate, or 
discontinue a subject:  
• 
Intradialytic hypotension/hypotensive (IDH) event: An SBP < 90 mmHg confirmed 
by repeat measurement. 
• 
Expected IDH Rate: The expected number of occurrences of IDH per weekly 
treatment period used to assess escalation, de-escalation, and discontinuation. Expected 
IDH Rate is derived from a subject’s Historical IDH Rate (see table below). 
• 
Historical IDH Rate: The number of occurrences of IDH as documented in a subject’s 
medical record during a recent 8-week period prior to the run-in period. Subjects with 7 
or more IDH events during this 8-week interval will be excluded. 
Table 3 below provides the corresponding Expected IDH Rate based on the Historical IDH Rate 
and summarizes the rules for escalation, de-escalation, or discontinuation based on the number 
of occurrences of IDH.  
 
Table 3.  Guidance for Escalation, De-escalation, and Discontinuation Based on IDH Rate 
 
Historical IDH Rate 
over 8 Weeks 
Expected Weekly 
IDH Rate 
Escalate to Next 
Column Size or Blood-
Flow Rate if IDH Rate 
in 1 Week is: 
De-escalation to Previous 
Treatment or Discontinue from 
Study if IDH Rate in 1 Week is: 
0 
< 1 
0 
> 1 
1 
< 1 
1 or less 
2 
< 1 
3 
< 1 
4 
< 1 
5 
< 1 
2 or less 
 > 2 
6 
~1 
 
17.1.1. 
Escalation Rules 
A subject may be escalated to the next larger column size or next blood-flow rate if they 
experience no more than the number of IDH events described in Table 3, maintain an Hgb level 
≥ 9 g/dL, and have no other safety signals that the investigator believes could put the subject at 
risk. If a subject has an SBP < 90 mmHg, confirmed by repeat measurement, before the start of 

Protocol AKST1210-101 V2.1                                                                                                                    13MAY2021 
 
 
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CONFIDENTIAL/PROPRIETARY 
Page 68 of 80 
HD, the subject will be withdrawn from the study because this constitutes significant 
hemodynamic compromise.  
If a subject cannot attain the planned high blood-flow rate (450 mL/min) due to technical factors 
(e.g. differential pressures in the dialysis circuit), the investigator can adjust the blood-flow rate 
down to such a rate that allows the 
 column to be tested at a higher rate than 
250 mL/min. 
 

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17.1.2. 
De-escalation Rules 
The purpose of the de-escalation rules is to ensure the safety of a subject who is experiencing 
IDH, anemia or other safety issues that may be related to the column size.  
A subject should be de-escalated if during the 1-week treatment period they experience the 
number of IDH events described in the table above and/or have an Hgb level < 9 g/dL despite 
receiving optimized treatment with ESA.  
De-escalation will only be applicable at V11 through V19 as shown in Figure 4 below. Subjects 
who do not tolerate treatment with the S-15 column at any time prior to V11 or after V19 will be 
discontinued (see Section 17.1.13. Discontinuation Rules). 
 
Figure 4. De-escalation Schematic 
 
Subjects will continue with the same visit schedule after de-escalation. At the visit following 
confirmation of de-escalation, treatment will resume with the previous column size at the high 
flow rate (up to 450 mL/min).  
 If de-escalation occurs during V11 through V16, subjects will resume treatment at the 
next scheduled visit with the S-15 column at up to 450 mL/min and will continue with 
this column size/flow rate combination through EOT (V22).   
 If de-escalation occurs during V17 through V19, subjects will resume treatment at the 
next scheduled visit with the S-25 column at up to 450 mL/min and will continue with 
this column size/flow rate combination through EOT (V22).   
 
Table 4 below illustrates the visit schedule for subjects who de-escalate. Note: the only change 
compared to Section 15 is column size and flow rate.  
 
 
 
 
 
 
 

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Table 4. Schedule of Events for Subjects Who De-escalate 
 
1. For additional information, see Section 7.1.1.2.2 Monitoring of Vital Signs. 
2. For additional information, see Section 15.3 Schedule of Laboratory Tests. 
 
17.1.3. 
Discontinuation Rules 
Subjects will be discontinued and complete the End of Study visit procedures if: 
• Subject does not tolerate the S-15 column at either flow rate 
• Subject does not tolerate the S-35 at the higher flow rate (up to 450 mL/min) 
• Subject has already de-escalated and they experience the number of IDH events 
described in the Table 3 and/or have an Hgb level < 9 g/dL despite receiving optimized 
treatment with ESA 
• At any time during the study at the investigator’s discretion 
As a reminder, all occurrences of IDH after the time of consent will be recorded as AEs. 
 
Treatment Period 
EOS 
Visit Number 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
(EOT) 
V23 
Study Week 
Week 3 
Week 4 
Week 5 
Week 6 
 
Week 
7 
Study Day(s)   
(± 1) 
Day 
15 
Day 
17 
Day 
20 
Day 
22 
Day 
24 
Day 
27 
Day 
29 
Day 
31 
Day 
34 
Day 
36 
Day 
38 
Day 
41 
Day 
43 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests2 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Column size 
S-15 
S-15 OR S-25 (if de-escalated after V16) 
 
Hemodialysis 
blood-flow rate 
(mL/min) 
Up to 450 
 
Assessment of 
fluid status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Kt/V assessment 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Adverse events 
and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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18. 
REVISION HISTORY 
18.1. Summary of Changes 
 
Protocol Version 2.1 dated 13MAY2021 
Replaces: Protocol Version 2.0 dated 12APR2021 
 
The following table describes changes from Version 2.0 (dated 12APR2021) with justifications 
provided. 
 
 
 
Protocol Version 2.0 dated 12APR2021 
Replaces: Protocol Version 1.2 dated 06JAN2021 
 
The following table describes changes from Version 1.2 (dated 06JAN2021) with justifications 
provided. 
 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read:  “V2.0_12APR2021” 
 
Now reads: “V2.1_13MAY2021” 
Version control. 
 
 
 
 
 
 
 
 
7.1.1.2.2 
The following content was removed: 
“If screening and/or EOS occur on a day in which a 
subject is not receiving HD, vital signs will be 
measured after the subject has been seated/reclined 
for ~5 minutes.” 
The proposed language 
regarding measurement of 
vital signs at screening and 
EOS caused confusion; 
therefore, the content was 
removed. 
13.4 
The following text was reinstated: 
“In compliance with The International Committee 
of Medical Journal Editors clinical trials 
registration policy and Section 801 of the FDA 
Amendments Act of 2007, this study will be 
registered by the Sponsor in ClinicalTrials.gov, a 
public trials registry which is sponsored by the 
National Library of Medicine. 
 
Notwithstanding the Sponsor’s requirements for 
registration and data sharing in ClinicalTrials.gov,” 
This Phase 1 study meets 
criteria for publication on 
ClinicalTrials.gov; 
therefore, Alkahest will add 
this study to the 
ClinicalTrials.gov registry. 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read:  “V1.2_06JAN2021” 
 
Version control. 

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Now reads: “V2.0_12APR2021” 
Throughout 
Minor grammar, content, and style updates.  
Minor content updates for 
clarity/accuracy/style of 
content. 
Table of 
Contents 
Minor content updates. 
Minor updates required to 
reflect revised content. 
List of 
Definitions, 
17.1 
The Definition of Historical IDH Rate has been 
revised as follows:  
Previously read: “The number of occurrences of 
IDH as documented in a subject’s medical record 
during a recent 8-week period prior to enrollment.” 
 
Now reads: “The number of occurrences of IDH as 
documented in a subject’s medical record during a 
recent 8-week period prior to the run-in period.” 
Clarification that the 
Historical IDH Rate begins 
prior to the run-in period 
rather than enrollment. 
Protocol 
Summary 
(Précis, 
Population), 
4.1, 5.1, 10.5  
The subject age range was previously 45-70 years; 
it has been changed to 40-75 years. 
 
Revised to expand 
recruitment. 
Protocol 
Summary 
(Précis), 4.1, 
15.1, 15.2, 
17.1.2 (Table 
4)  
The run-in period will now be considered Week -1 
of the study. Treatment with the 
 column 
will begin in Week 1. Previous and subsequent 
study weeks/days have been renumbered, as 
appropriate, throughout the document. 
For the purposes of 
accurate data collection, the 
run-in period will be 
considered Week -1, with 
 column 
treatment beginning at 
Week 1. 
Protocol 
Summary 
(Précis), 4.1,  
15.1, 15.2 
Content was added to clarify that the first treatment 
with the 
 column S-15 will occur mid-
week (e.g., on Wednesday for subjects on a 
Monday/Wednesday/Friday schedule and on 
Thursday for subjects on a 
Tuesday/Thursday/Saturday schedule). 
Clarification of treatment 
weekly treatment schedule. 
Protocol 
Summary 
(Précis), 2.2.1 
(Table 1) 
Minor modifications to the risk mitigation 
strategies for IDH including: 
• Supine positioning/lower limb elevation. 
• Avoidance of changes in medications, 
especially those that can affect BP, during the 
study. 
Clarification and provision 
of additional mitigation 
strategies for IDH. 
Protocol 
Summary 
(Number of 
Sites) 
The number of sites was changed as follows:  
Previously read: “2-3, US Only” 
 
Now reads: “Up to 4, US Only” 
Revised to expand 
recruitment.  
2.2.1 (Table 1), 
5.4.1 
Content revised to emphasize that subjects who 
have an SBP < 90 mmHg, confirmed by repeat 
measurement, before the start of HD will be 
withdrawn/discontinued from the study.   
Clarification that repeat 
measurement of SBP 
< 90 mmHg is required for 
confirmatory purposes. 
5.1 
Previously read:  
• “4. Absence of residual renal function (i.e., no 
urine output).”  
Clarification of renal 
function required for 
inclusion in the study. 

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Now reads: 
• “4. Absence of clinically-relevant residual 
renal function.” 
Previously read:  
• “9. Must be on stable doses (> 4 weeks) of all 
treatments for concomitant diseases (e.g., 
diabetes, hypertension).” 
 
Now reads: 
• “9. Must be on stable doses (> 4 weeks) of all 
treatments for concomitant diseases (e.g., 
diabetes, hypertension), but this does not apply 
to medications for conditions related to ESRD 
(e.g., medications for calcium and phosphate 
control, anemia).  
Clarification of treatments 
for concomitant diseases. 
5.2 
Previously read:  
• “18. Concurrent or have recent participation in 
another interventional clinical trial. Prior clinical 
trial subjects must have discontinued 
investigational agents/devices at least 30 days 
prior to screening.” 
 
Now reads: 
• “18. Concurrent or have recent participation in 
another interventional clinical trial. Prior clinical 
trial subjects must have discontinued 
investigational agents/devices at least 30 days 
prior to planned first use of the 
 
column.”  
Clarification of timing of 
discontinuation of 
investigational 
agents/devices from prior 
clinical trials. 
6.1.1 
 
 
  
 
 
 
 
  
 
 
address change. 
7.1.1.2.2 
The following content was added: 
“If screening and/or EOS occur on a day in which a 
subject is not receiving HD, vital signs will be 
measured after the subject has been seated/reclined 
for ~5 minutes.” 
Clarification of 
measurement of vital signs 
at screening and EOS. 
7.3.1 
Heading title was changed from “Screening” to 
“Screening/Run-In” 
Revision of heading title 
for accuracy. 
8.4.2.1 
Content related to event reporting has been revised 
as follows: 
Previously read:  
Revised to align with IRB 
reporting requirements. 

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Protocol Version 1.2 dated 06JAN2021 
Replaces: Protocol Version 1.1 dated 21DEC2020 
 
The following table describes changes from Version 1.1 (dated 21DEC2020) with justifications 
provided. 
 
• “All SAEs (including SADEs and UADEs) must 
be reported to the IRB as soon as possible but in 
no event later than 10 working days after 
becoming aware of the event.” 
 
Now reads: 
• “All applicable events (including UADEs) must 
be reported to the IRB as soon as possible but in 
no event later than 10 working days after 
becoming aware of the event.” 
 
13.4 
The following text was removed: 
“In compliance with The International Committee 
of Medical Journal Editors clinical trials 
registration policy and Section 801 of the FDA 
Amendments Act of 2007, this study will be 
registered by the Sponsor in ClinicalTrials.gov, a 
public trials registry which is sponsored by the 
National Library of Medicine. 
 
Notwithstanding the Sponsor’s requirements for 
registration and data sharing in ClinicalTrials.gov,” 
This content was removed 
as this Phase 1 study will 
not be published on 
ClinicalTrials.gov. 
15.3 
Testing of chloride was erroneously included at 
Visit 22; test was corrected to calcium (total).   
Correction of laboratory 
testing at Visit 22. 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read:  “V1.1_21DEC2020” 
 
Now reads: “V1.2_06JAN2021” 
Version control. 
5.2 
Previously read:  
• “8. […] Women of childbearing potential 
(WOCBP) must have a negative serum/urine 
pregnancy test at screening, prior to treatment, 
and at EOS.”  
 
Now reads:  
• “8. […] Women of childbearing potential 
(WOCBP) must have a negative serum 
pregnancy test at screening and prior to 
treatment.”  
Clarification to reflect that 
only serum pregnancy tests 
will be conducted in 
WOCBP. In addition, 
because a negative serum 
pregnancy test is not 
required for eligibility at 
EOS (but is required for 
safety purposes), this 
requirement has been 
removed from Section 5.2 
and added in Section 15.3. 
7.1.1.1 
Added that laboratory tests during run-in will 
include a pregnancy test for WOCBP. 
Clarification to align with 
Exclusion Criterion #8 

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Protocol Version 1.1 dated 21DEC2020 
Replaces: Protocol Version 1.0 dated 26OCT2020 
 
The following table describes changes from Version 1.0 (dated 26OCT2020) with justifications 
provided. 
 
which states that WOCBP 
must have a negative 
pregnancy test at screening 
and prior to start of the first 
treatment. 
7.3.4 
Previously read: “In the event of early withdrawal 
or discontinuation of a subject who has been 
randomized and received at least 1 HD treatment, 
the EOS procedures will be performed […]” 
 
Now reads: “In the event of early withdrawal or 
discontinuation of a subject who has received at 
least 1 HD treatment with the 
 column, 
the EOS procedures will be performed […]” 
Clarification to ensure 
alignment with Section 5.4.2. 
Handling of Participant 
Withdrawals/Discontinuation 
15.3 
Added serum pregnancy tests at V4 and EOS 
(WOCBP only) to the Schedule of Laboratory 
Assessments.  
Clarification to align with 
Exclusion Criterion #8 
which states that WOCBP 
must have a negative 
pregnancy test at screening, 
and prior to treatment. A 
negative pregnancy test at 
EOS is also required for 
safety purposes.. 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read:  “V1.0_26OCT2020” 
 
Now reads: “V1.1_21DEC2020” 
Version control. 
Throughout 
Minor grammar, content, and style updates.  
Minor content updates for 
clarity/accuracy/style of 
content. 
Table of 
Contents and 
List of 
Abbreviations 
Minor content updates. 
Minor updates required to 
reflect revised content. 
List of 
Definitions 
The Definition for Intradialytic 
Hypotension/Hypotensive Event (IDH) has been 
revised as follows:  
Previously read: “A systolic blood pressure (SBP) 
< 90 mmHg that occurs during hemodialysis.” 
 
Now reads: “A systolic blood pressure (SBP) < 90 
Clarification that an IDH 
requires confirmation by 
repeat measurement. 

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mmHg that occurs during hemodialysis and is 
confirmed by repeat measurement.” 
Protocol 
Summary 
(Endpoints), 
4.2.1 
The Primary Endpoints have been revised as 
follows:  
Previously read:  
• “Safety and tolerability of each column size and 
each blood-flow rate. 
o Safety assessments will include the number 
of treatment-emergent adverse events 
(TEAEs), number of IDH events, and 
changes in total and free hemoglobin (Hgb). 
o Tolerability will be assessed by the 
proportion of subjects who can escalate to 
and tolerate each column size and blood-
flow rate combination.” 
 
Now reads:  
• “Safety and tolerability of each column size and 
each blood-flow rate. 
o Evaluation of safety and tolerability will 
include assessment of the rate and severity 
of all adverse events (AEs), with analysis of 
adverse device effects (ADEs), treatment-
emergent AEs (TEAEs), number of IDH 
events, and changes in total and free 
hemoglobin (Hgb). 
o Tolerability will be assessed by the 
proportion of subjects who can escalate to 
and tolerate each column size and blood-
flow rate combination.” 
Provision of additional 
detail and clarification of 
the specific safety and 
tolerability assessments that 
will be evaluated. 
2.2.1 
An additional mitigation strategy was added for 
IDH: “Withdrawal of subjects who have a 
systolic blood pressure (SBP) < 90 mmHg 
before the start of HD (confirmed by repeat 
measurement).”  
 
Provision of additional 
precautionary safety 
measures to mitigate IDH. 
Additional potential risks (low incidence) and 
mitigation strategies were added for: allergic 
reaction/anaphylaxis, cramping, itching, 
headache, and hemolysis.   
 
Provision of additional 
potential risks and 
mitigation strategies. 
5.2 
The previous Exclusion Criterion #4 was split and 
revised as follows (split also required renumbering 
of subsequent Exclusion Criteria):  
Previously read:  
• “4. History of hypersensitivity to heparin, the 
 column, or materials in the column.”  
 
Now reads:  
• “4. History of hypersensitivity to heparin, 
Provision of additional 
detail and clarification of 
exclusions related to 
hypersensitivity to heparin 
and/or the 
 
column or its components.   

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including heparin-induced thrombocytopenia.” 
• 5. History of hypersensitivity to the 
 
column or its components.” 
5.4.1 
In bullet #1, the following content was added: 
Previously read:  
• “Occurrence of an AE, that represents and 
unacceptable risk…”  
 
Now reads:  
• “Occurrence of an AE, including significant 
hemodynamic compromise, that represents an 
unacceptable risk…” 
Clarification that 
significant hemodynamic 
compromise may require 
discontinuation from the 
study based on the 
determination of the 
investigator, Sponsor, or 
medical monitor. 
The content in Bullet #7 was expanded and an 
additional bullet was added: 
Previously read:  
• “A subject will be discontinued according to the 
discontinuation rules provided in Appendix 
17.1.” 
 
 
Now reads: 
• “A subject will be discontinued if they have a 
confirmed SBP < 90 mmHg before the start of 
an HD session. 
• A subject will be discontinued if the number of 
IDH events (defined as an SBP < 90 mmHg) 
during a treatment period exceeds the 
predetermined threshold of the subject’s 
Historical IDH Rate after de-escalation to the 
lowest column size (see Appendix 17.1).” 
Clarification that a subject 
will be discontinued due to 
a confirmed SBP 
< 90 mmHg prior to an HD 
session and/or IDH events 
in excess of the subject’s 
Historical IDH Rate after 
de-escalation to the lowest 
column size.  
8.1.1 
The section heading was revised as follows: 
Previously read:  
• “Definition of Adverse Event and Adverse 
Device Effect”  
 
Now reads:  
• “Definition of Adverse Event, Procedure-
Related Adverse Event, and Adverse Device 
Effect” 
 
The following text was also added to define a 
procedure-related adverse event: “In relation to 
Note 2 above, a sub-classification of an AE is a 
procedure-related AE (PRAE). A PRAE is an AE 
that most likely occurs as a result of HD or related 
procedures, irrespective of the investigational 
medical device. Examples of a PRAE in HD 
include vascular access site complications, 
including access hemorrhage and venous needle 
dislodgement; disruption or contamination of the 
Revised to define a PRAE, 
with examples, to promote 
investigator awareness and 
understanding. 

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dialysis water system; venous air embolism; sepsis; 
cardiac complications including arrhythmia, 
angina, and cardiac arrest; electrolyte imbalances 
including hypokalemia and hyperkalemia, etc. In 
cases where relatedness is unclear, a conservative 
stance is to consider the event as related to the 
investigational medical device.” 
 
8.3 
Section content expanded as follows: 
Previously read: 
• “At every clinic visit, subjects will be assessed 
for AEs and SAEs. After the subject has had 
an opportunity to spontaneously mention any 
problems, the investigator should inquire 
about AEs by asking a non-leading question 
such as the following: 
1. “How are you feeling?” 
2. “Have you had any changes since your last 
assessment/visit?” 
3. “Have you taken any new medicines since 
your last assessment/visit?” 
 
Now reads: 
• “At very clinic visit, subjects will be assessed 
for AEs and SAEs. All AEs and SAEs will be 
monitored and recorded by trained and 
knowledgeable personnel to protect subjects 
from harm. At the beginning of each visit, 
after the subject has had an opportunity to 
spontaneously mention any problems that may 
have occurred during the preceding 
interdialytic interval, the investigator should 
inquire about any possible interdialytic AEs 
by asking a non-leading question such as the 
following: 
 
1. “How are you feeling?” 
2. “Have you had any changes since your last 
assessment/visit?” 
3. “Have you taken any new medicines since 
your last assessment/visit?” 
 
     During and for a period after each HD session, 
participating subjects will be closely 
monitored by qualified healthcare personnel 
who are trained in HD and who have 
experience in the types of AEs that typically 
occur during HD. Any events that occur 
during or after HD (before the subject leaves 
the clinic), will be assessed by the HD 
Clarification of safety 
assessments and monitoring 
related to both procedures 
and personnel. 

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personnel (e.g. hemodialysis technician or 
nurse) and discussed as appropriate with the 
investigator or designee.” 
8.4.3 
Section heading included in error. 
Section heading removed to 
correct error. 
15.2 
The Kt/V assessment was removed from Visit 
23 (EOS).  
Assessment of Kt/V is not 
necessary as HD is not 
included in Visit 23 (EOS). 
15.3 
Expanded note to indicate that plasma-free Hgb 
should also be taken AFTER HD V4-V21. 
Clarification of timing of 
laboratory measurement. 
17.1 
The content in the initial paragraph was updated 
and expanded as follows:  
Previously read: 
• “The purpose of the escalation rules is to 
ensure the safety of the subject when 
transitioning to a larger-size column, since 
the main risk of 
 – IDH – is 
related to column size.”  
 
 
Now reads: 
• “The purpose of the escalation rules is to 
ensure the safety of the subject when 
transitioning to a larger-size column. Since 
the main risk of 
 – IDH – is 
related to column size, the occurrence of 
IDH will be the main criterion used to 
determine the appropriateness of escalation 
to a larger column size; however, other 
factors will be considered when escalating, 
including the overall status of the subject, 
other AEs, laboratory abnormalities, 
adequacy of HD, etc.”  
 
Clarification of the purpose 
of the escalation rules and 
definition of IDH. 
The initial bullet page was also updated as 
follows 
Previously read: 
• “Intradialytic hypotension/hypotensive 
(IDH) event: An SBP < 90 mmHg. 
 
Now reads: 
• “Intradialytic hypotension/hypotensive 
(IDH) event: An SBP < 90 mmHg 
confirmed by repeat measurement.” 

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17.1.1 
The content in the initial paragraph was updated 
and expanded as follows:  
Previously read: 
• “A subject may be escalated to the next larger 
column size or next blood-flow rate if they 
experience no more than the number of IDH 
events described in Table 3, have a level ≥ 9 g/dL, 
and have no other safety signals that the 
investigator believes could put the subject at risk.” 
Now reads: 
• “A subject may be escalated to the next 
larger column size or next blood-flow rate if 
they experience no more than the number of 
IDH events described in Table 3, maintain 
an Hgb level ≥ 9 g/dL, and have no other 
safety signals that the investigator believes 
could put the subject at risk. If a subject has 
an SBP < 90 mmHg (confirmed by repeat 
measurement) before the start of HD, the 
subject will be withdrawn from the study 
because this constitutes significant 
hemodynamic compromise.” 
Clarification of escalation 
rules with additional details 
related to SBP parameters.