A Randomized, Double-Blind, Phase 2a Study to Evaluate the Tolerability, Feasibility, and Efficacy of AKST1210 in Patients on Hemodialysis With Cognitive Impairment Associated With End-Stage Renal Disease
Phase: NA
Conditions: Cognitive Impairment, End Stage Renal Disease
Sponsor: Alkahest, Inc.



 
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5.1 
INCLUSION CRITERIA ....................................................................................................... 23 
5.2 
EXCLUSION CRITERIA ...................................................................................................... 23 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION .............................................. 24 
5.4 
SUBJECT WITHDRAWAL/DISCONTINUATION ........................................................... 24 
5.4.1 
REASONS FOR WITHDRAWAL/DISCONTINUATION ........................................................... 24 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS/DISCONTINUATION .............................. 25 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ..................................... 25 
6 
STUDY DEVICE .................................................................................................................... 26 
6.1 
STUDY DEVICE AND CONTROL DESCRIPTION ......................................................... 26 
6.1.1 
ACQUISITION ............................................................................................................................... 26 
6.1.2 
DESCRIPTION, APPEARANCE, PACKAGING, AND LABELING .......................................... 26 
6.1.3 
PRODUCT STORAGE .................................................................................................................. 28 
6.1.4 
PREPARATION ............................................................................................................................. 28 
6.1.5 
COLUMN SIZE ESCALATION AND ADMINISTRATION ....................................................... 28 
6.1.6 
DURATION OF THERAPY .......................................................................................................... 29 
6.2 
STUDY DEVICE AND CONTROL ACCOUNTABILITY ................................................ 29 
7 
STUDY PROCEDURES AND SCHEDULE ........................................................................ 30 
7.1 
STUDY PROCEDURES/EVALUATIONS ........................................................................... 30 
7.1.1 
STUDY SPECIFIC PROCEDURES .............................................................................................. 30 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ........................................................... 35 
7.2.1 
CLINICAL LABORATORY EVALUATIONS ............................................................................. 35 
7.2.2 
OTHER TESTS OR PROCEDURES ............................................................................................. 35 
7.2.3 
SPECIMEN PREPARATION, HANDLING, STORAGE, AND SHIPPING ................................ 35 
7.3 
STUDY SCHEDULE .............................................................................................................. 36 
7.3.1 
SCREENING/RUN-IN ................................................................................................................... 36 
7.3.2 
RANDOMIZATION/TREATMENT ............................................................................................. 36 
7.3.3 
END OF TREATMENT/END OF STUDY VISITS ...................................................................... 36 
7.3.4 
EARLY WITHDRAWAL .............................................................................................................. 36 
7.4 
CONCOMITANT MEDICATIONS ...................................................................................... 36 
7.5 
 ...................... 37 
8 
ASSESSMENT OF SAFETY ................................................................................................. 37 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ............................................................... 37 
8.1.1 
DEFINITION OF ADVERSE EVENT AND ADVERSE DEVICE EFFECT ............................... 37 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENT AND SERIOUS ADVERSE DEVICE   
EFFECT ........................................................................................................................................................ 37 

 
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8.2 
CLASSIFICATION OF AN ADVERSE EVENT ................................................................ 38 
8.2.1 
SEVERITY OF EVENT ................................................................................................................. 38 
8.2.2 
RELATIONSHIP TO STUDY DEVICE ........................................................................................ 38 
8.2.3 
EXPECTEDNESS OF ADVERSE DEVICE EFFECTS ................................................................ 39 
8.3 
TIME PERIOD/FREQUENCY FOR EVENT ASSESSMENT/FOLLOW-UP ................ 39 
8.3.1 
POST-STUDY SAFETY ASSESSMENT ...................................................................................... 39 
8.4 
REPORTING PROCEDURES .............................................................................................. 39 
8.4.1 
ADVERSE EVENT/EFFECT REPORTING ................................................................................. 39 
8.4.2 
SERIOUS AND UNANTICIPATED ADVERSE EVENTS/EFFECTS REPORTING ................. 40 
8.4.3 
REPORTING OF PREGNANCY ................................................................................................... 41 
8.5 
STUDY HALTING RULES ................................................................................................... 42 
8.6 
SAFETY OVERSIGHT .......................................................................................................... 42 
9 
CLINICAL MONITORING .................................................................................................. 42 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 43 
10.1 
STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS .................................... 43 
10.2 
STATISTICAL HYPOTHESES ............................................................................................ 43 
10.3 
ANALYSIS DATASETS ......................................................................................................... 43 
10.4 
DESCRIPTION OF STATISTICAL METHODS ............................................................... 43 
10.4.1 
GENERAL APPROACH ................................................................................................................ 43 
10.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT .............................................................................. 44 
10.4.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS ................................................. 44 
10.4.4 
ANALYSIS OF THE SECONDARY SAFETY ENDPOINTS ...................................................... 44 
10.4.5 
ADHERENCE AND RETENTION ANALYSES .......................................................................... 44 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS .................................................................................... 44 
10.4.7 
PLANNED INTERIM ANALYSES .............................................................................................. 45 
10.4.8 
ADDITIONAL SUBGROUP ANALYSES .................................................................................... 45 
10.4.9 
MULTIPLE COMPARISON/MULTIPLICITY ............................................................................. 45 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA ............................................................. 45 
10.4.11 
EXPLORATORY ANALYSES ................................................................................................... 45 
10.5 
SAMPLE SIZE ........................................................................................................................ 45 
10.6 
MEASURES TO MINIMIZE BIAS ...................................................................................... 45 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES ............................................ 45 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING ............................................................................ 45 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE .................................................................. 46 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............ 46 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................... 46 

 
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12.1 
ETHICAL STANDARD ......................................................................................................... 46 
12.2 
INSTITUTIONAL REVIEW BOARD .................................................................................. 46 
12.3 
INFORMED CONSENT PROCESS ..................................................................................... 47 
12.3.1 
CONSENT FORMS ....................................................................................................................... 47 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION .............................................................. 47 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY .......................................................... 48 
12.5 
FUTURE USE OF STORED SPECIMENS .......................................................................... 48 
13 
DATA HANDLING AND RECORD KEEPING ................................................................. 48 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ............................ 48 
13.1.1 
INVESTIGATOR RESPONSIBILITIES ....................................................................................... 49 
13.1.2 
STUDY FILES ............................................................................................................................... 50 
13.2 
STUDY RECORDS RETENTION ........................................................................................ 50 
13.3 
PROTOCOL DEVIATIONS .................................................................................................. 51 
13.4 
PUBLICATION AND DATA SHARING POLICY ............................................................. 52 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY ..................... 52 
15 
SCHEDULE OF EVENTS ..................................................................................................... 53 
15.1 
SCHEDULE OF STUDY EVENTS ....................................................................................... 53 
SECTION 15.1.1 SCREENING AND RUN-IN ........................................................................................... 53 
SECTION 15.1.2 TREATMENT PERIOD 1 (VISIT 2/MONTH 1) ............................................................ 54 
SECTION 15.1.3 TREATMENT PERIOD 2 (VISIT 3/MONTH 2) ............................................................ 55 
SECTION 15.1.4 TREATMENT PERIOD 3 (VISIT 4/MONTH 3) ............................................................ 56 
SECTION 15.1.5 END OF TREATMENT AND END OF STUDY VISITS .............................................. 57 
15.2 
SCHEDULE OF LABORATORY TESTS ........................................................................... 58 
16 
REFERENCES ........................................................................................................................ 61 
16.1 
PUBLISHED REFERENCES ................................................................................................ 61 
16.2 
UNPUBLISHED REFERENCES .......................................................................................... 62 
17 
APPENDICES ......................................................................................................................... 63 
APPENDIX 17.1 ESCALATION, DE-ESCALATION, AND DISCONTINUATION RULES FOR 
TREATMENT WITH AKST1210 OR CONTROL .......................................................................... 63 

 
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18 
REVISION HISTORY ........................................................................................................... 64 
18.1 
SUMMARY OF CHANGES .................................................................................................. 64 

 
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LIST OF ABBREVIATIONS 
ADE 
Adverse device effect 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
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 
BRINK 
Brain in Kidney Disease 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CMP 
Clinical Monitoring Plan 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
DBP 
Diastolic blood pressure 
 
 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EOS 
End of Study 
ESA 
Erythropoiesis-stimulating agents  
ESRD 
End-stage renal disease 
ESRD-CI 
End-stage renal disease with cognitive impairment 
eGFR 
Estimated glomerular filtration rate 
ENT 
Ear, nose, throat 
FACIT 
Functional Assessments of Chronic Illness Therapy 
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 
HDL 
High-density lipoprotein 
HF 
High-flux 
HgB 
Hemoglobin 

 
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LIST OF DEFINITIONS 
 
Intradialytic 
hypotension/hypotensive 
event (IDH) 
A decrease in systolic blood pressure (SBP) ≥ 20 mm Hg or a decrease in 
mean arterial pressure (MAP) ≥10 mm Hg associated with symptoms that 
include: abdominal discomfort; yawning; sighing; nausea; vomiting; 
muscle cramps; restlessness; dizziness or fainting; and anxiety (K/DOQI 
Workgroup 2005). 
 
Expected IDH Rate 
The expected number of occurrences of IDH per 4-week treatment period 
based on the Historical IDH Rate. This is used to assess whether an 
increase in IDH events has occurred and guide decisions about 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, consecutive 8-week interval prior to randomization. 
This 8-week period may include the 2-week Run-in. Subjects with 5 or 
more IDH events during this 8-week interval will be excluded. 
 
 
 
 
 

 
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STATEMENT OF COMPLIANCE 
 
Protocol Title: 
A Randomized, Double-Blind, Phase 2a Study to Evaluate the 
Tolerability, Feasibility, and Efficacy of AKST1210 in Patients on 
Hemodialysis with Cognitive Impairment Associated with End-Stage 
Renal Disease 
Protocol Number: 
AKST1210-201 
Version/Date: 
V2.1, 14FEB2020 
 
By my signature, I: 
• 
Confirm that my staff and I have carefully read and understand this protocol or protocol amendment and 
are thoroughly familiar with the appropriate use of the investigational device 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, the 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) or Independent Ethics Committee (IEC), 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/IEC inspectors. 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 

 
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PROTOCOL SUMMARY 
 
 
Title: 
A Randomized, Double-Blind, Phase 2a Study to Evaluate the Tolerability, 
Feasibility, and Efficacy of AKST1210 in Patients on Hemodialysis with 
Cognitive Impairment Associated with End-Stage Renal Disease  
Précis:  
This is a randomized, double-blind study, to be conducted at up to 
5 hemodialysis (HD) centers in approximately 20 evaluable subjects 
randomized in a 1:1 ratio (n=10 per arm) to either the AKST1210 column 
(the investigational treatment) or to the control (no column), to assess the 
tolerability, feasibility, and efficacy of AKST1210 (a beta 2-microglobulin 
[b2M] apheresis column) in subjects with end-stage renal disease with 
cognitive impairment (ESRD-CI) undergoing HD 3 times per week. 
Subjects will undergo a Screening visit followed by a 2-week Run-in 
period. During the Run-in period, subjects’ HD flow rate will be adjusted to 
a maximum of 250 mL/min. Subjects that meet all inclusion criteria and 
none of the exclusion criteria will then be randomized to either receive HD 
with the AKST1210 column or control (i.e., no column). The AKST1210 
column will be connected in series before (upstream of) the HD cartridge 
for the duration of each HD session. The control will consist of a covered 
surrogate object of similar size/shape as the AKST1210 column which will 
be set up in such a way to mimic the appearance of an in-line AKST1210 
column. The subject, investigator, and outcomes assessor will be blinded as 
to treatment.  
There will be three (3) 4-week treatment periods, and all subjects will 
receive 3 HD treatments per week for 12 weeks. Subjects who may 
occasionally require an additional HD session per week would not receive 
the investigational intervention on that additional day. Subjects randomized 
to the AKST1210 column will start with a 150 mL column (S-15) used 
during Weeks 1 to 4 (Treatment Period 1). Subjects who meet specific 
criteria will undergo escalation of the column size to a 250 mL column (S-
25) during Weeks 5 to 8 (Treatment Period 2) and then to a 350 mL column 
(S-35) during Weeks 9 to 12 (Treatment Period 3). Subjects randomized to 
control (no column) will receive identical escalation evaluations to maintain 
the treatment assignment blind. The rules specifying the criteria for 
escalation, de-escalation, and discontinuation are provided in Appendix 
17.1.  
Following Treatment Period 3, subjects should resume HD in accordance 
with standard of care. Subjects will return for an End of Study (EOS) Visit 
during Week 14. 
Objectives: 
The primary objective is evaluation of the safety and tolerability of 
AKST1210 for the treatment of ESRD-CI in subjects receiving HD.  
The secondary objectives are to evaluate the feasibility of conducting 
expanded studies of AKST1210 in subjects with ESRD-CI who are 
undergoing HD 3 times per week as well as the efficacy of the column. 

 
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The exploratory objectives include serial compositional analysis of plasma 
to identify specific biomarkers possibly associated with cognitive function 
and/or indicators of disease progression by proteomic analyses, magnitude 
of b2M removal, and possible relationship to changes in cognition. 
 
Endpoints: 
Primary Endpoint:  
• 
Incidence of treatment-emergent adverse events (TEAEs) and 
serious adverse events (SAEs) coded by the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term (PT) and MedDRA 
System Organ Class (SOC). 
 
Secondary Endpoints:  
• 
Feasibility of all procedures, including blinding. 
• 
Tolerability of each column size escalation, as measured by subject 
compliance with study visit schedule/completion, visit procedures, 
and subject retention. 
• 
The change in IDH Rate above each subject’s Historical IDH Rate 
for each column size. 
• 
The incidence of IDH leading to de-escalation or discontinuation. 
• 
The incidence of worsening anemia by column size. 
• 
The incidence of anemia leading to de-escalation or discontinuation. 
• 
Change from baseline in levels of b2M at Weeks 4, 8, 12 and EOS 
and evaluation of any differences in the magnitude of change based 
on column size and duration of treatment with a specific column 
size.  
• 
Change in Montreal Cognitive Assessment (MoCA) from baseline to 
EOS. 
• 
Change in cognitive domains as measured with the Cogstate battery 
(i.e., verbal learning, psychomotor function, visual attention, 
working memory, executive function, and verbal delayed recall).  
• 
Change in quality of life per the Short-Form Health Survey (SF-36).  
• 
Change in the Patient Health Questionnaire-9 (PHQ-9).  
• 
Change in sleep quality as measured by the Pittsburgh Sleep Quality 
Index (PSQI).  
• 
Change in fatigue as measured by the Fatigue Questionnaire – 
Functional Assessments of Chronic Illness Therapy (FACIT).  
• 
Changes from baseline in laboratory test data, vital sign 
measurements, and electrocardiograms (ECGs). 
 
Exploratory Endpoints: 
• 
Serial compositional analysis of plasma to identify specific 
biomarkers associated with cognitive function and/or indicators of 
disease progression by proteomic analyses. 
• 
Magnitude of b2M removal and possible relationship to changes in 
cognition. 
 
Population: 
Approximately 26 male and female subjects, ≥ 40 years of age on HD with 
ESRD-CI, will be enrolled. Assuming a drop-out rate of 20%, enrollment at 

 
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3 
OBJECTIVES AND PURPOSE 
 
The primary objectives of this study are to assess the safety and tolerability of AKST1210 in subjects with 
ESRD-CI who are receiving HD. Secondarily, this study aims to assess the feasibility of device size escalation as 
well as the efficacy of AKST1210. Exploratory objectives include blood and plasma collection to identify specific 
biomarkers associated with cognitive function and/or indicators of ESRD-CI and b2M progression.  
 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
 
This will be a randomized, double-blind study conducted at up to 5 sites in the US. Approximately 26 male and 
female subjects, ≥ 40 years of age on HD with ESRD-CI, will be enrolled. Assuming a drop-out rate of 20%, 
enrollment at this level will yield approximately 20 evaluable subjects. 
 
During Screening (Visit 1, Day -42 through Day -14), subjects and/or their legally authorized representative 
(LAR) will provide informed consent, and subjects will undergo screening assessments including provision of 
demographics and medical history, physical examination, 12-lead ECG, laboratory testing (including pregnancy 
testing if applicable), as well as tests to assess cognitive function and depression. A blood sample will also be 
obtained and sent to the site’s local laboratory to determine baseline b2M concentration. 
 
If the Visit 1 Screening eligibility criteria are met, subjects will commence the Run-in Period (Visits 1.1-1.6, Day 
-14 through Day -1). During Run-in, subjects will undergo HD at a reduced flow rate; have safety assessments; 
complete tests to assess cognitive function, quality of life, quality of sleep, and fatigue; and have blood samples 
collected for b2M and plasma proteomics. All subjects will have their HD flow rate adjusted to a maximum flow 
rate of 250 mL/minute, thus necessitating an increase in the overall length of dialysis time to approximately 4 
hours.  
 
Subjects who continue to meet eligibility requirements will be randomized at Visit 2 (Day 1) to one of two 
treatment arms: AKST1210 (the investigational treatment) or control (no column). The AKST1210 column will 
be connected in series before (upstream of) the HD dialyzer for the duration of each HD session, and an 
appropriate covering of either the AKST1210 column or control will be in place for blinding purposes. All 
randomized subjects will continue to undergo dialysis at the adjusted, maximum flow rate of 250 mL/minute at 
the extended dialysis time, similar to the Run-in Period. The subject, investigator, and outcomes assessor(s) will 
be blinded as to treatment (i.e., double-blind study). 
 
There will be three (3) 4-week treatment periods, and subjects will receive 3 HD treatments with AKST1210 or 
control per week for 12 weeks. Subjects who may occasionally require an additional HD session per week would 
not receive the intervention on that additional day. Subjects randomized to the AKST1210 column will receive a 
150 mL column (AKST1210 S-15) during Weeks 1 to 4 (Treatment Period 1). Subjects will then be evaluated for 
escalation to the 250 mL column (AKST1210 S-25) during Weeks 5 to 8 (Treatment Period 2) followed by 
evaluation for escalation to the 350 mL column (AKST1210 S-35) for Weeks 9 to 12 (Treatment Period 3). 
Subjects will be evaluated for escalation, de-escalation, or discontinuation based on specific criteria as specified 
in Appendix 17.1. Subjects will complete an EOS Visit during Week 14.  
 
Subjects randomized to control will also receive 3 HD treatments per week for 12 weeks for blinding purposes 
with similar escalation, de-escalation, and discontinuation procedures (see Appendix 17.1).  
  

 
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During each Treatment Period, subjects will undergo tests to assess cognitive function, quality of life, quality of 
sleep, and fatigue, as well as collection of blood samples for b2M and plasma proteomics. AE assessments; 
review of concomitant medications; targeted physical examinations; monitoring of vital signs; and assessment of 
fluid status will occur at every treatment visit.  
 
In the event of early termination of a subject who has been randomized and received at least 1 HD treatment, the 
EOS procedures will be performed unless the subject has withdrawn consent.  
 
The overall duration of the study/recruitment period is approximately 12 months from study initiation 
(i.e., following consent of first subject) to study completion (i.e., last subject, last visit). Subject participation is 
expected to be approximately 16 to 20 weeks, unless prematurely discontinued.  
 
4.2 
STUDY ENDPOINTS 
 
4.2.1 
PRIMARY ENDPOINT 
 
• Incidence of TEAEs and SAEs coded by MedDRA PT and MedDRA SOC.  
 
4.2.2 
SECONDARY ENDPOINTS 
 
• Feasibility of all procedures, including blinding. 
• Tolerability of each column size escalation, as measured by subject compliance with study visit 
schedule/completion, visit procedures, and subject retention. 
• The change in IDH Rate above each subject’s Historical IDH Rate for each column size. 
• The incidence of IDH leading to de-escalation or discontinuation. 
• The incidence of worsening anemia by column size. 
• The incidence of anemia leading to de-escalation or discontinuation. 
• Change from baseline in levels of b2M at Weeks 4, 8, 12 and EOS and evaluation of any differences in 
the magnitude of change based on column size and duration of treatment with a specific column size.  
• Change in MoCA from baseline to EOS (Nasreddine 2005). 
• Change in cognitive domains as measured with the Cogstate battery (i.e., verbal learning, psychomotor 
function, visual attention, working memory, executive function, and verbal delayed recall). 
• Change in quality of life per the SF-36 (Laucis 2015). 
• Change in sleep quality as measured by the PSQI (Buysse 1989). 
• Change in fatigue as measured by the FACIT (Webster 2003).  
• Changes from baseline in laboratory test data, vital sign measurements, and ECGs. 
 
4.2.3 
EXPLORATORY ENDPOINTS 
 
• 
Serial compositional analysis of plasma to identify specific biomarkers associated with cognitive 
function and/or indicators of disease progression by proteomic analyses. 
• 
Magnitude of b2M removal and possible relationship to changes in cognition.  
 
 

 
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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 or the subject’s LAR (e.g., subject withdraws consent), investigator, 
Sponsor, or regulatory authority. 
• 
Pregnancy. 
• 
A subject will be discontinued if the number of IDH events during a treatment period exceeds a 
predetermined threshold above the subject’s Historical IDH Rate after de-escalation to the lowest 
column size (see Appendix 17.1). 
• 
A subject will be discontinued if Hgb levels remain < 9 g/dL despite optimized iron and ESA 
treatment and after de-escalation to the lowest column size (see Appendix 17.1). 
In the event of early withdrawal/discontinuation of a subject who has been randomized and received at least 
1 HD treatment, the EOS procedures will be performed unless the subject has withdrawn consent.  
 
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 26 subjects will be enrolled with the intent of obtaining 20 evaluable subjects randomized in a 
1:1 ratio to either active (AKST1210 column) or control. Subjects who discontinue or are unblinded prior to 
Week 8 may be replaced.  
 
Subjects who have received at least 1 HD with AKST1210/control but are withdrawn or withdraw from the 
study will be encouraged to complete the EOS procedures within 4 to 6 weeks of their last visit. The primary 
reason for study discontinuation will be documented on the case report form (CRF). 
 
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: 
• 
(Immediate) 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/Good Clinical Practice (GCP). 
• 
Unacceptable emergent safety profile. 
 
If Alkahest were to receive withdrawal of IRB or FDA approval, or other action on the part of the IRB or FDA that 

 
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Table 2 Description of the AKST1210 Model Sizes 
Model 
Column Capacity (mL) 
Extracorporeal Volume (mL) 
S-15 
150 
65 
S-25 
250 
105 
S-35 
350 
177 
 
The AKST1210 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 AKST1210 
column in the HD blood circuit.  
Figure 3 AKST1210 Column in the Hemodialysis Blood Circuit 
 
 
The control will consist of a covered surrogate object of similar size/shape as the AKST1210 column. The 
control will not in any way be in contact with circulating blood, as it sits external to the blood circuit. The 
control will be set up and draped in the same fashion as the AKST1210 column. Additional details can be 
found in the Device Procedures Manual.  

 
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6.1.2.2 
Packaging and Labeling 
 
The AKST1210 columns will be individually packaged in a plastic bag bearing an investigational label. Six 
columns will be packaged in each white kit and each carton will contain 2 kits for a total of 12 columns per 
carton. 
 
The 
 devices 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."  
6.1.3 
PRODUCT STORAGE 
 
The AKST1210 column should be handled with care during transportation and storage. The AKST1210 
column should be kept in a clean place between 5 °C and 30 °C. Direct sunlight, high humidity, excessive 
vibration, and freezing conditions should be avoided. Do not drop the AKST1210 column or strike it with a 
hard instrument (e.g., forceps). Do not use any AKST1210 column that has been damaged or frozen. 
The fluid pathway of the AKST1210 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 AKST1210 column will be connected in series before (upstream of) the dialyzer for the duration of each 
HD session. The control will be set up such that it appears to be connected in series before (upstream of) the 
dialyzer. The subject, investigator, and outcomes assessor must remain blinded to treatment assignment 
throughout. Specifics of column/control preparation (rinsing, priming, and disposal) and blinding procedures 
are specified in the Device Procedures Manual.  
. 
6.1.5 
COLUMN SIZE ESCALATION AND ADMINISTRATION 
 
The initial AKST1210 size used during Weeks 1 to 4 (Treatment Period 1) will be the 150 mL column 

 
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(AKST1210 S-15). Following evaluation for IDH Rate and anemia (see Appendix 17.1), subjects may be 
escalated to the 250 mL column (AKST1210 S-25) for Weeks 5 to 8, followed by the 350 mL column 
(AKST1210 S-35) for Weeks 9 to 12. The subject, investigator, and outcomes assessor must remain blinded 
to treatment assignment at all times. Careful attention should be given to ensure that all subjects, regardless of 
treatment assignment, undergo the same evaluations for escalation, de-escalation, and discontinuation.   
 
6.1.6 
DURATION OF THERAPY 
 
The treatment period for each subject is 12 weeks. The total duration of subject participation is expected to be 
approximately 16 to 20 weeks. 
 
6.2 
STUDY DEVICE AND CONTROL ACCOUNTABILITY 
 
Under the blinded supervision of the investigator, the unblinded study coordinator or other qualified personnel is 
responsible for ensuring adequate accountability of all used and unused AKST1210 columns and controls. This 
includes acknowledgment of receipt of each shipment of AKST1210 (quantity and condition), subject dispensing 
records, and destruction of used study devices. Study device 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 
unblinded dialysis nurse, or other qualified medical professional, administering the study device. When subjects 
receive a control rather than an AKST1210 column, key information will also be captured for each treatment. 
Device/control accountability will be monitored by an unblinded 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 study 
device accidentally wasted or intentionally disposed of must be maintained. As these records contain unblinding 
information, they must be stored in a securely locked, controlled-access location.  
 
All unused AKST1210 study devices should be kept securely at the site until otherwise instructed. All unused 
containers of study devices 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 national regulations. The site’s procedure(s) for study device 
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/Run-In Procedures 
 
During the Screening Visit(s)*, the following procedures will be performed: 
• 
Informed consent 
• 
Evaluation of inclusion/exclusion criteria 
• 
Demographics 
• 
Medical history and review of medications 
• 
Physical examination, including measurements of height and weight 
• 
12-lead ECG  
• 
Screening laboratory tests (including pregnancy test for WOCBP only) 
• 
b2M laboratory test (assayed at a local laboratory) 
• 
MoCA 
• 
PHQ-9 
 
*Note: The Screening Visit may be split to allow for sufficient time to complete all required procedures.  
Review AEs and concomitant medications during split visits, as applicable.   
 
During the Run-in period, the following procedures will be performed: 
• 
HD at an adjusted maximum flow rate of 250 mL/min 
• 
Vital signs 
• 
Targeted physical examination, including weight measurement 
• 
b2M/proteomic samples collected  
• 
Laboratory tests (e.g., Prothrombin Time [PT], Blood Urea Nitrogen [BUN], Creatinine, and 
serum pregnancy test for WOCBP) 
• 
Concomitant medication review 
• 
AE evaluation/collection 
• 
Verification of eligibility 
 
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 15.1.1. 
 
7.1.1.1.1 Demographics 
Demographic information such as the subject’s education level, ethnicity, and race will be collected by 
interview with the subject.  
 
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, with an emphasis on the history of cognitive 
symptoms related to ESRD-CI. Additionally, the medical history should include: 
• 
Current/past illnesses and conditions 
• 
Current symptoms of any active medical condition 

 
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• 
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/chest, heart, abdomen, musculoskeletal, extremities, and 
neurologic and lymphatic systems. The neurological exam will include cranial nerves (fundoscopic exam, 
pupillary light reflex, extraocular muscles, facial sensation and symmetry, palate and tongue, and head turning 
and shoulder shrug); muscle strength; reflexes (biceps, triceps, knees, ankles, and plantar); coordination 
(finger-to-nose, heel-knee-shin); sensory function (light touch and pinprick); and gait. Physical and 
neurological 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 throughout the study. 
 
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 Screening and Run-In Laboratory Evaluations 
Biological samples will be collected and analyzed at Screening and Run-In. Blood will be drawn by a 
qualified medical provider. Labs will be completed by the site’s local laboratory. Samples for Screening labs 
should be collected either on a non-dialysis day or prior to HD. For additional information, refer to  
Section 15.2 Schedule of Laboratory Tests.  
 
7.1.1.1.6 Hemodialysis  
Beginning at Run-in, HD will be conducted 3 times weekly at a modified maximum flow rate of 250 mL/min 
over a period of approximately 4 hours. The following key dialysis parameters will be captured: post-pump 
perfusion pressure (mm Hg), blood flow rate (mL/min), 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 Section 2.3.1 for risks associated with the AKST1210 column as well 
as proposed mitigation strategies. 
 
 
 
 
 
 
 
 

 
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7.1.1.1.6.1 Heparinization 
Subjects will undergo heparinization according to institutional practices at the start of, and throughout, each 
HD session. The schedule below is a guideline for proposed heparin bolus and continuous heparin treatment 
during the Treatment Periods. The investigator may modify dose and schedule according to the subject’s 
condition(s) or measured coagulation parameters e.g. activated partial thromboplastin time (aPTT) values.  
• 
S-15: 1,000 IU bolus, followed by 1,000 IU per hr (continuous infusion until the end of the procedure) 
• 
S-25: 1,500 IU bolus followed by 1,500 IU per hr (continuous infusion until the end of the procedure)   
• 
S-35: 2,000 IU bolus followed by 2,000 IU per hr (continuous infusion until the end of the procedure) 
At the discretion of the investigator, heparin de-escalation of 250 IU/hr can be instituted with the S-25 or S-35 
column beginning with the second hour of dialysis, with the heparin dose not to fall below 1,000 IU/hr. 
 
7.1.1.1.7 Montreal Cognitive Assessment 
The MoCA (Nasreddine 2005) is a commonly used screening test easily administered by non-specialist staff. 
It assesses the domains of attention and concentration, executive functions, memory, language, visuo-
constructional skills, conceptual thinking, calculations, and orientation. 
 
7.1.1.1.8 Patient Health Questionnaire-9 
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring, and measuring the severity of 
depression. The 9 items of the PHQ-9 are based directly on the 9 diagnostic criteria for major depressive 
disorder. Symptoms are rated from 0 (not at all) to 3 (nearly every day) (Kroenke 2001). It takes about 5 to 
7 minutes to complete. 
 
7.1.1.1.9 Biospecimen Collection for Beta 2-Microglobulin (b2M) and Proteomics 
Blood levels of b2M are required to be collected at Screening and results obtained from the site’s local 
laboratory to evaluate eligibility (Section 5). Samples for Screening labs should be collected either on a non-
dialysis day or prior to HD. 
 
Blood and plasma samples obtained for b2M and proteomics for all other study visits will be collected, 
processed, stored, and shipped to a designated biorepository in accordance with the AKST1210 b2M and 
Proteomics Lab 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 investigational 
device and intervention. 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 Schedule of 
Events. 
• 
Review of AEs 
• 
Vital signs 
• 
Assessment of fluid status  
• 
Targeted physical exam, 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, refer to Section 8.  
 

 
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7.1.1.2.2 Monitoring Vital Signs  
Vital signs monitoring will occur at every visit. Seated/reclined BP will be recorded before each dialysis 
session, 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). During Run-in if a subject experiences 3 or more IDH 
events then they will be excluded from further participation (see Section 5.2). After randomization, should the 
number of occurrences of IDH exceed a predetermined threshold based on the subject’s Expected IDH Rate, 
then the subject will be de-escalated to a lower column size or discontinued as appropriate (Appendix 17.1). 
 
In subjects who experience IDH, the following questions must be asked to assess whether the IDH is 
accompanied by cognitive impairment (confusion, disorientation): 
• 
What is your name? 
• 
Where are you? 
• 
What is the day of the week? 
• 
What is today’s date and what is the month? 
• 
Who is the President? 
• 
Who is the Governor? 
 
Regardless of whether the subject shows signs of cognitive impairment, it is important that the IDH be 
addressed expeditiously as per standard procedures at the site. These procedures may include changes to the 
ultrafiltration rate, Trendelenburg position, and administration of saline. Once the IDH has been addressed 
and the dialysis session has concluded, the same questions should be asked again to assess whether the 
transient cognitive impairment (if present) resolved with the resolution of the episode of IDH.  
 
7.1.1.2.3 Assessment of Fluid Status 
Fluid status will be assessed during the Treatment Periods according to institutional standards of care. This 
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 according to the Schedule of Events 
(Section 15). Weight will be monitored throughout the study.  
 
7.1.1.2.5 Laboratory Evaluations 
Biological samples will be collected and analyzed according to the Schedule of Laboratory Tests (Section 
15.2). Blood will be drawn by a qualified medical provider. Clinical labs will be processed and resulted by the 
site’s local laboratory. 
 
7.1.1.2.5.1 Pregnancy Testing  
Serum pregnancy testing will be performed in WOCBP in accordance with the Schedule of Events (Section 
15). 

 
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7.1.1.3 Procedures to Assess Efficacy 
Cognitive function, depression, sleep quality, quality of life, and fatigue will be assessed using validated 
instruments. To limit subject fatigue, all testing will be conducted prior to HD. All testing will be performed 
by qualified evaluators who have undergone standardized rater training and certification, as appropriate. The 
same evaluator should be used for the duration of each subject’s participation unless a change in rater is 
unavoidable. The following scales will be administered to subjects enrolled in the trial in accordance with the 
Schedule of Events (Section 15):  
1. MoCA 
2. PHQ-9 
3. Cogstate test battery 
4. SF-36 Short Form  
5. FACIT 
6. PSQI 
 
Descriptions of each assessment are provided below.  
 
7.1.1.3.1 Montreal Cognitive Assessment 
See Section 7.1.1.1.7. 
 
7.1.1.3.2 Patient Health Questionnaire-9 
See Section 7.1.1.1.8. 
 
7.1.1.3.3 Cogstate Test Battery 
The Cogstate test battery is intended to assess cognitive function in several areas including verbal learning, 
psychomotor function, visual attention, working memory, executive function, and verbal delayed recall. To 
maintain quality and interrater reliability, all raters will be trained on each assessment before study start, and 
assessments will be administered in a quiet environment by trained personnel. 
 
To avoid any confusion while testing, it is important that subjects take 2 familiarization assessments to 
become acquainted with the device and requirements of the tests. This helps achieve a stable baseline to more 
accurately reflect subjects’ true cognitive function. The familiarization assessments can be administered at 
any time during Run-in but prior to randomization. 
 
7.1.1.3.4 Short Form-36 
The SF-36 is a set of generic, coherent, and easily administered quality of life measures. These measures rely 
on patient self-reporting and are now widely utilized by managed care organizations and Medicare for routine 
monitoring and assessment of care outcomes in adult patients. 
 
7.1.1.3.5 Fatigue Questionnaire - Functional Assessment of Chronic Illness Therapy 
The FACIT Fatigue Scale (Webster 2003) is a short, 13-item tool that is easy to administer and measures an 
individual’s level of fatigue during their usual daily activities over the past week. The level of fatigue is 
measured on a 4-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The score range 0 to 52. 
A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of life.  
 
7.1.1.3.6 Pittsburgh Sleep Quality Index 
The PSQI (Buysse 1989) is an effective instrument used to measure the quality and patterns of sleep in older 
adults. It differentiates “poor” from “good” sleep by measuring 7 domains: subjective sleep quality, sleep 
latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime 

 
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dysfunction over the last month. The subject self-rates each of these 7 areas of sleep. Scoring of the answers is 
based on a 0 to 3 scale, whereby 3 reflects the negative extreme on the Likert Scale. A global sum of “5” or 
greater indicates a “poor” sleeper.  
 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
 
Biological samples will be collected for laboratory evaluations in accordance with Section 15.2 Schedule of 
Laboratory Tests. Screening and clinical labs, including the screening measurement of b2M for inclusion, will 
be processed by each site’s local laboratory and results entered in the CRF.  
 
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 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.  
 
7.2.2 
OTHER TESTS OR PROCEDURES 
 
7.2.2.1  
Plasma Proteomics 
 
For more information regarding the timing and procedures for sample collection and related requirements, 
refer to the AKST1210 b2M and Proteomics Laboratory Manual as well as Section 15.1 Schedule of Events 
Tables and Section 15.2 Schedule Of Laboratory Tests. 
 
Serial compositional analysis of plasma will be conducted to identify specific biomarkers associated with 
cognitive function and/or indicators of disease progression by proteomic analyses. Plasma will be analyzed by 
proteomics using mass spectrometry and targeted approaches to assess the specific signature of proteins in 
subjects at baseline and to assess the changes in the proteome with repeated AKST1210 treatment. These 
methodologies will provide a broad overview of the proteins that are present in the plasma sample. From this 
research, it is hoped that key proteins that are drivers of cognitive function and/or indicators of disease 
progression can be identified. By understanding the composition and function of plasma samples from the 
trial, the goal is to identify potential biomarkers relevant to further optimizing treatment in ESRD-CI.  
 
7.2.3 
SPECIMEN PREPARATION, HANDLING, STORAGE, AND SHIPPING 
 
Each site should follow their local laboratory’s standard procedures for specimen preparation, handling, 
storage, and shipping of Screening and clinical labs, including the screening sample for b2M.  
 
Site personnel should refer to the AKST1210 b2M and Proteomics Laboratory Manual for instructions 
pertaining to the preparation, handling, storage, and shipping of specimens for b2M and proteomics. 
 
 

 
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7.3 
STUDY SCHEDULE 
 
7.3.1 
SCREENING/RUN-IN 
 
For a complete list of Screening/Run-In procedures and assessments, please see Section 15.1.1. 
 
7.3.2 
RANDOMIZATION/TREATMENT 
 
Subjects will be randomized after eligibility has been confirmed at Visit 2.1.  
 
For a complete list of Treatment Period 1 (Visit 2/Month 1) procedures and assessments, please see Section 
15.1.2. 
 
For a complete list of Treatment Period 2 (Visit 3/Month 2) procedures and assessments, please see Section 
15.1.3. 
 
For a complete list of Treatment Period 3 (Visit 4/Month 3) procedures and assessments, please see Section 
15.1.4. 
 
 
7.3.3 
END OF TREATMENT/END OF STUDY VISITS 
 
For a complete list of the End of Treatment (Visit 5) and EOS (Visit 6) procedures and assessments, please 
see Section 15.1.5. 
 
7.3.4 
EARLY WITHDRAWAL 
 
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 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. 
 
 

 
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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 2.3.1 and the AKST1210 
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 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?” 
 
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 the Sponsor 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. 
 
8.4 
REPORTING PROCEDURES 
 
8.4.1 
ADVERSE EVENT/EFFECT REPORTING 
 
All subjects who have given informed consent will be evaluated for AEs/ADEs. All AEs/ADEs that occur 
after initiation of treatment with the study device/control will be considered treatment emergent (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 in the eCRF. 

 
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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 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, 

 
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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 
 
The Data and Safety Monitoring Board (DSMB) will make recommendations concerning the continuation, 
modification, or termination of the trial.  
 
8.6 
SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate expertise, 
including ESRD and hemodialysis. Members of the DSMB will be independent from the study conduct and free 
of actual or perceived conflict of interest. The DSMB will meet at least quarterly (or more frequently as needed) 
to assess safety data. The DSMB will operate under the rules of an approved charter that will be written and 
reviewed at the organizational meeting of the DSMB. At this time, each data element that the DSMB needs to 
assess will be clearly defined. The DSMB will provide its input to Alkahest, Inc.  
 
In addition, the Sponsor will perform ongoing monitoring of cumulative safety data in a systematic manner to 
ensure that any safety signals that may impact the overall benefit/risk ratio in this specific population will be 
detected, assessed, and any necessary action taken. Blinded cumulative safety data (e.g., AE listings, vital sign 
plots, safety laboratory values, ECGs, physical examination results) will be reviewed by the CRO’s Medical 
Monitor(s) and/or by the Sponsor’s Program Physician throughout the study. If either physician detects any safety 
trends of concern, an ad-hoc meeting of the DSMB may be triggered. 
 
9 
CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being 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). 
• 
Monitoring will be performed to ensure the safety of clinical subjects and the accuracy and completeness 
of study data.  
• 
The Sponsor will be provided with copies of monitoring reports per the timelines specified within the 
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 
 
A Statistical Analysis Plan (SAP) with analytical details and assumptions will be developed and finalized before 
database lock and unblinding of the study data. 
 
10.2 STATISTICAL HYPOTHESES 
 
Because the primary objective of the study is safety and tolerability, the study is not designed to detect 
statistically significant differences between the AKST1210 column and control treatment on the efficacy 
endpoints. The statistical approach toward secondary efficacy endpoints will be primarily descriptive; 
within-subject changes from baseline for each treatment group and among-group differences will be evaluated.  
 
10.3 ANALYSIS DATASETS 
 
Three (3) analysis datasets are possible; however, analyses may not necessarily be conducted with all 3: 
• 
Intention-to-Treat (ITT) Dataset: all randomized subjects. 
• 
Safety Dataset: all subjects who received HD after randomization.  
• 
Evaluable Dataset: all subjects who complete through Week 8. 
o Per Protocol Dataset: a subset of the Evaluable Dataset. A detailed description of the reasons 
for exclusion from the Per Protocol population will be included in the SAP.  
The presentation of baseline characteristics will be conducted on the ITT dataset. All safety analyses will be 
performed for the Safety Dataset. Analyses of the secondary endpoints will focus on the Evaluable Dataset. 
 
10.4 DESCRIPTION OF STATISTICAL METHODS  
 
10.4.1 
GENERAL APPROACH 
 
Using the Evaluable Dataset, all secondary endpoints will be summarized serially over time using 
descriptive statistics to assess the within-subject changes and between-group 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) 
values will be presented as descriptive summary 
• For endpoints that are categorical in nature: 
– Frequency counts and percentages will be presented as descriptive summary 
 
Subject disposition (e.g., the number of subjects randomized, completed, and discontinued) 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. 

 
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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.  
 
Summary tabulations of the reported AEs will be presented by arm and column size after the verbatim terms 
have been coded to PTs and SOCs using the MedDRA Version 21.0 coding dictionary. 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. 
 
Additional details are presented in Section 10.4.4.   
 
10.4.3 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINTS 
 
The study is not powered to detect significant changes in cognition, function, etc.; however, using available 
data from analysis of the secondary efficacy endpoints, including changes in scores from baseline, descriptive 
summaries will be developed. Of particular interest will be the within-subject changes from baseline and their 
distribution around a null value of zero and a comparison between groups to evaluate any trends in differences 
between subjects randomized to active vs. control.  
 
10.4.4 
ANALYSIS OF THE SECONDARY SAFETY ENDPOINTS 
 
Actual values and changes from baseline in clinical laboratory measurements, vital signs, and body weight, 
will also 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 documenting 
whether an abnormal laboratory finding or other abnormal assessment is clinically significant. 
 
For secondary safety endpoints that are continuous in nature (e.g., clinical laboratory parameters, systolic and 
diastolic BP, heart rate, respiratory rate, body temperature, and body weight) the mean, median, minimum, 
maximum, and standard deviation will be summarized. 
 
For secondary safety endpoints that are categorical in nature (e.g., physical examination or ECG 
abnormalities), the frequency counts and percentages will be presented as a descriptive summary. 
 
Per-subject extent of exposure will be listed. 
 
10.4.5 
ADHERENCE AND RETENTION ANALYSES 
 
Subject adherence with the study visits schedule, visit procedures, HD procedures, and subject retention will 
be assessed. Subject adherence may vary across the treatment arms. Reasons for study discontinuation will be 
compared across treatment arms and across other subgroups of interest, as appropriate. 
 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS 
 
See Section 10.4.1. 
 

 
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10.4.7 
PLANNED INTERIM ANALYSES 
 
 
Not applicable. 
 
10.4.8 
ADDITIONAL SUBGROUP ANALYSES 
 
Not applicable. 
 
10.4.9 
MULTIPLE COMPARISON/MULTIPLICITY 
 
No adjustments for multiplicity will be employed. 
 
10.4.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
 
This will be further defined in the SAP. 
 
10.4.11 EXPLORATORY ANALYSES 
 
Not applicable. 
 
10.5 SAMPLE SIZE 
 
Approximately 26 male and female subjects, ≥ 40 years of age on HD with ESRD-CI, will be enrolled. Assuming 
a drop-out rate of 20%, enrollment at this level will yield approximately 20 evaluable subjects (evaluable is 
defined as completed through Week 8). Subjects will be randomized in a 1:1 ratio consisting of 1 treatment arm 
(AKST1210) and 1 non-active, control arm; n=10 per group. The sample size was chosen based on clinical 
considerations of an exploratory study designed to test safety and tolerability (Thabane 2010). 
 
While the study is not statistically powered to detect differences in measures of clinical efficacy or biomarker 
endpoints, the proposed sample size may be sufficient to identify trends in efficacy endpoints that will be used to 
determine the appropriate sample size for subsequent studies. 
 
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 
ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES 
 
To minimize the potential bias at the time of randomization, the study will be double-blinded (the subject, 
investigator, and outcomes assessor will be blinded as to treatment assignment and randomized in a 1:1 ratio 
[AKST1210: control]). The randomization codes will be generated by a statistician that has no involvement in 
the study other than generation and maintenance of the randomization codes. Blinding and randomization 
procedures are described in the Device Procedures Manual.  
 
10.6.2 
EVALUATION OF SUCCESS OF BLINDING 
 
Success of blinding will be assessed based on all occurrences (intentional or unintentional) of unblinding of 
blinded study subjects, or study personnel (e.g., investigators, medical providers, outcomes assessors, the 

 
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Sponsor or their representatives). All intentional and unintentional unblinding will be documented and 
reported.  
 
10.6.3 
BREAKING THE STUDY BLIND/SUBJECT CODE 
 
This is a double-blind study. Blinding procedures are described in the Device Procedures Manual.  
 
If unintentional unblinding occurs during the study, root cause analysis will be evaluated, and corrective 
actions implemented as applicable. 
 
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 
quality assurance 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 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. 
 
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 

 
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previously consented subjects need to be re-consented. 
 
Any 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 or 
subject’s LAR 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 or their legally authorized representative 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. The subjects may withdraw consent at any time throughout 
the course of the trial. The rights and welfare of the subjects will 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/or their legally authorized 
representative and the person obtaining consent. A copy of the signed consent form will be provided to the 
subject and/or their legally authorized representative. 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 the Health Insurance Portability and Accountability Act (HIPAA). 

 
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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 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 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, Institutional regulations or Clinical Trial Agreement, whichever is longest. Subject data 
that is transmitted to the Sponsor, CRO, and/or IRB will not include contact or identifying information. Rather, 
individual subjects and their research data will be identified by a unique study number. This unique study number 
should be recorded on non-local lab samples, requisitions, and any documents submitted to the CRO, Sponsor, 
and/or IRB. The study data entry and study management systems used by clinical sites and by research staff will 
be secured and password protected. 
 
12.5 FUTURE USE OF STORED SPECIMENS 
 
With the subject’s approval and as approved by IRBs, biological samples may be stored at Alkahest, or designee, 
for future use. These samples could be used for future research designed to improve methods for diagnosis, 
prevention, and/or 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 blinding 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. However, withdrawal of consent for biospecimen storage will not be 
possible after the study is completed. 
 
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. 
 
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 CRFs that are transcribed from 

 
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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.  
• 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. 
 
 

 
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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 device. 
• All clinical forms and documentation, including:  
– Records of each subject's case history and exposure to the device. 
– A copy of the signed subject consent form. 
– Date and time of exposure to the investigational device. 
– 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. 
 
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. 
 
 

 
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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. 
 
Major Protocol Deviations may result in data that are not deemed evaluable for the per protocol 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. 
 

 
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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 (ICMJE) clinical trials registration 
policy and Section 801 of the Food and Drug Administration 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. 
 
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. 
 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY 
 
A separate financial disclosure agreement will be made between each investigator and Alkahest, Inc. or its 
authorized representative before the study device 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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18 
REVISION HISTORY 
18.1 SUMMARY OF CHANGES  
 
Protocol Version 2.1 dated 14FEB2020 
Replaces: Protocol Version 2.0 dated 24JAN2020 
 
The following table describes changes from Version 2.0 (dated 24JAN2020) with justifications 
provided. 
 
 
 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read:  V2.0_24JAN2020 
 
Now reads: V2.1 14FEB2020 
Version control. 
5.2 
Previously read:  Pregnant or breast-feeding subjects 
or subjects 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, prior to treatment, and at EOS. 
WOCBP must agree to use highly effective 
contraception (Clinical Trial Facilitation Group 
2014) prior to study entry. A WOCBP is defined as a 
woman who can become pregnant. Should a woman 
become pregnant or suspect she is pregnant while 
she or her partner is participating in the study, she 
should inform her treating physician immediately 
 
Now reads: Pregnant or breast-feeding subjects or 
subjects who are planning to become pregnant. 
Female subjects must not be pregnant or 
breastfeeding. Women of childbearing potential 
(WOCBP) must have a negative serum/urine 
pregnancy test at Screening, prior to treatment, and 
at EOS. 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 partner is 
participating in the study, she should inform her 
treating physician immediately. 
Reverted to the original 
language to ensure safety, 
including the need for male 
subjects to use highly 
effective contraception for 
safety reasons. 
 
 
15.1.2, 15.1.3, 
15.1.4 
Updated the Schedule of Events to indicate that local 
laboratory testing will be performed on Days 15, 43, 
and 71, as specified in Section 15.2. 
For protocol clarity and 
consistency with the Schedule 
of Laboratory Tests. 

 
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AKST1210 on plasma levels of medications are 
limited, it is recommended that all IV and oral 
medications be given after each dialysis session, 
unless clinically needed before or during dialysis. 
as to the timing of IV 
medications given that data 
regarding potential clearance 
of medications is limited. 
4.1, Schedule of 
Events 
Extended Screening Visit window from 2 weeks 
(Day -28 to -14) to 4 weeks (Day -42 to -14). 
To enhance feasibility of 
performing required 
screening assessments within 
window. 
4.1 
Added language to reflect that informed consent may 
be obtained by a subject’s legally authorized 
representative (LAR) when applicable. 
Updated for clarity and 
consistency with Section 12. 
4.1, Schedule of 
Events 
Incorporated language to clarify that the blood 
sample to assess b2M levels at Screening should be 
sent to a site’s local laboratory. 
Updated for clarity and 
consistency. 
4.1, 5.2, 
Schedule of 
Events 
Incorporated language to clarify that eligibility will 
be assessed during Run-in. 
 
 
Updated for clarity and 
consistency. 
4.1 
Modified to include a more comprehensive overview 
of study visit procedures (e.g., targeted physical 
examinations, monitoring of vital signs). 
Updated for clarity and 
consistency with Section 7 
and the Schedule of Events. 
5.1 
Previously read: 5. Medical records indicating 
occurrence of < 5 intradialytic hypotensive events 
related to HD in 8 weeks prior to randomization. 
 
This has been revised to be an exclusion criterion 
(see Section 5.2, new #7, bullet 1) and Now reads:  
Subjects with medical records indicating the 
occurrence of ≥ 5 events of IDH during a recent, 
consecutive 8-week interval prior to randomization. 
 
Updated for clarity and to 
enhance protocol feasibility 
in obtaining sufficient 
medical records to assess a 
subject’s Historical IDH Rate. 
 
Modified the window in which subjects should be on 
a stable regimen of either medications for cognition 
and/or antidepressants to be 8 weeks prior to 
Screening.   
 
Updated for clarity and to 
help ensure consistency in 
results obtained from the 
scales conducted during 
Screening. 
 
5.2 
Updated exclusion criterion #2 as follows: 
Previously read: Subjects who are not able to 
tolerate extended duration of > 4 hours at a 
maximum flow rate of 250 mL/min. 
 
Now reads: During Run-in, subjects who are not 
able to comply with or tolerate extended HD 
duration of approximately 4 hours at a maximum 
flow rate of 250 mL/min as assessed by the 
investigator.  
 
Added exclusion criterion #3 as follows: 
Subjects who experience 3 or more IDH events 
Clarification of evaluation 
period for tolerability of flow 
rate.  
 
 
 
 
 
 
 
 
 
Incorporated to clarify 

 
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extensive fluid management; 
• 
Presence of pre-dialysis hypotension, defined as 
a systolic blood pressure (SBP) < 90 mm Hg 
and/or a diastolic blood pressure (DBP) 
< 50 mm Hg, before any of the last 3 dialysis 
sessions prior to screening; 
• 
A diagnosis of interdialytic hypotension; 
• 
A diagnosis of IDH; and/or 
• 
A diagnosis of autonomic dysfunction. 
 
 
 
Updated exclusion criterion #8 (previously #7) as 
follows: 
Previously read:  Pregnant or breast-feeding subjects 
or subjects who are planning to become pregnant. 
Female subjects must not be pregnant or 
breastfeeding. Women of childbearing potential 
(WOCBP) must have a negative serum/urine 
pregnancy test at Screening, prior to treatment, and 
at EOS. 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 partner is 
participating in the study, she should inform her 
treating physician immediately. 
 
Now reads:  Pregnant or breast-feeding subjects or 
subjects 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, prior to treatment, and at EOS. 
WOCBP must agree to use highly effective 
contraception (Clinical Trial Facilitation Group 
2014) prior to study entry. A WOCBP is defined as a 
woman who can become pregnant. Should a woman 
become pregnant or suspect she is pregnant while 
she or her partner is participating in the study, she 
should inform her treating physician immediately. 
 
 
 
Added exclusion criterion #12 as follows:  
Subjects on anti-seizure medications for a seizure 
disorder. 
 
Revised to clarify that women 
who have undergone 
sterilization are not considered 
WOCBP; removed urine 
pregnancy test as only a serum 
pregnancy test will be used; 
eliminated the need for men to 
use highly effective 
contraception based on safety 
information from previous 
trials. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incorporated to exclude 
subjects requiring anti-seizure 
medications. 
 

 
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Added exclusion criterion #14 as follows: 
Subjects with a hemoglobin level < 9 g/dL. 
 
 
Incorporated to exclude 
subjects with anemia. 
 
 
 
 
Updated exclusion criterion #15 (previously #12)  as 
follows: 
Previously read: 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 for small molecules, and 1 year prior to 
Screening for vaccine or immunotherapy agents. 
 
Now reads: 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. 
 
 
Updated exclusion criterion #16 (previously #13)  as 
follows: 
Previously read: History of severe depression/suicidality 
requiring hospitalization.  
 
Now reads:  History of severe depression/suicidality 
requiring hospitalization in the last 6 months.  
Clarification of timing of use 
for investigational agents prior 
to Screening. 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification of timing of 
hospitalization for severe 
depression/suicidality. 
5.3, 5.4.2 
Content revised to indicate that subjects who 
discontinue or are unblinded prior to Week 8 may be 
replaced (previously indicated prior to Week 5).  
Revised to provide clarity 
regarding timing for 
replacement of subjects. 
5.4.1 
Added:  
• 
A subject will be discontinued if the number of 
IDH events during a treatment period exceeds a 
predetermined threshold above the subject’s 
Historical IDH Rate after de-escalation to the 
lowest column size (see Appendix 17.1). 
• 
A subject will be discontinued if hemoglobin 
levels remain < 9 g/dL despite optimized iron 
and ESA treatment and after de-escalation to the 
lowest column size (see Appendix 17.1). 
Clarification to align with 
revised Definitions, study 
procedures, and Appendix 
17.1.  
6.1.2.1 
Clarified that the control will consist of a covered 
surrogate object of similar size/shape as the 
AKST1210 column and incorporated a reference to 
the Device Procedures Manual. 
Revised for clarity and 
consistency. 
6.1.5 
Added: Careful attention should be given to ensure 
that all subjects, regardless of treatment assignment, 
undergo the same evaluations for escalation, de-
escalation, and discontinuation. 
 
Added for clarity and to 
ensure adequacy of blinding 
procedures. 
6.1.6 
Removed Section 6.1.6 Route of Administration  
Route of administration is not 

 
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applicable, and information 
regarding how the device is 
connected to the circuit is 
described elsewhere in the 
protocol (6.1.4) and Device 
Procedures Manual. 
7.1.1.1, Schedule 
of Study Events 
(15.1.1-15.1.5) 
Updated to account for all procedures performed at 
Screening and during Run-in. 
 
Added: The Screening Visit may be split to allow for 
sufficient time to complete all required procedures.  
 
To provide clarity and 
consistency. A split visit at 
Screening is intended to aid 
feasibility.  
7.1.1.1.5, 
7.1.1.1.9, 
7.1.1.2.5, 7.2.1, 
7.2.3, Schedule 
of Study Events 
(15.1.1-15.1.5) 
Modified to more clearly specify laboratory tests that 
should be conducted at Screening and Run-in and 
which laboratory tests should be performed locally 
versus those required to be stored and shipped to a 
repository. Samples for screening labs should be 
collected either on a non-dialysis day or prior to HD. 
In addition, urine testing will be eliminated. 
Updated to provide enhanced 
clarity; urine testing removed. 
7.1.1.1.6 
Added a reference to Table 1 in Section 2.3.1 to 
highlight proposed mitigations for known safety 
risks, such as IDH and anemia.  
Updated to provide cross-
reference to additional 
assessments for enhanced 
safety. 
7.1.1.1.6.1 
Created a subsection to 7.1.1.1.6 specific to 
heparinization procedures and restructured the 
content to more clearly specify the guidance for de-
escalation of heparinization. 
Updated for clarity. 
7.1.1.1.9 
Content revised to indicate that detailed procedures 
for b2M collection will be included in the 
AKST1210 b2M and Proteomics Lab Manual. 
Updated for clarification of 
location of details for 
procedures related to 
collection of b2M and 
proteomics. 
7.1.1.2 
Updated to provide a more comprehensive list of 
procedures performed to assess safety (e.g., targeted 
physical exams, weight measurements).  
Updated for clarity. 
7.1.1.2.2 
Added an assessment for cognitive dysfunction 
(confusion, alteration of consciousness) in the 
context of IDH. 
 
 
 
 
Added that BP can be obtained in a seated or 
reclined position. 
 
Added procedures related to evaluation of IDH. 
Updated to enable prompt 
identification and intervention 
in the event of decreased 
cerebral blood flow in the 
context of IDH and/or 
hypovolemia 
 
Clarification for positioning 
options for BP. 
 
Clarification of monitoring for 
IDH. 
7.1.1.2.4 
Updated to describe a “targeted” physical 
examination versus a (complete) physical 
examination as described in Section 7.1.1.1.3 
Revised to differentiate 
between a “targeted” physical 
examination and (complete) 

 
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physical examination. 
7.3.4 
Updates/removal of duplicative content related to 
withdrawal and evaluation. 
Clarification of content. 
7.5  
Updated the list of prohibited concomitant 
medications, treatments, and procedures. 
Revised for clarity and 
consistency with the 
Inclusion/Exclusion Criteria. 
8 
Previously read: Assessment of safety will be 
conducted by blinded study personnel except in 
extraordinary circumstances where knowledge of 
whether AKST1210 was received by a subject is 
essential. 
 
Now reads:  Assessment of safety will be conducted 
by blinded study personnel who are medically 
qualified by training and experience (e.g., study 
investigators) except in extraordinary circumstances 
where knowledge of whether AKST1210 was 
received by a subject is essential. 
Added to clarify assessment 
of safety. 
8.5, 8.6 
Modified to indicate that safety oversight will be 
under the direction of a Data and Safety Monitoring 
Board (DSMB). 
Added to clarify safety 
oversight. 
10.3, 10.5 
Defined the evaluable dataset as all subjects who 
complete through Week 8. 
The definition of Evaluable 
subjects for analysis had not 
been included previously. 
Further details on the 
statistical populations will be 
included in the Statistical 
Analysis Plan. 
13.3 
Updated the definitions of Major and Minor Protocol 
Deviations and included examples of each for clarity.  
To align with the definitions 
in Alkahest’s SOP-CL-007 on 
Protocol Deviations 
Oversight and Reporting. 
Schedule of 
Study Events 
(15.1.1 – 15.1.5), 
Schedule of  
Laboratory Tests 
Revisions to study events/timing and laboratory 
testing. Key changes relate to extension of Screening 
period from -4 to -2 weeks to -6 to -2 weeks (now     
-42 to -14 days [previously -28 to -14 days]), 
removal of laboratory samples that are not relevant 
to the subject population, and additional testing of 
Hgb to support monitoring for anemia.  
Revised to align with changes 
described in the protocol, 
specifically Section 7.   
Appendix 17.1 
Updated the escalation, de-escalation, and 
discontinuation rules to specify criteria related to the 
occurrence of worsening anemia. Under the revised 
criteria, subjects with a hemoglobin (HgB) < 9 g/dL 
will not be escalated to the next column size and 
subjects whose HgB decreases to < 9 g/dL at a given 
column size despite optimized ESA treatment will be 
de-escalated or discontinued as applicable. 
Updated to account for 
monitoring of anemia and to 
provide enhanced clarity 
concerning escalation, de-
escalation, and 
discontinuation rules.  
Appendix 17.2 
Appendix was eliminated. 
Duplicative content was 
removed for clarity. 

 
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Protocol Version 1.2 dated 13NOV2019 
Replaces: Protocol Version 1.0 dated 11OCT2019 
 
The following table describes changes from Version 1.1 (dated 11OCT2019) with justifications 
provided. 
 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read: V1.1_11OCT2019 
 
Now reads: V1.2_13NOV2019 
Version control. 
Throughout 
Minor grammar and content updates. 
Minor grammar/content 
updates for clarity/accuracy of 
content. 
Table of 
Contents 
Minor content updates. 
Minor updates required to 
reflect revised content. 
List of 
Abbreviations 
Minor content updates. 
Minor updates required to 
reflect revised content. 
6.1.2.1 
Content revised to remove term “control device” and replace 
with “control” only.  
 
Revised to prevent confusion 
regarding control. 
6.2, 15.1.2, 
15.1.3, 15.1.4, 
15.1.5 
Control accountability added to heading (6.2) and content of 
sections. 
Revised to include 
accountability for control. 
8 
The following sentence was added,  
“When assessing relatedness, it should be assumed the 
subject was randomized to the AKST1210 column unless 
unblinding is required.” 
Revisions related to prevention 
of inadvertent unblinding. 
8.1.2 
Section removed and Section 8.1.3 renumbered to Section 
8.1.2. 
Device deficiencies and user 
errors will now be reported as 
technical errors. 
8.2.1 
Term “ADE” added to section. 
Provide clarity regarding 
adverse event classification. 
8.2.3 
Heading changed to, “Expectedness of Adverse Device 
Effects.” 
Provide clarity regarding 
section content. 
8.2.3.1 
Second paragraph revised to information regarding 
assessment and reporting of a UADE. 
Provide clarity regarding 
UADE assessment and 
reporting. 
8.3.1 
Heading changed to “Post-Study Safety Assessment.” 
Avoid use of abbreviations in 
heading per style guidelines. 
8.4.1, 8.4.2 
Extensive content revisions related to reporting procedures. 
Revisions related to 
compliance with standard 
device protocols. 
8.5 
Refinement of content related to description of the “Safety 
Evaluation Meeting.” 
Minor updates for 
clarity/accuracy of content. 
12.2 
Content updates related to written notification IRB/IEC 
withdrawal of approval. 
Minor updates for 
clarity/accuracy of content. 
12.3.2 
The following sentence was removed, “It is required that 
Duplication of content now 

 
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Protocol Version 1.1 dated 11OCT2019 
Replaces: Protocol Version 1.0 dated 06SEP2019 
 
The following table describes changes from Version 1.0 (dated 06SEP2019) with justifications provided. 
 
written informed consent be obtained within 5 working 
days of the use of the investigational device. 
provided in (new) Section 
13.1.1.1. 
13.1.1 
Content updates related to investigator reporting 
responsibilities. 
Revisions related to 
compliance with standard 
device protocols. 
Section(s) 
Description 
Justification 
Throughout 
Protocol version update.  
Previously read: V1.0_06SEP2019 
 
Now reads: V1.1 11OCT2019 
Version control. 
Throughout 
Minor grammar and content updates. 
Minor grammar/content 
updates for clarity/accuracy of 
content. 
Table of 
Contents 
Minor content updates. 
Minor updates required to 
reflect revised content. 
List of 
Abbreviations 
Added abbreviations related to device events. 
Revisions related to 
compliance with standard 
device protocols. 
Protocol 
Approval 
Page 
Addition of 21 Code of Federal Regulations (CFR) 
812, and International Organization for 
Standardization (ISO) 14155:2011. 
Revisions related to 
compliance with standard 
device protocols. 
Protocol 
Summary, 4.1, 
5.3, 5.4.2, 
10.5 
Content added to indicate there will be approximately 
26 subjects enrolled with the intent of obtaining 20 
evaluable subjects (assuming a drop-out rate of 20%).  
Revised subject enrollment to 
obtain appropriate number of 
evaluable subjects.  
2.3.1 
Content revised and extended to include detailed description 
of known potential risks for device (previously only 
included a cross-reference to the Investigator’s Brochure. 
 
Revisions related to 
compliance with standard 
device protocols 
4.1 
Clarification of maximum flow rate of 250 mL/minute, 
which increased overall length of dialysis time to 
approximately 4 hours. 
Provide clarity regarding flow 
rate and extended length of 
dialysis. 
5.5 
Content added regarding Sponsor/investigator notification of 
IRB withdrawal. 
Revisions related to 
compliance with standard 
device protocols. 
6 
Extensive content additions to fully describe device labeling, 
storage, escalation, and administration. A brief description 
of the control was also added. 
Revisions related to 
compliance with standard 
device protocols. 
7.1.1.1.6 
Content revised for clarification of heparin regimen during 
Treatment Periods. 
Provide clarity regarding 
heparin regimen. 
7.1.1.1.8 
Content revised for clarification of PHQ-9 administration. 
Provide clarity regarding PHQ-
9 administration. 

 
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8 
Extensive content revisions related to safety parameters as 
well as device event descriptions, classifications, 
expectedness, reporting procedures, and study halting rules. 
Revisions related to 
compliance with standard 
device protocols. 
12, 13 
Content updates related to reporting procedures, data 
handling, and record keeping that are specific to device 
trials. 
Revisions related to 
compliance with standard 
device protocols. 
15.2 
Added Calcium (Total/Free) to serum chemistry. 
Added for monitoring of 
calcium levels.