A Randomized, Open-label, Controlled, Parallel, Multicenter Study in Kidney Failure Patients on Hemodialysis Comparing the Theranova Dialyzer to Hemodiafiltration
Phase: NA
Conditions: Chronic Kidney Failure, Acute Kidney Failure
Sponsor: Vantive Health LLC



Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 2 of 74 
 
Instructions:  
1. 
For multicenter clinical studies, only the leading site is filled in the cover, and other 
institutions of the clinical study are listed in the protocol content.  
2. 
For multicenter clinical studies, the coordinating investigator is filled in as the 
investigator in the cover.  
 
 
Date 
Original Protocol: 
2021 MAY 19 
Amendment 1.0 
2021 DEC 01 
Amendment 1.1 
2022 MAY 30 
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 3 of 74 
 
Table of Contents  
 
TABLE OF CONTENTS ..................................................... 3 
SYNOPSIS .............................................................. 6 
LIST OF ABBREVIATIONS ................................................ 12 
1. SPONSOR .......................................................... 14 
2. LIST OF CLINICAL STUDY INSTITUTIONS AND INVESTIGATORS ............. 14 
3.  
STUDY OBJECTIVES ................................................ 15 
3.1 OBJECTIVES .............................................................................................................................................. 15 
3.2 CONTENT .............................................................................................................................................. 15 
4. BACKGROUND ....................................................... 16 
5. PRODUCT FEATURES, STRUCTURAL COMPOSITION, OPERATING PRINCIPLE, 
ACTION MECHANISM AND TEST SCOPE ...................................... 17 
5.1 PRODUCT FEATURES .................................................................................................................................. 17 
5.2 PRODUCT STRUCTURE ................................................................................................................................ 17 
5.3 OPERATING PRINCIPLE ............................................................................................................................... 17 
5.4 ACTION MECHANISM ................................................................................................................................. 18 
5.5 SCOPE OF STUDY ....................................................................................................................................... 18 
6. INTENDED USE, CONTRAINDICATIONS AND PRECAUTIONS OF PRODUCT ........ 18 
6.1 INTENDED USE .......................................................................................................................................... 18 
6.2 CONTRAINDICATIONS ................................................................................................................................. 18 
6.3 PRECAUTIONS ........................................................................................................................................... 18 
7. OVERALL DESIGN ................................................... 18 
7.1 STUDY DESIGN .......................................................................................................................................... 19 
7.1.1 Study Purpose ............................................................................................................................... 19 
7.1.2 Rationale of Study Design ............................................................................................................ 19 
7.1.3 Measures to Reduce and Avoid Bias ............................................................................................ 20 
7.1.4  Study Medical Device and Control Device ................................................................................. 20 
7.1.5 Patient Selection ........................................................................................................................... 21 
7.1.6 Evaluation of Efficacy ................................................................................................................... 24 
7.1.6.1 Endpoints ................................................................................................................................... 24 
(1) 
Primary Endpoints:  .................................................................................................................. 24 
(2) 
Secondary Endpoints: ................................................................................................................ 25 
7.1.7. Safety Assessments ...................................................................................................................... 26 
7.2 STUDY PROCESS ........................................................................................................................................ 27 
7.2.1 Study Flow ..................................................................................................................................... 27 
7.2.2 Specification on Device Usage ...................................................................................................... 32 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 4 of 74 
 
7.2.3 Operating Procedure .................................................................................................................... 33 
7.2.4 Possible Adverse Reactions from use of Dialyzer and their Management [20] ............................ 34 
7.2.5 Adverse Reactions of Hemodialysis and Handling [1] ................................................................... 35 
7.2.6 Adverse Reactions of Hemodiafiltration and Handling [1] ........................................................... 35 
8. STATISTICAL CONSIDERATIONS ....................................... 35 
8.1 STATISTICAL DESIGN, METHODS AND ANALYSIS PROCEDURES ........................................................................... 35 
8.2 DETERMINATION OF SAMPLE SIZE ................................................................................................................ 35 
8.2.1. Total Sample Size ......................................................................................................................... 35 
8.2.2 Sample Size for each Disease and Justification ............................................................................ 36 
8.3 SIGNIFICANCE LEVEL AND POWER OF CLINICAL STUDY...................................................................................... 36 
8.4 EXPECTED DROPOUT RATE .......................................................................................................................... 36 
8.5 ELIGIBILITY/FAIL CRITERIA FOR CLINICAL STUDY RESULTS ................................................................................. 36 
8.6 CRITERIA FOR DISCONTINUATION OF STUDY BASED ON STATISTICAL REASONS AND JUSTIFICATION ........................... 36 
8.7 STATISTICAL METHODS OF ALL DATA, TOGETHER WITH PROCESSING OF MISSING, UNUSED OR ERRONEOUS DATA 
(INCLUDING MIDWAY EXIT AND WITHDRAWAL) AND UNREASONABLE DATA................................................................ 37 
8.7.1 Data Statistical Analysis ............................................................................................................... 37 
8.7.2. Processing of Missing, Unused or Erroneous Data (including midway exit and withdrawal) and 
Unreasonable Data ................................................................................................................................ 38 
8.8 PROCEDURES FOR REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PROGRAM ....................................... 39 
8.9 CRITERIA FOR SELECTION OF PATIENTS INCLUDED IN THE ANALYSIS AND JUSTIFICATION .......................................... 39 
8.10 EXCLUSION OF SPECIAL INFORMATION WHEN VERIFYING ASSUMPTIONS AND JUSTIFICATION, IF APPLICABLE ............ 39 
8.11 INTERIM ANALYSIS ................................................................................................................................... 39 
9. DATA MANAGEMENT ................................................... 40 
9.1 ORIGINAL DOCUMENTATION FORMS............................................................................................................. 40 
9.2 ELECTRONIC DATA CAPTURE SYSTEM ............................................................................................................ 41 
9.3 DESIGN OF ELECTRONIC CASE REPORT FORM ................................................................................................. 41 
9.4 ELECTRONIC CASE REPORT FORM COMPLETION .............................................................................................. 41 
9.5 DATA VERIFICATION AND QUERY MANAGEMENT ............................................................................................ 41 
9.6 MEDICAL MONITORING.............................................................................................................................. 41 
9.7 DATA QUALITY ASSURANCE ......................................................................................................................... 41 
9.8 DATA MANAGEMENT PLAN ......................................................................................................................... 42 
9.9 EXTERNAL DATA MANAGEMENT .................................................................................................................. 42 
9.10 BLIND REVIEW ........................................................................................................................................ 42 
9.11 DATABASE LOCKING ................................................................................................................................. 42 
9.12 SUBMISSION AND ARCHIVING OF DATA MANAGEMENT DOCUMENTS ............................................................... 42 
10. 
FEASIBILITY ANALYSIS ............................................ 42 
10.1 ANALYSIS OF THE POSSIBILITY OF SUCCESS ................................................................................................... 42 
10.2 ANALYSIS OF THE POSSIBILITY OF FAILURE .................................................................................................... 43 
11. QUALITY CONTROL OF CLINICAL STUDY ................................ 44 
11.1 SITE QUALITY CONTROL............................................................................................................................ 44 
11.2 MONITORING ......................................................................................................................................... 44 
11.3 AUDIT AND INSPECTION ........................................................................................................................... 44 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 5 of 74 
 
12. 
ETHICAL REVIEW AND INFORMED CONSENT ............................. 44 
12.1 ETHICAL CONSIDERATIONS ........................................................................................................................ 44 
12.2 INFORMED CONSENT ............................................................................................................................... 45 
13. 
PROVISIONS FOR REPORTING ADVERSE EVENTS AND PRODUCT COMPLAINTS  . 45 
13.1 ADVERSE EVENTS .................................................................................................................................... 45 
13.1.1 Definition of Adverse Events ........................................................................................................ 46 
13.1.2 Safety Reporting .......................................................................................................................... 46 
13.2 PRODUCT COMPLAINTS ..................................................................................................................... 50 
13.3 SAFETY REPORTING TO AUTHORITIES AND ETHICS COMMITTEE ....................................................................... 51 
14. 
DETERMINATION, DEVIATION AND AMENDMENT OF CLINICAL STUDY PROTOCOL
 
51 
14.1 DETERMINATION OF THE CLINICAL STUDY PROTOCOL ..................................................................................... 51 
14.2 DEVIATIONS FROM THE CLINICAL STUDY PROTOCOL ....................................................................................... 51 
14.3 AMENDMENTS TO THE CLINICAL STUDY PROTOCOL ....................................................................................... 52 
15. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ...................... 52 
16. 
FINANCE AND INSURANCE ........................................... 52 
17. 
 ASSESSMENTS COVERED IN THE CLINICAL STUDY REPORT ............... 52 
18. 
CONFIDENTIALITY ................................................. 53 
19. 
AGREEMENT ON PUBLISHING STUDY RESULTS ........................... 53 
20. 
RESPONSIBILITIES ASSUMED BY EACH PARTY .......................... 54 
20.1 RESPONSIBILITIES OF CLINICAL STUDY INSTITUTIONS AND INVESTIGATORS ......................................................... 54 
20.2 SPONSOR’S RESPONSIBILITIES .................................................................................................................... 54 
21. 
APPENDICES ..................................................... 56 
APPENDIX 1  .............................................................................................................................................. 56 
OPERATING PROCEDURES FOR HEMODIALYSIS ....................................................................................... 56 
APPENDIX 3 OPERATING PROCEDURES FOR HEMODIAFILTRATION ........................................................ 60 
APPENDIX 4 ADVERSE REACTIONS OF HEMODIALYSIS AND TREATMENT ............................................... 62 
APPENDIX 5 ADVERSE REACTIONS OF HEMODIAFILTRATION AND TREATMENT .................................... 71 
22. 
REFERENCES ..................................................... 72 
INVESTIGATOR’S STATEMENT ............................................ 74 
 
 

Gambro Dialysatoren GmbH                                                 Protocol Number: BXU561424  
 
  
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 6 of 74 
 
 
SYNOPSIS  
Study Title:  
A randomized, controlled, open-label, parallel, multicenter study in kidney failure 
patients on hemodialysis comparing the Theranova Dialyzer to hemodiafiltration 
Study Objectives  
Primary Objective:  
The primary objective is to demonstrate non-inferiority of the Theranova 400 Dialyzer 
in hemodialysis (HD) mode (hereinafter referred to as Theranova 400) compared to 
hemodiafiltration (HDF), using FX 800 in HDF mode (hereinafter referred to as FX 800), 
in regard to the reduction ratio (RR) of lambda free light chains (λ FLC), and beta-2 
microglobulin (β2-MG) at the  mid-week treatment day dialysis session. 
Secondary Objectives: 
1. To evaluate the Theranova 400 compared to FX 800 in regard to assessments of 
Kt/Vurea, Urea Reduction Ratio (URR) at the mid-week treatment day dialysis 
session. 
2. To evaluate the RRs of α1-microglobulin (α1-MG), Chitinase-3-like protein 1 
(YKL-40), complement factor D (CFD), myoglobin, and kappa free light chains 
(κ FLC) at the mid-week treatment day dialysis session.  
 
Study Design  
A randomized, controlled, open-label, parallel, multicenter study. 
Device in the  
Test Group  
Product name: Hollow fiber dialyzers with medium cut-off membrane 
Model and Specification: Theranova 400  
Registrant: Gambro Dialysatoren GmbH  
Device in the 
Control Group  
Product name: Hollow fiber hemodialysis filter  
Model and Specification: FX 800 HDF  
Registrant: Fresenius Medical Care AG & Co. KGaA.  
Study Population  
The study population consists of patients with kidney failure on a stable HD and/or 
HDF prescription. A sufficient number of patients will be enrolled to ensure 272 
patients are randomized 1:1 to receive 1 mid-week therapy with either Theranova 400 
(136 patients) or FX 800 (136 patients). 
Inclusion 
Criteria   
All of the following criteria must be met for the patient to be eligible for participation.  
1. 
Patients aged ≥18 years old and ≤80 years old, regardless of gender; 
2. 
Patients who are able to sign informed consent form (ICF) after an explanation of 
the proposed study; 
3. 
Patients who receive in-center HD treatment at a site that routinely implements high 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 7 of 74 
 
flux dialysis and HDF; 
4.  Patients who have been stable receiving in-center HD/HDF for >3 months prior to 
study enrollment; 
5. 
Patients with kidney failure receiving maintained HD treatment with a history of 
thrice weekly HD, and at least 1 HDF session within 1 month prior to the study shall be 
judged by the investigator; 
6.  Patients who have an adequate arteriovenous (AV) fistula or graft, or dual-lumen 
tunneled catheter capable of providing a blood flow rate (QB) of at least 250 mL/min; 
7. 
Patients have no changes in dialysis prescription (dialyzer, time, dialysis fluid flow 
rate (QD), QB, sufficient dialysis anticoagulation, and stable prescribed doses) over last 
6 treatments as judged by investigator. The dialysis treatment time should be 3.5 to 4.5 
hours per session with a minimum QB of 250 mL/min and QD of 500 mL/min; 
8. 
Patients with a minimum total convective volume (including ultrafiltration [UF]) of 
16 L post-dilution for the most recent HDF treatment; 
9.  Patients who have Kt/Vurea > 1.2 for the last 2 measurements, with the most recent 
Kt/Vurea measurement taken within 4 weeks before or during study screening. 
Exclusion 
Criteria 
Patients who meet any of the following criteria will be excluded from the study:  
1. 
Patients who have acute kidney injury with the chance for recovery;  
2. 
Pregnant and lactating women; 
3.  Patients diagnosed with a New York Heart Association (NYHA) Class IV 
congestive heart failure, or acute coronary syndrome, and/or who have suffered a 
myocardial infarction within 3 months prior to the start of the study; 
4.  Patients with known hemodynamic instability, anemia (hemoglobin <90 g/L), and/or 
patients with hemoglobin >130 g/L for coagulation risk; 
5. 
Patients with active or ongoing infection as per investigator's judgement (eg. C-
reactive protein [CRP] level more than 5 folds of normal); 
6. 
Patients who are severely malnourished or with significant disease that interferes 
with liver synthetic function (e.g. with serum albumin <30 g/L); 
7.  Patients with positive serology tests for Hepatitis B surface antigen, Hepatitis C total 
antibody, and advanced liver, or pulmonary disease as judged by the investigator; 
8.  Patients with positive serology tests for human immunodeficiency virus (HIV), 
Syphilis; 
9.  Patients receiving immunosuppressive treatment or with autoimmune disease;  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 8 of 74 
 
10. Patients with a history of solid tumors requiring anti-cancer therapy in the past or 
next 6 months, or with a life expectancy of <1 year, or patients with a history of 
hematology neoplasm;  
11. Patients who are pre-scheduled for a living donor kidney transplant within the next 
1 year, who plan a change to peritoneal dialysis (PD) within the next 1 year, or who 
require single-needle dialysis therapy;  
12. Patients who have had an allergic response to polyarylethersulfone (PAES) or 
polysulfone (PS) membrane or have a history of poor tolerance to dialyzers with 
synthetic membranes; 
13.  Patients with a history of severe mental disorders who are unable to provide 
consent or comply with study procedures as assessed by the investigator;  
14. Patients who are currently participating in or have previously participated in other 
interventional clinical studies during the past 30 days;  
15. Patients with any comorbidity possibly conflicting with the study as judged by the 
investigator. 
Duration of 
Treatment  
The study will have a duration of 3 weeks per per patient in total. The study will consist 
of:  
1) 
Screening Period: 2 weeks;  
2) 
Treatment Period: 1 week, 1 session in mid-week therapy with either 
Theranova 400 or FX 800; (Note: visit ought to be conducted within 2 weeks 
after randomization).  
Follow-up: review of treatment-related AEs conducted at the next dialysis 
session (end-week therapy session), but prior to treatment commencement. 
 
Study Medical 
Device, 
Frequency and 
Mode of 
Administration 
In-center HD mid-week therapy with the Theranova 400 Dialyzer in HD mode, or with 
the FX 800 Dialyzer in HDF mode, 1 mid- week session as per patient randomization. 
Efficacy 
Endpoints  
Primary Endpoints:  
1. 
RR of λ FLC;  
2. 
RR of β2-MG.  
Secondary Endpoints:  
At the mid-week treatment day dialysis session 
1. 
Kt/Vurea;  
2. 
URR;  
3. 
RR of α1-MG;  
4. 
RR of YKL-40;  
5. 
RR of CFD;  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 9 of 74 
 
6. 
RR of myoglobin;  
7. 
RR of κ FLC.  
Safety 
Assessments  
Safety Assessments 
- 
Adverse events (AEs) and serious adverse event (SAEs).  
- 
CRP analysis  
- 
Routine serum chemistry and hematology assessments 
- 
Vital signs pre-and post-dialysis per treatment 
- 
Device deficiencies (during use of the investigational product; which would 
include functional characteristics [e.g., leaks, tubing separations, etc.]) 
 
Sample Size  
The goal of this study is to demonstrate non-inferiority of Theranova 400 compared to 
FX 800 in the 2 primary endpoints and the non-inferiority margins selected are 
considered clinically acceptable.  
The sample size calculation is performed using PASS procedure Mann-Whitney U or 
Wilcoxon Rank-Sum Tests for Non-Inferiority. A separate sample size calculation is 
performed for both primary endpoints using a specified non-inferiority margin of 10% 
and a one-sided alpha level of 0.025, where the true difference in means is assumed to 
be zero (0).  
Sample size calculation in regard to λ FLC reduction ratio:  
A previously conducted Theranova HDF study was used to obtain λ FLC RR mean and 
standard deviation (SD) of 37.83 and 8.26. Based on a 1:1 randomization, with a 
sample size of 129 patients in the Theranova 400 group and 129 patients in the FX 800 
group, a Wilcoxon Rank-Sum test with a 0.025 one-sided significance level will have 
90% power to demonstrate non-inferiority of the Theranova 400 Dialyzer compared to 
the FX 800 Dialyzer as assessed by λ FLC RR with a non-inferiority margin of 10% 
(i.e. 3.783).  
Sample size calculation in regard to ß2- microglobulin reduction ratio:  
A previously conducted Theranova HDF study was used to obtain ß2-MG RR mean 
and SD of 78.48 and 6.75; a higher estimate for SD of 14.28 is used to calculate 
sample size to account for a potential increase in variability based on a literature 
review of studies conducted in China. Based on a 1:1 randomization, with a sample 
size of 75 patients in the Theranova 400 group and 75 patients in the FX 800 group 
(total N = 150), a Wilcoxon Rank-Sum test with a 0.025 one-sided significance level 
will have 90% power to demonstrate non-inferiority of the Theranova 400 Dialyzer 
compared to the FX 800 Dialyzer as assessed by β2-MG RR with a non-inferiority 
margin of 10% (i.e. 7.848).  
Sample size for this study:  
Consequently, in order to demonstrate non-inferiority between Theranova 400 and FX 
800 in both primary endpoints, a sample size of 129 patients in the Theranova 400 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 10 of 74 
 
group and 129 patients in the FX800 group is required to guarantee 90% power for the 
analysis of λ FLC and > 90% power for the analyses of ß2-MG. To allow for 5% of 
patients to drop out or be excluded from the Per-protocol population as a result of 
patient classification, a total of 272 patients will be randomized 1:1 to treatment with 
the Theranova 400 Dialyzer (136 patients) or treatment with the FX 800 Dialyzer 
(136 patients). 
Statistical 
Analysis  
The analysis details of the planned statistical methods will be provided in the study 
statistical analysis plan (SAP). The draft SAP is formed after determination of the study 
protocol and electronic case report form (eCRF). It will be finalized prior to database 
lock. 
Analysis of Primary Endpoints: For λ FLC and ß2-MG RR, a t-test will be utilized to 
generate a two-sided 95% confidence interval (CI) for the difference in means (μT- μR). 
If the lower bound of the CI for the 2 endpoints are greater than the predefined 
noninferiority margins, then non-inferiority between the Theranova 400 and FX 800 
treatment group can be demonstrated. In case the assumption of a normal distribution is 
not justified, RRs can be log transformed in order for the measurements to follow a 
normal distribution. If, after transformation, measurements still do not follow a normal 
distribution, the above statistical analyses methods will be replaced with their non-
parametric equivalents. The Wilcoxon Rank-Sum Test will be used in place of the t-test 
while the Kruskal Wallis test will be used in place of the ANOVA.  
Analysis of Secondary Endpoints:  
Secondary endpoints will be evaluated as follows:  
A t-test or Wilcoxon Rank-Sum test, as applicable, will be used to evaluate differences 
between treatment groups in Kt/Vurea and URR.  
A t-test or Wilcoxon Rank-Sum test, as applicable, will be used to evaluate differences 
between treatment groups for the RRs of α1-MG, YKL-40, CFD, myoglobin and κ FLC 
obtained at the mid-week treatment day dialysis session.  
Analysis of Safety Endpoints:  
Safety endpoints will be evaluated as follows:  
The summary of AEs will include AEs that occur on the day of or after the study 
treatment. Pre-treatment AEs including AEs reported at Screening and Randomization 
will be recorded in the eCRF but will not be summarized in the safety tables. Adverse 
events will be mapped to a Primary SOC and Preferred Term (PT) according to Medical 
Dictionary for Regulatory Activities (MedDRA) and summarized descriptively by SOC, 
PT and treatment group. Treatment group comparability in the incidence of AEs will be 
evaluated using Fisher's exact test.  
Investigational device related product defects will be summarized descriptively. 
Comparator related product defects will not by collected or analyzed by Baxter.  
Serum chemistry, hematology assessments, patient vital signs and CRP will be 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 11 of 74 
 
summarized descriptively per measurement time point using n, mean, median, standard 
deviation, minimum, and maximum.  
Other Assessments:  
Continuous and categorical demographic and baseline characteristics will be 
summarized by treatment groups. A t-test or Wilcoxon Rank-Sum test, as applicable, 
will be used to assess differences between treatment groups in continuous variables 
and Fisher's exact test will be used to assess differences between treatment groups in 
categorical variables.  
Interim Analysis:  
A blinded interim analysis for sample size re-estimation will be conducted when 
approximately 50% of patients complete their mid-week treatment day dialysis session 
and corresponding λ FLC and β2-MG RRs are available. 
For sample size re-estimation, for each primary endpoint, the same sample size 
calculation will be carried out using the one-sample variance estimator which is based 
on the pooled variance (across both treatment groups) of the RRs as observed in the 
patients included in the interim analysis. In case the re-estimation for the sample size 
of λ FLC or β2-MG yields a patient number > 272 (including 5% drop out), the sample 
size of the study will be increased to this re-calculated number but will not exceed 350. 
In case the sample size reassessment for λ FLC or β2-MG yields a patient number ≤ 
272 (including 5% drop out), the sample size of the study will not be adjusted and the 
original sample size of 272 will be maintained. Due to this blinded and pooled (non-
treatment group based) approach in re-estimation of the sample size and the absence of 
early stopping for futility and efficacy, no alpha adjustment is required for the final 
analysis. 
Visit Schedule  
Refer to 7.2.1.1 Study Flow. 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 12 of 74 
 
LIST OF ABBREVIATIONS  
Abbreviation  
Definition of Term  
AE  
adverse events  
α1-MG  
alpha-1 microglobulin  
AV  
arteriovenous  
β2-MG  
beta-2 microglobulin  
BP  
blood pressure  
Ca  
calcium  
Cl  
chlorine  
CFD  
complement factor D  
CRP  
c-reactive protein  
eCRF  
electronic case report form  
DD 
device deficienies 
DMP  
Data Management Plan  
EDC  
electronic data capture system  
FAS  
full analysis set  
GCP  
good clinical practice  
HD  
hemodialysis  
HDF  
hemodiafiltration  
HF  
high flux  
HIV  
human immunodeficiency virus  
ICF  
informed consent form  
κ FLC  
kappa free light chain  
K  
potassium  
Kt/Vurea  
formula used to quantify hemodialysis and peritoneal dialysis adequacy  
λ FLC  
lambda free light chain  
Na  
sodium  
NMPA  
National Medical Products Administration  
P  
phosphorus  
QB 
blood flow rate 
QD  
dialysis fluid flow rate  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 13 of 74 
 
RR  
reduction ratio  
SAE  
serious adverse event  
SAP  
statistical analysis plan  
SOP  
standard operating procedure  
UF  
ultrafiltration  
URR  
urea reduction ratio  
YKL-40  
chitinase-3-like protein 1  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 14 of 74 
 
1. Sponsor  
Company name  
Gambro dialysatoren GmbH 
Address  
Holger-Crafoord-Strasse 26, 72379 Hechingen, Germany 
Tel  
+49 7471171227 
Fax  
+49 7471171227 
Qualification  
Production license  
 
Agent  
Baxter Medical Products Trading (Shanghai) Co., Ltd.  
Address  
12 floor, Changle Road 989#, Xuhui District, Shanghai 
Tel  
+86 21 24012366  
Fax  
+86 21 24012466  
Qualification  
Business license  
 
2. List of Clinical Study Institutions and Investigators  
Clinical 
study 
institution 
code  
Address  
Clinical study institution 
name  
Investigator  Technical 
title  
Contact  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 15 of 74 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  Study Objectives 
3.1 Objectives  
Primary Objective:  
The primary objective is to demonstrate non-inferiority of the Theranova 400 Dialyzer in 
hemodialysis (HD) mode (hereinafter referred to as Theranova 400) compared to 
hemodiafiltration (HDF), using FX 800 in HDF mode (hereinafter referred to as FX 800), in 
regard to the reduction ratio (RR) of lambda free light chains (λ FLC), and beta-2 microglobulin 
(β2-MG) at the mid-week treatment day dialysis session. 
 
Secondary Objectives: 
1. To evaluate the Theranova 400 compared to FX 800 in regard to assessments of Kt/Vurea’ 
Urea Reduction Ratio (URR) at the mid-week treatment day dialysis session. 
2. To evaluate the RRs of urea, α1-microglobulin (α1-MG), Chitinase-3-like protein 1 
(YKL-40), complement factor D (CFD), myoglobin, and kappa free light chains (κ FLC) 
at the mid-week treatment day dialysis session. 
3.2 Content  
The clinical study is conducted in accordance with relevant regulations of National Medical 
Products Administration (NMPA).  
To ensure approximately 272 patients with kidney failure on a stable HD and/or HDF 
prescription will be enrolled in this study.  
The investigational product is hollow fiber dialyzers with medium cut-off volume of Gambro 
Dialysatoren GmbH (model: Theranova 400), and the control product is hollow fiber HD filter 
(model: FX 800 HDF) of Fresenius Medical Care AG & Co. KGaA.  
This study is a randomized, controlled, open-label, parallel multicenter study. Ensure to recruit 
a sufficient number of patients, 272 patients are randomized at a 1:1 ratio to receive treatment 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 16 of 74 
 
with Theranova 400 (136 patients) or FX 800 (136 patients) at the mid-week treatment day 
dialysis session. A follow-up visit to assess treatment related AEs is to be conducted at the next 
end-week dialysis session, but prior to treatment commencement. The RRs of large middle-
molecular-weight toxins are observed and compared in the 2 groups. The indicators such as 
adverse events (AEs), laboratory tests and vital signs of patients and the device defects are 
monitored to evaluate the safety and efficacy of Theranova 400.  
4. Background  
The incidence of chronic kidney disease is increasing worldwide, and if it is not controlled and 
treated in time, it may develop into kidney failure, previously referred to as end-stage kidney 
disease (ESRD). In China, there are more than 2.9 million kidney failure patients[1]; however, 
given the limited supply of donor kidneys, dialysis remains the mainstay treatment. There are 
about 700,000 patients receiving dialysis treatment in China [1]. Although HD has been 
implemented for over 50 years, the all-cause mortality of patients receiving HD is still increasing, 
with poor long-term prognosis[2].  
Uremic toxins accumulated in patients with kidney failure include: low-molecular-weight 
(<500 Da) and middle-molecular-weight (500~60 KDa) water-soluble toxins and protein-
binding toxins[3]. Cardiovascular disease is the leading cause for death of dialysis patients, 
accounting for 55.2% of deaths[4]. Traditional HD therapy is very effective in clearing urea and 
smaller middle molecules, but is limited in clearing larger middle molecules. These accumulated 
large middle-molecular-weight uremic toxins may cause and aggravate inflammation, 
atherosclerosis and calcification, which indirectly lead to the death of patients[5]. Studies have 
shown that, compared to conventional high-flux HD (HF-HD), HDF that combines diffusion and 
convection can reduce the all-cause mortality. Compared to the conventional HF-HD, HDF can 
more effectively clear larger molecular toxins in one session, which may be related to the better 
clearance effect of HDF on middle-molecular-weight toxins[6,7]. The high-convection online 
hemodiafiltration (OL-HDF) is not suitable for all patients due to the problems such as vascular 
access dysfunction, inability of the water treatment system to provide ultrapure water, and 
expenses[8].  
Theranova’s innovative Medium Cut-Off® membranes has high permeability and selectivity to 
uremic toxins (clearance of a molecular weight of up to 45 kDa) and can retain essential proteins, 
to maintain patient's albumin level during the HD treatment[9]. Its unique membrane and high 
cut-off characteristics expand the clearance range beyond those of flux membrane dialyzers. 
Theranova 400 can be widely used in most blood purification centers under conventional HD 
equipment and treatment modes, with the effect similar to HDF[10].  
Theranova 400 has been marketed in European Union (EU) since 2016, and accredited De Novo 
certification in the United States of America (US) in 2020. At present, a large amount of research 
data on the efficacy and safety has been accumulated. The PerCOM study laying the foundation 
for Theranova's marking in EU [11,12] showed that, Theranova is superior to HF-HD in terms of 
clearance of middle molecular weight toxins, and is equivalent or superior to high-convection 
HDF; Theranova and HDF have almost the same clearance for low molecular weight toxins. The 
pivot study [13] laying a foundation for Theranova's approval by US FDA (Food and Drug 
Administration) showed that, Theranova is much better than HF-HD in clearing large middle 
molecules (λ FLC), and there is no significant change in serum albumin level of patients after 24 
weeks of observation. The preclinical data and in vitro performance data provided by Boschetti 
de Fierro et al. (2015), Hulko et al. (2015), Voigt et al. (2016) confirmed that the performance of 
Theranova 400 was similar to HDF. In addition, a number of studies on Theranova 400 that are 
published in international journals have proven its safety and efficacy. 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 17 of 74 
 
Presently, it is proposed to conduct clinical studies to evaluate the safety and efficacy of 
Theranova 400 in China. The dialyzer has been tested by the Guangdong Medical Device Quality 
Surveillance and Test Institute and is qualified for clinical studies. Therefore, this clinical trial 
protocol is formulated and implemented after approval of the hospital's ethics committee. The 
clinical study summary report will be submitted to the NMPA for product registration application.  
5. Product Features, Structural Composition, Operating Principle, Action Mechanism 
and Test Scope  
5.1 Product Features  
Expanded hemodialysis (HDx), enabled by the Theranova dialyzer, expands the range of uremic 
solutes (up to 45,000 Da) efficiently removed during intermittent HD.  
The Theranova dialyzer provides removal of small molecules (<500 Da, such as urea) equivalent 
to high flux membranes used in HD and HDF. Removal of conventional middle molecules (500 
- <25,000 Da, such as κ FLC) is increased compared to high flux membranes used in HD. 
Removal of large middle molecules (25,000 – 45,000 Da, such as λ FLCs) is increased compared 
to high flux membranes used in HD and HDF.  
Expanded hemodialysis, enabled by the Theranova dialyzer, achieves its performance using 
existing HD workflow and infrastructure[13,14].  
5.2 Product Structure  
The membrane material used in Theranova 400 is a composite of polyaryl ether sulfone (PAES) 
and polyvinylpyrrolidone (PVP). Both ends of the dialyzer are filled with polyurethane (PUR) 
hollow fibers to separate the blood chamber from the dialysate chamber. The inner diameter of 
each hollow fiber is approximately 180 μm, and the wall thickness is approximately 35 μm. The 
effective length of the membrane is 236 mm. The number of hollow fibers of Theranova 400 is 
about 13,000, and the surface area of Theranova 400 is 1.7 m2. The material of the shell and end 
cap of the dialyzer is polycarbonate.  
5.3 Operating Principle  
The blood (after anticoagulation treatment) is transported from the patient's blood channel to the 
dialyzer through the extracorporeal circulation pipeline system through the HD machine. The 
blood enters the blood inlet and is dispersed into the cavity containing hollow fibers. 
The Theranova dialyzer uses the principle of countercurrent concentration difference to enhance 
solute exchange. The dialysate pumped by the HD machine flows through the dialysate chamber 
through the dialysate inlet from the opposite direction to the blood flow in the extracorporeal 
circulation (reverse flow). 
Hydrostatic pressure or transmembrane pressure (TMP) is produced by the combination of 
positive and negative pressure across the membrane. The pressure difference between the blood 
chamber and the dialysate chamber causes solute-dissolved plasma and certain lower molecular 
weight molecules to pass through the membrane and enter the dialysate chamber of the device 
(convection). At the same time, the solute dissolved in the plasma diffuses into the dialysate 
chamber along the concentration gradient between the plasma and the dialysate. During 
treatment, in these devices, uremic toxins and waste products enter the reverse-flowing dialysate 
through transmembrane convection and diffusion to achieve the effect of being removed from 
the patient's blood. The dialysate flows out of the device through the dialysate outlet. 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 18 of 74 
 
Due to its larger membrane pore size, Theranova 400 has a significantly higher permeability for 
middle molecules in the molecular weight range of 15-45 kDa in comparison to conventional HF 
membranes. A narrow pore size distribution in the Theranova 400 membrane ensures that during 
HD there is an effective retention of larger proteins with molecular weights greater than 60 kDa 
such as albumin, coagulation factors or immunoglobulins. For certain molecules like β2-MG, 
myoglobin, κ-FLC, Interleukin-6 (IL-6), CFD, α1-MG, YKL-40 and λ- FLC, Theranova 400 has 
been reported to provide equivalent or superior solute clearance than HDF. [15]  
Use of HF membranes, such as the FX 800 HDF allows the removal of uremic toxins, particularly 
middle molecules such as β2-MG. Theranova 400 and FX 800 HDF use the same principles of 
operation, i.e. diffusive and convective transport when performing HF-HD.  
5.4 Action Mechanism  
Same as the operating principle.  
5.5 Scope of Study  
It is proposed to conduct this study in 11 medical institutions with qualifications for clinical 
studies.  
6. Intended Use, Contraindications and Precautions of Product  
6.1 Intended Use  
THERANOVA dialyzers are indicated for treatment of chronic and acute kidney failure by HD.  
6.2 Contraindications  
There are no known contraindications for the use of the Theranova 400.  
6.3 Precautions  
The dialyzers are for single use only.  
Follow the product instructions to use the product. 
The quality of the product is guaranteed for first use only,and only when prepared and used 
according to the procedures described. Reprocessing this dialyzer may cause serious damage to 
the product resulting in patient hazard.  
Treatment parameters should be chosen within the limitations given in the specification table.  
The dialyzer is used together with a dialysis device that can precisely control and monitor the 
ultrafiltration rate and blood in the dialysate circuit (leakage detector).  
Expanded removal of molecules may lead to increased removal of certain drugs. Clinicians 
should consider this when prescribing the device and make any necessary dosing adjustments.  
Do not apply isolated/sequential ultrafiltration when using THERANOVA dialyzers, due to 
higher permeability for larger plasma proteins such as free haemoglobin. In dialysis patients, 
plasma free haemoglobin is usually present in low concentrations (up to 239 mg/L [16]). During 
isolated/sequential ultrafiltration, free haemoglobin is filtered and concentrated in the dialysate 
compartment. This leads to a reddish coloration of the ultrafiltrate which may trigger the internal 
blood leak detector.  
7. Overall Design  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 20 of 74 
 
addition, the RRs of β2-MG and λ FLC in this trial are not affected by subjectivity of 
investigators or patients, so an open-label design is utilized in this trial.  
(4)  
Parallel control: There is no similar product available yet. The hollow fiber HD/filter 
(model: FX 800 HDF) is similar to the investigational product in intended uses, 
structures and performances as the control product in this trial.  
  
7.1.3 Measures to Reduce and Avoid Bias  
(1)  
Multicenter clinical study: Patients are from multiple study sites, avoiding the bias of test 
results caused by systematic errors in a single study site.  
(2)  
A randomized design is utilized in this study to ensure comparability between groups and 
reduce selection bias.  
(3)  
Participating investigators and operators in various sub-sites will be trained on the use of 
the Theranova 400 Dialyzer; the study must be conducted in strict accordance with the 
clinical study protocol and China's standard operating procedures for HD.  
7.1.4  Study Medical Device and Control Device  
(1)  
Study Medical Device  
Product name  
Hollow fiber dialyzers with medium cut-off membrane  
Model and Specification  Theranova 400  
Registrant  
Gambro Dialysatoren GmbH 
Shelf Life  
Refer to IFU 
Storage  
<30ºC/86ºF 
Structural composition  
The membrane material used in Theranova 400 is a composite of polyaryl ether 
sulfone (PAES) and polyvinylpyrrolidone (PVP). Both ends of the dialyzer are 
filled with polyurethane (PUR) hollow fibers to separate the blood chamber from 
the dialysate chamber. The inner diameter of each hollow fiber is approximately 
180 μm, and the wall thickness is approximately 35 μm. The effective length of 
the membrane is 236 mm. The number of hollow fibers of Theranova 400 is 
about 13,000, and the surface area of Theranova 400 is 1.7 m2. The material used 
for the dialyzer housing and end caps is polycarbonate. 
Scope/Intended Use  
THERANOVA dialyzers are indicated for treatment of chronic and acute kidney 
failure by HD.  
 
(2)  
Control Device:  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 21 of 74 
 
Product name  
Hollow fiber hemodialysis filter  
Model and Specification  FX 800 HDF  
Registrant  
Fresenius Medical Care AG & Co., KGaA.  
Registration No.  
GXZJ 20193101929  
Shelf Life  
Refer to IFU 
Storage  
Refer to IFU 
Structural composition  
This product consists of fiber membrane, housing, packaging material, top cover, 
sealing ring, blood protective cap and dialysate protective cap. The materials of 
hollow fiber membrane, housing, packaging, topcover, sealing ring, blood 
protective cap and dialysate protective cap are a mixture of polysulfone fiber-
polyvinylpyrrolidone, polypropylene, polyurethane, polypropylene, silicon resin 
and polypropylene, respectively. This product is sterilized by flowing steam, and 
it is disposable.  
Scope/Intended Use  
The product is indicated for conventional HD or HDF treatment.  
7.1.5 Patient Selection  
7.1.5.1 Inclusion Criteria  
All of the following criteria must be met for the patient to be eligible for participation.  
1. Patients aged ≥18 years old and ≤80 years old, regardless of gender; 
2. Patients who are able to sign informed consent form (ICF) after an explanation of the 
proposed study;  
3. Patients who receive in-center HD treatment at a site that routinely implements high flux 
dialysis and HDF; 
4.  Patients who have been stable receiving in-center HD/HDF for >3 months prior to study 
enrollment; 
5. Patients with kidney failure receiving maintained HD treatment with a history of thrice 
weekly HD, and at least 1 HDF session within 1 month prior to the study shall be judged by the 
investigator; 
6.  Patients who have an adequate arteriovenous (AV) fistula or graft, or dual-lumen tunneled 
catheter capable of providing a blood flow rate (QB) of at least 250 mL/min; 
7. Patients have no changes in dialysis prescription (dialyzer, time, dialysis fluid flow rate 
(QD), QB, sufficient dialysis anticoagulation, and stable prescribed doses) over last 6 treatments 
as judged by the investigator. The dialysis treatment time should be 3.5 to 4.5 hours per session 
with minimum QB of 250 mL/min and QD of 500 mL/min; 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 22 of 74 
 
8. Patients with a minimum total convective volume (including ultrafiltration (UF)) of 16 L 
post-dilution for the most recent HDF treatment; 
9.  Patients who have Kt/Vurea > 1.2 for the last 2 measurements, with the most recent Kt/Vurea 
measurement taken within 4 weeks before or during study screening. 
7.1.5.2 Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from the study:  
1. Patients who have acute kidney injury with the chance for recovery;  
2. Pregnant and lactating women; 
3.  Patients diagnosed with a New York Heart Association (NYHA) Class IV congestive heart 
failure, or acute coronary syndrome, and/or who have suffered a myocardial infarction within 3 
months prior to the start of the study; 
4.  Patients with known hemodynamic instability, anemia (hemoglobin <90 g/L), and/or 
patients with hemoglobin >130g/L for coagulation risk; 
5. Patients with active or ongoing infection as per investigator's judgement (e.g C-reactive 
protein [CRP] level more than 5 folds of normal); 
6. Patients who are severely malnourished or with significant disease that interferes with liver 
synthetic function ( e.g. with serum albumin <30 g/L); 
7.  Patients with positive serology tests for Hepatitis B surface antigen, Hepatitis C total 
antibody, and advanced liver, or pulmonary disease as judged by the investigator; 
8.   Patients with positive serology tests for human immunodeficiency virus (HIV), Syphilis; 
9.   Patients receiving immunosuppressive treatment or with autoimmune disease;  
10.  Patients with a history of solid tumors requiring anti-cancer therapy in the past or next 6 
months, or with a life expectancy of <1 year, or patients with history of hematology neoplasm;  
11.  Patients who are pre-scheduled for a living donor kidney transplant within the next 1 year, 
who plan a change to peritoneal dialysis (PD) within the next 1 year, or who require single-
needle dialysis therapy; 
12.  Patients who have had an allergic response to polyarylethersulfone (PAES) or polysulfone 
(PS) membrane or have history of poor tolerance to dialyzers with synthetic membranes; 
13.  Patients with a history of severe mental disorders who are unable to provide consent or 
comply with study procedures as assessed by the investigator;  
14. Patients who are currently participating in or have previously participated in other 
interventional clinical studies during the past 30 days;  
15. Patients with any comorbidity possibly conflicting with the study as judged by the 
investigator. 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 23 of 74 
 
7.1.5.3 Study Suspension and Discontinuation  
7.1.5.3.1 Criteria for Study Suspension and Discontinuation  
The main purpose of study suspension or discontinuation is to protect rights and interests of 
patients, ensure the study quality and avoid unnecessary economic losses. Study suspension or 
discontinuation will be performed in case of the following circumstances (including without 
limitation):  
（1） Clinical study institutions and investigators assess that the risks outweigh the benefits if 
the study continued;  
（2） The Ethics Committee finds that the rights and interests of patients cannot be guaranteed;  
（3） Discontinuation of study is required by the Sponsor for various reasons;  
（4） Discontinuation of study is instructed by regulatory authorities.  
7.1.5.3.2 Procedure for Study Suspension and Discontinuation  
When deciding to suspend or discontinue the study, the Sponsor shall promptly inform the study 
management departments of the clinical study institutions who will inform the investigators and 
the Ethics Committee, and provide them with relevant data supporting this decision. The 
resumption of the clinical study needs approval of the Ethics Committee. After the end of the 
clinical study, the sponsor shall inform the Shanghai Medical Products Administration in writing.  
7.1.5.4 Patient Withdrawal  
7.1.5.4.1 Criteria for Patient Withdrawal:  
All patients are entitled to withdraw at any time throughout the study. Patients will withdraw 
from the study under the following circumstances:  
（1） Withdrawal of ICF;  
（2） AEs/serious adverse events (SAEs) occur that make treatment inapplicable;  
（3） Serious protocol violation;  
（4） Death;  
（5） Pregnancy;  
（6） Kidney transplantation;  
（7） Switch to PD;  
（8） Other reason.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 24 of 74 
 
Process of Withdrawal from the Study:  
（1） Details of the time and reasons for withdrawal from the study are recorded in the 
electronic case report form (eCRF);  
（2） Patients' data will not be collected after their withdrawal from the study, but patients who 
withdraw from the study due to AEs must be followed up until the AEs are stable or 
resolved or are deemed no need of further follow-up by investigators.  
7.1.5.5 Time of Enrollment  
All patients who sign the ICF will be enrolled into the study after judged to meet the inclusion 
criteria but not to meet the exclusion criteria by the investigators.  
The enrollment period is expected to be approximately 8 months, which will be adjusted 
according to the actual enrollment situation.  
7.1.5.6 The Expected Overall Duration of Clinical Study and Justification  
It is expected that the overall duration of the clinical study is approximately 31 months. The 
overall duration of this clinical study from preliminary preparation, initiation of sub-site, 
enrollment of patients to last patient out is approximately 19 months. The database lock, 
statistical analysis, writing of summary reports and closing of centers will take approximately 
12 months. The duration of the study may be adjusted according to the actual progress. If the 
study is not completed as scheduled, it will be extended accordingly until completion of the study.  
7.1.5.7 Expected Duration per Patient  
The study will have a duration of 3 weeks at maximum per patient in total see Figure 1). The 
study will consist of:  
（1） Screening Period: 2 weeks;  
（2） Treatment Period : 1 week, 1 session in mid-week therapy with either Theranova 400 or 
FX 800; (Note: visit ought to be conducted within 2 weeks after randomization ) 
 
Follow-up review of treatment-related AEs conducted at the next dialysis session (end-
week therapy session), but prior to treatment commencement. 
7.1.5.8 Sample Size for this Clinical Study  
Based on statistical calculation, the effective sample sizes for the test group and the control group 
are at least 129 and 129 cases, respectively. Taking 5% dropout rate and loss due to major 
protocol violation into account, the sample size in the test group is 136 cases and that in the 
control group is 136 cases, 272 cases in total.  
7.1.6 Evaluation of Efficacy  
7.1.6.1 Endpoints  
The following endpoints will be assessed at the mid-week treatment day dialysis session . 
(1) Primary Endpoints:  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 25 of 74 
 
1) RR of λ FLC;  
2) RR of β2-MG.  
(2) Secondary Endpoints:  
1) Kt/Vurea;  
2) Urea Reduction Ratio (URR);  
3) RR of α1-MG;  
4) RR of YKL-40;  
5) RR of CFD;  
6) RR of myoglobin;  
7) RR of κ FLC.  
7.1.6.2 Method for Evaluation, Recording and Analysis of Efficacy Endpoints and Time 
Selection  
7.1.6.2.1 Evaluation Methods  
(1)  
Reduction ratio (RR):  
The RR for each solute, based on the change in the arterial plasma concentration over the dialysis 
session, will be calculated as:  
RR(%) =  （1 −
Cpost
Cpre ）× 100% 
Where CPre and CPost are the measured arterial plasma concentrations of the solute before and 
after dialysis, respectively [17].  
However, for the middle molecules (λ FLC, κ FLC, α1-MG, CFD, YKL-40, myoglobin and β2-
MG) CPost will be first corrected (CPost-corr ) for the decrease in total extracellular volume due to 
fluid removal as follows:  
CPost-corr =  （
Cpost
1+BWPre − BWPost
0.2 × BWPost
） 
Where C Post is the measured plasma concentration of the solute after dialysis; and BWPre and 
BWPost are the patient's body weight before and after dialysis, respectively[18].  
(2)  
spKt/Vurea refers to single pool Kt/V. The single pool Kt/V will be calculated as[1]:  
spKt/Vurea= -ln[
post dialysis Urea
pre dialysis Urea −0.008 × total dialysis time(h)] + [4 −3.5 ×
post dialysis Urea
pre dialysis Urea ] ×
ultrafiltration volume (in liters)
post dialysis Weight
 
7.1.6.2.2 Time Selection  
Blood samples will be taken for testing before and after the dialysis treatment at themid-week 
treatment day dialysis session.  
7.1.6.2.3 Analysis Method  

Ga m br o dial ysat ore n G m b H      
Pr ot o c ol N u m b er: B X U 5 6 1 4 2 4    
 
Pr ot oc ol versi o n n u m b er a n d d ate: V 1. 1 , A me n d me nt 1 . 1   3 0  Ma y  2 0 2 2 
Pa g e 2 6   of 7 4 
 
F or t he statistical a nal ysis met h o d, refer t o Secti o n 8. 7.   
7. 1. 7. S afet y A ss ess me nts   
1)    A Es  a n d S A Es ; 
2)    C R P  a nal ysis ; 
3)    R o uti ne ser u m c he mistr y a n d he mat ol o g y assess me nts; 
4)    V ital si g ns pre- a n d p ost-dial ysis per treat me nt . 
5)    De vice defi cie ncies  ( D Ds) (d uri n g use of  t he i n vesti gati o nal pr o d uct; w hic h w o ul d i ncl u de 
f u ncti o nal c haracteristics [e. g., lea ks, t u bi n g se parati o ns, etc.]) 
7. 1. 7. 2 Met h o d f or E v al u ati o n,  R ec or di n g a n d A n al ysis of S afet y E n d p oi nts  a n d T i me 
S electi o n  
7. 1. 7. 2. 1 Met h o d f or E v al u ati o n a n d R ec or di n g a n d T i me S electi o n  
( 1) E n d p oi nts:  
  1)     A d vers e e v e nts ( A Es ) a n d S A Es: All A Es a n d S A Es o cc urri n g i n t he d urati o n of I C F 
si g ni n g a n d t he e n d of t he trial will be rec or d e d, a n d S A Es will be re p orte d acc or di n g t o 
re g ulat or y r e q uire me nts;   
2)  
C- reacti ve pr otei n ( C R P): Bl o o d will be ta ke n f or testi n g bef ore t he mi d-wee k treat me nt 
da y dial ysis sessi o n   
3)  
Bl o o d r o uti ne, electr ol ytes :    
  Bl o o d r o uti ne: He mat ocrit, he m o gl o bi n , mea n c or p usc ular he m o gl o bi n    , mea n 
c or p usc ular h e m o gl o bi n c o nce ntrati o n , mea n c or p usc ular v ol u me , platelet c o u nt, 
re d bl o o d cell    c o u nt, w hite bl o o d cell    c o u nt, perce nt a ge of e osi n o p hils;   
 Bl o o d electr ol yte s: P h os p h or us ( P), p otassi u m ( K), s o di u m ( Na), calci u m ( Ca), 
c hl ori ne ( Cl).   
Bl o o d will be ta ke n f or testi n g bef ore a n d aft er t h e dial ysis treat me nt at t he mi d -wee k 
treat me nt da y dial ysis sessi o n;   
4)  
Li ver f u ncti o n: Bl o o d will be ta ke n f or testi n g bef ore t he dial ysis treat me nt at t he  mi d -
wee k treat me nt da y dial ysis sessi o n ;   
5)    C ollect i n g vital si g ns (acc or di n g t o vari o us sta n dar d o perati o n pr oce d ure):   
Bl o o d press ure ( B P), p ulse rate : Bef ore a n d after t he mi d -wee k H D  treat me nt  
Res pirat or y rate a n d b o d y te m perat ure: Bef ore t h e mi d -wee k H D  treat me nt;     
6) 
De vice d eficie n cies  ( D Ds) ( d uri n g use of t he i n vesti gati o nal pr o d uct; w hic h w o ul d 
i ncl u de f u ncti o nal c h aracteristics [e. g., lea ks, t u bi n g se parati o ns, etc.]). All D Ds  
occ urri n g i n t he tr eat me nt peri o d will be rec or de d.   
7. 1. 7. 2. 2 A n al ysis M et h o d  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 29 of 74 
 
previous HD treatment, presence of side effects, history of dialysis-related hypotension during dialysis, history 
of previous infectious diseases (hepatitis, HIV and syphilis, etc.);  
3)  Previous dialysis parameters: Prescriptions of the last 6 HD treatments [QD, QB, replacement volume, 
treatment time, type of vascular access, anticoagulant prescription and dosage], dry weight and dialysis 
initiation time. 
4)  Coagulation function: Activated partial thromboplastin time (APTT), prothrombin time (PT) and international 
normalized ratio (INR); 
5) 
Pregnancy blood test (human chorionic gonadotropin): Applicable to women of childbearing age and within 
1 year of menopause;  
6)  Liver function: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, 
glutamyltransferase (GGT), bilirubin, total bilirubin, total protein, globulin, albumin; 
7)  Blood routine: Hematocrit, hemoglobin , mean corpuscular hemoglobin , mean corpuscular hemoglobin 
concentration , mean corpuscular volume , platelet  count, red blood cell  count, white blood cell  count, 
percentage of eosinophils; 
8) Electrolytes: Phosphorus (P), potassium (K), sodium (Na), calcium (Ca), chlorine (Cl);  
9)  Vital signs: Blood pressure (BP), pulse rate, respiratory rate and body temperature; BP, pulse rate: Before and 
after the mid-week HD treatment. Respiratory rate and body temperature: Before the mid-week HD treatment ;   
10) Treatment parameters: Dialysis date, start time and end time of each HD/HDF session, dialyzer used, the name 
of dialysate, dialysate type and composition (sodium, bicarbonate, A-concentrate used), programmed QB, QD 
and ultrafiltration flow rate (QUF; all in mL/min), Initial ultrafiltration volume (unit: L); actual total 
ultrafiltration volume at the end of treatment (unit:L); supplementary additional collection: scheduled 
replacement fluid volume and actual replacement volume (unit: L); during the study visit , It needs to be 
recorded at the beginning of treatment and when QB needs to be adjusted during treatment; QD (mL/min) at 
the end of treatment, total dialysis time; duration and reason of any treatment interruption; 
11) Product complaints will be recorded along with device deficiencies 
12)  Previous/ Concomitant medications: Previous medications (name of medication, start time of medication, 
treatment of disease, medication dose and frequency) 14 days before signing the ICF. 
 
 
7.2.1.2 Screening Phase (day -14 to -1) , Randomization and Enrollment 
Patients will enter the screening period only after the ICF has been signed. The maximum 
duration of the screening period is 2 weeks. Signing of the ICF and the screening visit may 
take place on the same day, if necessary. The following visit activities should be carried out 
before dialysis. (Assessment of blood urea nitrogen/blood urea will be conducted after dialysis 
as well.) 
1) 
The screening number of the enrolled patients will be registered and the inclusion and 
exclusion criteria reviewed for patients;  
2) 
If the patient meets all inclusion and none of the exclusion criteria, the patient will be 
assigned random numbers from small to large according to the order in which they are 
enrolled in the group.  
The following data will be collected: 
1)   Demographic data: Age, sex, height, ethnicity, dialysis vintage;  
2) 
Medical history: including history of kidney disease, presence or absence of combined 
tumors, mental disorders, cardio cerebrovascular diseases and severe liver and lung 
diseases, history of bleeding, abnormal blood coagulation, and any other medical history 
referred to inpatient records , history of allergies, the frequency of previous HD 
treatments, history of dialysis-related hypotension, and the last 6 diabetes treatments 
Prescription [QD, QB, replacement volume, treatment time, vascular access type, 
anticoagulation prescription and dose, dry weight, and dialysis initiation time], presence 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 30 of 74 
 
of side effects, history of insulin-related hypotension episodes, history of past infectious 
diseases (Hepatitis, HIV, syphilis, etc.); 
3) 
Coagulation function: Activated partial thromboplastin time (APTT), PT, and INR;  
4) 
Liver function: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, glutamyltransferase (GGT), bilirubin, total bilirubin, total protein, 
globulin, albumin;  
5) 
Blood glucose, cholesterol, triglyceride;  
6) 
Hepatits B surface antigen,hepatitis C virus antibody, HIV,syphilis;  
7) 
Pregnancy blood test: human chorionic gonadotropin (HCG) blood test, for women of 
childbearing age and within 1 year of menopause;  
8) 
Blood routine: Hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, platelet count, red 
blood cell count, white blood cell count, eosinophil percentage;  
9) 
Creatinine;  
10) 
Blood urea nitrogen/blood urea;  
11) 
CRP;  
12) 
Electrolytes: P, K, Na, Ca, Cl;  
13) 
Vital signs: BP, pulse rate, respiratory rate and body temperature;  
14) 
Pre- and Post- dialysis body weight, dry weight;  
15) 
Recording of previous/concomitant medications: Previous medications (name of 
medcation, start time of medication, disease treatment, medication dosage and frequency) 
within the 14 days before signing the ICF and concomitant medications after signing the 
ICF are recorded as previous/concomitant medications in the eCRF; 
16) 
Documented AEs/SAEs.  
7.2.1.3 Treatment Period (mid-week session)  
（Note: Must be conducted within 2 weeks after randomization） 
During the mid-week treatment, the patient will undergo HD/HDF treatment, according to the 
according to the randomization number corresponding to the treatment group. Blood samples 
before dialysis should be collected as baseline data for patients. See Section 7.2.3 for detailed 
requirements for blood sample collection. All the following visit contents need to be collected 
before and after dialysis except for 24-h urine protein, which needs to be collected only before 
dialysis.  
Parameter setting of HD/HDF treatment: QB ≥250 mL/min, QD ≥500 mL/min, QR 
(including UF)≥16 L, treatment time: 4 hours.  
Items tested at the Clinical Lab of Research Center.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 31 of 74 
 
1) 
Blood routine: Hematocrit , hemoglobin , mean corpuscular hemoglobin , mean 
corpuscular hemoglobin concentration , mean corpuscular volume , platelet  count, red 
blood cell  count, white blood cell  count, eosinophil percentage;  
2) 
Creatinine;  
3) 
Blood urea nitrogen/blood urea;  
4) 
CRP;  
5) 
Electrolytes: P, K, Na, Ca, Cl 
6)    Liver function: ALT, AST, GGT, bilirubin, total bilirubin, total protein, globulin, albumin; 
Items need to be tested at the Central Laboratory:  
1) 
β2-MG;  
2) 
α1-MG;  
3) 
λ FLC;  
4) 
κ FLC;  
5) 
YKL-4;  
6) 
CFD;  
7) 
Myoglobin;  
8)    Serum Albumin  
Other visit assessments:  
1) 
Vital signs: collect vital signs pre- and post-dialysis (according to various standard 
operating procedures): BP, pulse: pre- and post-dialysis; breathing rate and axillary 
temperature: Before dialysis treatment. 
2) 
Body weight, dry weight (pre- and post-dialysis)  ;  
3) 
Treatment parameters: Dialysis date, start time and end time of each HD/HDF treatment, 
dialysis machine used, name of dialyzer, dialysate type and composition (sodium, 
bicarbonate, A concentrate used), preset QB, QD and ultrafiltration rate (QUF) (in 
mL/min), preset ultrafiltration volume (in L); actual total ultrafiltration volume at the end 
of treatment (unit: L); additional collection in control group: The preset amount of 
replacement fluid and the actual amount of replacement (unit: L); during the study visit, 
the QB should be recorded at the beginning of treatment and if there is any adjustment 
during the treatment; QD (mL/min) at the end of the treatment, and total dialysis time; 
The duration and reason of any treatment interruption; 
4）   Device deficiencies. 
5) 
Documented concomitant medications;  
6) 
Documented AEsSAEs.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 32 of 74 
 
7.2.1.4 Follow-Up 
A follow-up session is to be conducted at the next (end-week dialysis) treatment session.  
Adverse events which would have occurred on the mid-week treatment day or the day after will 
be collected during this session. 
7.2.1.5 Missed Visits  
Under normal circumstances, missed visits will not be rescheduled. 
If the patient misses a planned mid-week dialysis treatment, the missed mid-week dialysis 
treatment will be replaced in the following week, and subsequent visits and follow-ups will be 
carried out as planned. If the patient cannot make up for the missed mid-week dialysis treatment 
in the following week, the patient will be withdrawn from the study. 
The reason for the missed visit must be recorded on the eCRF. 
7.2.1.6 Concomitant Medications during Study Participation  
No medicine is forbidden during the participation in the study. Detailed information on any 
concomitant medication must be documented. Any changes in concomitant medications must be 
documented in corresponding visits. The information collected on concomitant medications 
should (or at least) include the trade name or common name of the drug, indications, usage and 
dosage, start date and discontinuation or persistence state.  
7.2.2 Specification on Device Usage  
7.2.2.1 Training  
People designated by the Sponsor will provide trainings on the use of Theranova 400 dialyzer 
for investigators participating in the study, including doctors, nurses in the dialysis room, and 
other operators. The training dates and training materials will be saved in the folders in the 
research center.  
7.2.2.2 Labeling  
The Sponsor shall properly mark the medical devices for the study in accordance with the 
Regulations on the Administration of Medical Device Insert Sheet and Labeling, and the labeled 
contents include: Name of the medical device for the clinical study (marked " for clinical only 
study"), specification and model, unique number, storage, period of validity, and provider.  
7.2.2.3 Reception, Storage and Safekeeping  
During this clinical study, the Sponsor will provide a sufficient number of medical devices for 
each research center. Each research center shall designate special people to be responsible for 
the reception, storage and safekeeping of medical devices for the study, and fill in the relevant 
records as required.  
The clinical study institutions and investigators shall be responsible for the use of medical 
devices for the study, and shall not transfer them to any non-participant of the clinical study. The 
investigators should ensure that all devices for the study are used only for the patients of this 
clinical study.  
7.2.2.4 Disposal and Recovery  
All medical devices used in the research center must be disposed of according to the requirements 
of the research center.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 33 of 74 
 
When the research is completed, all unused medical devices of the treatment group shall be 
returned to the Sponsor or Sponsor’s designee.  
7.2.2.5 Documentation  
The investigators shall save the disposal records of relevant medical devices for the study, mainly 
including but not limited to:  
（1） Reception date of the research center;  
（2） Quantities of medical devices received;  
（3） Label of medical devices (batch/lot numbers or unique code number); ;  
（4） Date of use;  
（5） Patient identifier (unique identification number);  
（6） Date of return of unused, expired or malfunctioning medical devices (if applicable).  
The Sponsor shall be responsible for the production and inspection records such as the 
production date, batch number, serial number and inspection report of the devices for the study, 
as well as the transportation and use records when the device is delivered to the clinical study 
institutions and the records of recovery and disposal after the study.  
7.2.3 Operating Procedure  
7.2.3.1 Hemodialysis Operation  
See Appendix 2 for this operating procedure. It is prepared with reference to Blood Purification 
Standard Operating Procedure (2021 Edition) and only provides suggestions for the operations 
in this study. If the centers have relevant standard operating procedures (SOP), they can also 
operate in accordance with the SOP of this center.  
7.2.3.2 Hemodiafiltration Operation  
See Appendix 3 for this operating procedure. It is prepared with reference to Blood Purification 
Standard Operating Procedure (2021 Edition) and only provides suggestions for the operations 
in this study. If the centers have relevant SOP, they can also operate in accordance with the SOP 
of this center.  
7.2.3.3 Blood Sampling  
The research center or central laboratory will collect, store, transport, and process all blood 
samples in accordance with the requirements and operating procedures of the clinical trial center. 
The special requirements related to blood sample collection specified in this test protocol shall 
be subject to the description of this test protocol. Before the start of the study, the relevant 
parameter detection methods, units and normal ranges involved will be provided to the Sponsor. 
Patients will be in supine position during blood collection. No puncture of the patient is necessary, 
as the blood samples will be taken from the fistula needle or from the sampling port of the blood 
line. The specific requirements are as follows:  
Figure 3: Blood Sample Requirements 
 
Pre-Dialysis  
Post-Dialysis  

Ga m br o dial ysat ore n G m b H      
Pr ot o c ol N u m b er: B X U 5 6 1 4 2 4    
 
Pr ot oc ol versi o n n u m b er a n d d ate: V 1. 1 , A me n d me nt 1 . 1   3 0  Ma y  2 0 2 2 
Pa g e 3 4   of 7 4 
 
S a m pli n g 
l oc ati o n   
Bl o o d sa m ples fr o m fist ula nee dle or 
ce ntral ve n o us cat heter.  
Bl o o d sa m ples fr o m arterial sa m pli n g p ort  
of bl o o dli ne.   
S a m ple t u be  
Pre pare t he sa m ple t u be acc or di n g t o 
s u bsta nce t o be a nal yze d.   
Pre pare t he sa m ple t u be acc or di n g t o 
s ubsta nce t o be a nal yze d.   
S a m pli n g 
m et h o d  
 
Patie nts wit h A V  fist ula: Bl o o d 
sa m ples are ta ke n fr o m t he access 
nee dle i m me diatel y f oll o wi n g 
nee dle i nserti o n. T he pre -dial ysis 
bl o o d sa m ple m ust be dra w n bef ore 
i njecti n g sali ne, he pari n, or ot her 
p ote ntial dil ue nts.  
  
F or patie nts wit h a ce ntral ve n o us 
cat heter, t he first 1 0 m L of bl o o d 
dra w n bef ore dial ysis m ust be 
discar de d bef ore sa m pli n g. T his is 
d o ne t o a v oi d dil uti o n b y t he 
he pari n t u be seali n g s ol uti o n.   
  
T he p ost- dial ysis bl o o d sa m ple 
s h o ul d be dra w n fr o m t he arterial e n d 
usi n g a sl o w- fl o w met h o d 
( ultrafiltrati o n fl o w rate [ Q U F] is 
first set t o 0 m L/ mi n, f oll o we d b y a 
Q B of 1 0 0 m L/ mi n. Sa m pli n g ca n 
t he n be carrie d o ut after 1 5-
3 0 sec o n ds).  
 
P ost -dial ysis  bl o o d sa m pli n g will be 
d o ne wit hi n 2 4 0 士 5 mi n utes of 
treat me nt ti me. 
  F or patie nts i n w h o m t he dial ysis 
treat me nt st o ps earlier d ue t o reas o ns 
ot her t ha n t he dial yzer: bl o o d sa m pli n g 
ca n be c o m plete d at t he e n d of t he dial ysis 
treat me nt if t he act ual treat me nt d urati o n 
is at least 2 1 0 mi n utes.  
 
7. 2. 4 P ossi ble A d verse R e acti o ns fr o m use of D i al yzer a n d t heir M a n a ge me nt [2 0 ]   
（1 ） If bl o o d lea ka g e is f o u n d i nsi de t he dial yzer, t he o perat or m ust st o p t he treat me nt a n d 
re place t he dial yzer. D o n ot ret ur n t h e bl o o d t o t he patie nt si nce it ma y ha ve b ec ome 
c o nta mi nate d  b y  t he  di al ysis  fl ui d.  If  n ecess ar y,  a d mi nister  a de q uat e  re place me nt  
s ol uti o n t o t he patie nt t o c o m pe nsate f or t he bl o o d l oss.   
（2 ） If a n e xter n al bl o o d lea k is o bser ve d, s ec ure c o n necti o ns or re place t h e dial yzer. If 
necessar y,  a n  a d e q uate r e place m e nt s ol uti o n s h o ul d be a d mi nistere d t o t he patie nt t o 
c o m pe nsate f or t he bl o o d l oss.   
（3 ） If  a  di al ysate  c o m p art me nt  lea k  is  o bser ve d  t h e  o perat or  has  t o  c hec k  t he  c orrect  
place me nt of t he dial ysate c o n nect ors or t o st o p t he treat me nt a n d re place t he dial yzer. If 
necessar y, a d mi nister a d e q uate re place me nt s ol uti o n t o t he patie nt t o c o m pe nsate fl ui d 
i m bala nce.  
（4 ） If air e nters t he e xtrac or p oreal bl o o d circ uit, a n air e m b olis m ma y occ ur. T his ca n b e 
hazar d o us t o t he p atie nt. To mi ni mize t he ris k of air e m b olis m, c o nsta nt m o nit ori n g of 
t he e xtrac or p or eal bl o o d circ uit, b ot h vis uall y a n d wit h a n air det ect or, is rec o m me n de d. 
Strict a d here n ce t o t h e m a n ufact urer's rec o m me n de d acti vities will facilitate t he re m o val 
a n d pre ve nt t he acc u m ul ati o n of air i n t he dial yzer bef ore t he treat me nt sessi o n. If air 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 35 of 74 
 
enters or is identified in the dialyzer during priming and cannot be removed with the use 
of additional priming, the dialyzer must be replaced.  
（5） If clotting occurs in the dialyzer, both the dialyzer and the blood lines must be replaced. 
Flush the vascular access devices according to clinic procedure. Discard the dialyzer and 
the blood lines. Do not return the blood to the patient.  
7.2.5 Adverse Reactions of Hemodialysis and Handling [1]  
The following are adverse reactions that have been reported related to HD therapy: hypotension, 
muscle cramps, nausea, vomiting, and headache, etc. For details, refer to Appendix 4.  
7.2.6 Adverse Reactions of Hemodiafiltration and Handling [1]  
Patients may experience similar complicationsas those related toHD and hemofiltration during 
HDF, in addition to the following: reverse ultrafiltration and wasting syndrome. For details, 
refer to Appendix 5.  
8. Statistical Considerations  
8.1 Statistical Design, Methods and Analysis Procedures  
The analysis details of the planned statistical methods will be provided in the study statistical 
analysis plan (SAP). The draft SAP is formed after determination of the study protocol and eCRF. 
It will be finalized prior to database lock.  
8.2 Determination of Sample Size  
8.2.1. Total Sample Size  
The goal of this study is to demonstrate non-inferiority of Theranova 400 compared to FX 800 
in the 2 primary endpoints and the non-inferiority margins selected are considered clinically 
acceptable.  
The sample size calculation is performed using PASS procedure Mann-Whitney U or Wilcoxon 
Rank-Sum Tests for Non-Inferiority. A separate sample size calculation is performed for both 
primary endpoints using a specified non-inferiority margin of 10% and a one-sided alpha level 
of 0.025, where the true difference in means is assumed to be zero (0).  
8.2.1.1 Sample Size Calculation in regard to λ FLC Reduction Ratio 
A previously conducted Theranova HDF study [21] was used to obtain λ FLC RR mean and 
standard deviation (SD) of 37.83 and 8.26; a higher estimate for SD of 9.09 is used by adding an 
additional +10% error to calculate sample size to account for a potential increase in variability. 
Based on a 1:1 randomization, with a sample size of 129 patients in the Theranova 400 group 
and 129 patients in the FX 800 group (total N = 258), a Wilcoxon Rank-Sum test with a 0.025 
one-sided significance level will have 90% power to demonstrate non-inferiority of the 
Theranova 400 Dialyzer compared to the FX 800 Dialyzer as assessed by λ FLC RR with a non-
inferiority margin of 10% (i.e. 3.783).  
8.2.1.2 Sample Size Calculation in regard to ß2- MG Reduction Ratio 
A previously conducted Theranova HDF study [21] was used to obtain ß2-MG RR mean and SD 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 36 of 74 
 
of 78.48 and 6.75; a higher estimate for SD of 14.28 is used to calculate sample size to account 
for a potential increase in variability based on a literature review of studies conducted in China. 
Based on a 1:1 randomization, with a sample size of 75 patients in the Theranova 400 group and 
75 patients in the FX 800 group (total N = 150), a Wilcoxon Rank-Sum test α with a 0.025 one-
sided significance level will have 90% power to demonstrate non-inferiority of the Theranova 
400 Dialyzer compared to the FX 800 Dialyzer as assessed by β2-MG RR with a non-inferiority 
margin of 10% (i.e. 7.848).  
8.2.1.3 Sample Size for this Study 
Consequently, in order to demonstrate non-inferiority between Theranova 400 and FX 800 in 
both primary endpoints, a sample size of 129 patients in the Theranova 400 group and 129 
patients in the FX800 group is required to guarantee 90% power for the analysis of λ FLC and > 
90% power for the analyses of ß2-MG. To allow for 5% of patients to drop out or be excluded 
from the Per-protocol population as a result of patient classification, a total of 272 patients will 
be randomized 1:1 to treatment with the Theranova 400 Dialyzer (136 patients) or treatment with 
the FX 800 Dialyzer (136 patients).  
8.2.2 Sample Size for each Disease and Justification  
This clinical study does not involve the determination of sample size for each disease.  
8.3 Significance Level and Power of Clinical Study  
A 0.025 one-sided significance level and a power of 90% were used in planning this study.  
8.4 Expected Dropout Rate  
It is estimated that the expected ratio of cases with dropout or serious protocol violations is about 
5%.  
This ratio refers to the proportion of patients who ultimately cannot be evaluated for primary 
efficacy on the per-protocol analysis set. This part of patients are those who have been dropped 
out or have serious protocol violation (affecting the evaluation of primary endpoints) after 
confirmed by the principal investigator (PI).  
8.5 Eligibility/Fail Criteria for Clinical Study Results  
Let μT denote the Theranova 400 treatment mean and let μR denote the FX 800 treatment mean. 
The statistical hypothesis of the study can be written as: 
Ho: μT-μR≤-δ 
Ha: μT-μR >-δ 
When evaluating the primary endpoint of λ FLC, the non-inferiority margin is -3.783 (10% of 
assumed mean RR of 37.83%). When evaluating the primary endpoint of ß2-MG RR, the non-
inferiority margin is -7.848 (10% of assumed mean reduction ratio of 78.48%). When the non-
inferiority of the two primary endpoints of λ FLC and β2-MG RRs are both established, the non-
inferiority of this study is established. 
8.6 Criteria for Discontinuation of Study Based on Statistical Reasons and Justification  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 37 of 74 
 
No statistical stopping rules are stipulated for this study.  
8.7 Statistical Methods of all Data, together with Processing of Missing, Unused or 
Erroneous data (including midway exit and withdrawal) and Unreasonable Data  
8.7.1 Data Statistical Analysis  
8.7.1.1Analysis of Primary Endpoints  
For the λ FLC and ß2-MG RR endpoints, let μT denote the Theranova 400 treatment mean and 
let μR denote the FX 800 treatment mean. Then the null hypothesis to demonstrate non-inferiority 
using a 10% margin for λ FLC RR can be expressed as: Ho: μT-μR≤-3.783. The alternative 
hypothesis is expressed as: Ha: μT-μR>-3.783. A t-test will be utilized to generate a two-sided 
95% confidence interval (CI) for the difference in means (μT- μR). If the lower bound of the CI 
is > -3.783, then non-inferiority between the Theranova 400 and FX 800 treatment group can be 
demonstrated for λ FLC RR. If the lower bound of the CI > 0, then superiority of Theranova 400 
treatment over FX 800 treatment can be concluded.  
Equivalently the null hypothesis to demonstrate non-inferiority using a 10% margin for ß2-MG 
RR can be expressed as Ho: μT-μR≤-7.848. The alternative hypothesis is expressed as: μT-μR >-
7.848. A t-test will be utilized to generate a two-sided 95% confidence interval (CI) for the 
difference in means (μT-μR). If the lower bound of the CI is > -7.848, then non-inferiority between 
the Theranova 400 and FX 800 treatment group can be demonstrated for ß2-microglobulin RR. 
If the lower bound of the CI > 0, then superiority of Theranova 400 treatment over FX 800 
treatment can be concluded.  
Two sensitivity analysis will be conducted for both endpoints: 
1. An ANOVA model with fixed effects for treatment group and study site to evaluate 
differences between the treatment groups will be analyzed and corresponding two-sided 
95% CIs derived. 
A non-parametric method: Wilcoxon Rank-Sum Test will be used to analyze the primary 
endpoints. 
In case the assumption of a normal distribution is not justified, RRs can be log transformed in 
order for the measurements to follow a normal distribution. If, after transformation, 
measurements do still not follow a normal distribution, above statistical analyses methods will 
be replaced with their non-parametric equivalents. The Wilcoxon Rank-Sum Test will be used in 
place of the t-test while the Kruskal Wallis test will be used in place of the ANOVA.  
8.7.1.2 Analysis of Secondary Endpoints 
Secondary endpoints will be evaluated as follows:  
A t-test or Wilcoxon Rank-Sum test, as applicable, will be used to evaluate differences between 
treatment groups in Kt/Vurea and URR.  
A t-test orWilcoxon Rank-Sum test, as applicable, will be used to evaluate differences between 
treatment groups for the RRs of α1-MG, YKL-40, CFD, myoglobin and κ FLC obtained at the 
mid-week treatment day dialysis session.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 38 of 74 
 
8.7.1.3 Analysis of Safety Endpoints 
Safety endpoints will be evaluated as follows:  
1. The summary of AEs will include AEs that occur on the day of or after the study treatment. 
Pre-treatment AEs including AEs reported at Screening and Randomization will be recorded 
in the eCRF but will not be summarized in the safety tables. Adverse events will be mapped 
to a Primary System Organ Class (SOC) and Preferred Term (PT) according to Medical 
Dictionary for Regulatory Activities (MedDRA) and summarized descriptively by SOC, PT 
and treatment group. Treatment group comparability in the incidence of AEs will be 
evaluated using Fisher's exact test. An overview (overall) summary table of all AEs will be 
generated that includes the total number of AEs, number and percentage of patients with at 
least one AE, number and percentage of patients with at least one SAE, number and 
percentage of patients with at least one severe AE, number and percentage of patients with 
at least one AE probably associated with study treatment, number and percentage of patients 
with an AE leading to study discontinuation and number and percentage of patients with an 
AE leading to death. This summary will be presented by treatment group and combining both 
groups (Total). In addition, two separate AE summary tables will be provided, one for 
analysis by severity and relationship to the study dialyzer, and the other will provide a 
separate AE summary table for SAEs and AEs that led to withdrawal from the study. 
2. Device deficiencies (DD) will be summarized descriptively.  
3. Serum chemistry, hematology assessments, liver function, patient vital signs, and CRP will 
be summarized descriptively per measurement time point using n, mean, median, standard 
deviation, minimum, and maximum.  
8.7.1.4 Other Assessments 
Continuous and categorical demographic and baseline characteristics will be summarized by 
treatment groups. A t-test or Wilcoxon Rank-Sum test, as applicable, will be used to assess 
differences between treatment groups in continuous variables and Fisher's exact test will be used 
to assess differences between treatment groups in categorical variables.  
8.7.2. Processing of Missing, Unused or Erroneous Data (including midway exit and 
withdrawal) and Unreasonable Data  
All missing, unused or erroneous data (including midway exit and withdrawal) and unreasonable 
data will be discussed and finalized determined by the investigators and biostatisticians during 
the data review phase. The basic statistical principles of these data processing are as follows:  
（1） Describe the details of each dropout case, and compare the dropout between the test group 
and the control group by using χ2 or Fisher's exact probability method;  
（2） Missing data at baseline will not be imputed;  
（3） Missing values of primary efficacy endpoints of λ FLC and β2-MG RRs will not be 
imputed. 
（4） Missing values of the secondary efficacy endpoints and safety endpoints will not be filled;  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 39 of 74 
 
（5） Erroneous and unreasonable data will be processed as missing values;  
（6） Sensitivity analysis will be performed for the primary efficacy endpoints using the full 
analysis set (FAS), after utilize last observation carried forward (LOCF) to impute the 
missing values of the λ FLC and β2-MG RRs.  
8.8 Procedures for Reporting Deviations from the Original Statistical Program  
Generally, only the statistical analysis content stipulated in advance in the statistical analysis 
plan can be presented in the clinical study report of this study. The additional statistical analysis 
due to various uncertain reasons is only for exploratory purpose.  
Any deviations from the statistical analysis plan will be documented and described with details.  
8.9 Criteria for Selection of Patients Included in the Analysis and Justification  
(1)  
Intention-to-treat FAS: Includes all randomized patients. Patient assignment will be based 
on the treatment randomized.  
(2)  
Per-Protocol Set (PPS): Is a subset of the FAS and meets the following requirements: 
Patients were randomized to the respective treatment at themid-week treatment day 
dialysis session and did not have any major protocol deviations that could affect the 
assessment of the primary endpoint when dividing the patient population. Major protocol 
deviations when dividing the patient population are defined as follows: :  
1) The actual QB of the patient is < 220 mL/minute for a duration of more than 30 min 
or for a total duration of > 60 minute at themid-week treatment day dialysis session; 
patients in control group who actually do not achieve at least 16 L convective volume 
(including UF) 
2) The actual dialysis time of the patient is < 210 minute at themid-week treatment day 
dialysis session.    
(3)  
Safety analysis set (SS): Includes all enrolled patients (ICF signed) that have been treated. 
Patient assignment will be based on actual treatment received.  
The analysis of the primary endpoint will be based on the PPS, with a supportive analysis of the 
primary endpoint based on the FAS. Unless otherwise specified, the remaining analyses will be 
based on the FAS. All safety related analyses will be based on the SS.  
8.10 Exclusion of Special Information when Verifying Assumptions and Justification, if 
applicable  
Not applicable. 
8.11 Interim Analysis  
A blinded interim analysis for sample size re-estimation will be conducted when approximately 
50% of patients complete theirmid-week treatment day dialysis session and corresponding λ FLC 
and β2-MG RRs are available. 
This interim analysis allows for modifying the sample size while the study is ongoing and is 
based on a blinded estimate of the variance. The one-sample estimator which will be calculated 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 40 of 74 
 
from the pooled data maintains trial integrity, shows good performance and is therefore 
recommended for application [22]. 
The data utilized during the interim analysis will be based on the FAS and statistics will be 
limited to the calculated one-sample variance estimator (not split by treatment group) of the 
λ FLC and β2-MG RRs measured at themid-week treatment day dialysis session. For sample 
size re-estimation, for each primary endpoint, the same sample size calculation as outlined in 
Section 8.2 will be carried out using the one-sample variance estimator which is based on the 
pooled variance (across both treatment groups) of the RRs as observed in the patients included 
in the interim analysis. In case the re-estimation for the sample size of λ FLC or β2-MG yields a 
patient number > 272 (including 5% drop out), the sample size of the study will be increased to 
this re-calculated number but will not exceed 350. In case the sample size reassessment for λ 
FLC or β2-MG yields a patient number ≤ 272 (including 5% drop out), the sample size of the 
study will not be adjusted and the original sample size of 272 will be maintained. Due to this 
blinded and pooled (non-treatment group based) approach in re-estimation of the sample size 
and the absence of early stopping for futility and efficacy, no alpha adjustment is required for the 
final analysis.  
This interim analysis does not involve comparison of efficacy between groups, and will be 
performed by the sponsor or a Contract Research Organization (CRO) or a third party authorized 
by the sponsor. The details will be described in the Statistical Analysis Plan. 
9. Data Management  
In principle, the Sponsor and the initiating unit are jointly responsible for data management and 
analysis in the clinical study. In this study, data management will be carried out by the data 
management specialist from the CRO with the approval of the Sponsor. The data management 
specialist will develop the Data Management Plan (DMP) according to the project requirements 
and carry out data management based on the DMP to ensure the authenticity, integrity and 
traceability of clinical study data.  
9.1 Original Documentation Forms  
The original materials can prove the authenticity of the patients and the integrity and authenticity 
of the data. All data recorded in the electronic data capture (EDC) system are derived from the 
original data and should be consistent with the original materials. If the data in EDC system is 
inconsistent with the original materials, it is necessary to make modifications according to the 
original materials or provide reasonable explanations. The original materials are stored in each 
study site. The original materials include but are not limited to the following documents:  
•  Outpatient medical records and medical records for HD treatment;  
•  HD (filtration) treatment record sheets;  
•  Laboratory test reports;  
•  Other medical examination reports;  
•  ICFs;  
•  Medical device use records, etc.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 41 of 74 
 
9.2 Electronic Data Capture System  
In this study, data will be collected by using an EDC system, which is well validated to enable 
preservation of audit trails and good management of accounts and authorities.  
The EDC system will automatically retain the audit trail of data, including the time of data entry 
and change, operator, data operator’s name, reason for change, data value before the change, and 
data value after change, so as to ensure the traceability of data.  
The system administrator creates accounts for different roles, grants different access permissions, 
and strictly manages and controls the application and cancellation of accounts.  
9.3 Design of Electronic Case Report Form  
The data management specialist firstly designs the eCRF according to the study protocol and the 
Clinical Data Acquisition Standard Harmonization (CDASH), and then the database designer 
establishes the eCRF in EDC and sets the procedure for logic verification of the data to be 
collected; The database can be only launched upon the test by t the data management specialist.  
9.4 Electronic Case Report Form Completion  
The eCRF will be completed by the investigator or authorized clinical research coordinator (CRC) 
according to the source documents (including original medical records, examination reports, etc.). 
The investigator is responsible for timely and accurately entering the study data into the EDC 
system. The clinical research associate (CRA) approved by the Sponsor is responsible for 
confirming that all data records and reports are correct and complete, and that all data in the EDC 
system are consistent with the original materials.  
9.5 Data Verification and Query Management  
The reliability, completeness and accuracy of data in the EDC system will be verified according 
to the Data Verification Plan (DVP) which mainly includes logic verification and manual 
verification. Data entry into the EDC system will be performed by the investigator or the staff 
designated by the investigator with their accounts. The data management specialist is responsible 
for data validation. If questionable data are found, queries could be raised in the system. The 
investigator or the staff designated by the investigator will verify and corrected the data or 
respond to the queries. All data modifications would have modification trace in the system. If 
CRA may also raise queries in the system if questionable data are found when performing source 
data verification (SDV).   
9.6 Medical Monitoring  
Medical monitoring will be completed by the medical monitor throughout the study, including 
but not limited to review of eligibility, protocol violations, periodic clinical study data, and 
treatment data.  
9.7 Data Quality Assurance  
This study will use quality control and data validation processes to ensure the reliability and 
accuracy of the clinical database. The Monitoring Plan and DMP will detail the data entry, 
verification, clarification and validation processes to be followed by all relevant study personnel 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 42 of 74 
 
to ensure compliance with Good Clinical Practice.  
9.8 Data Management Plan  
The medical coder will be responsible for medical coding in this study. The MedDRA will be 
used for coding of AEs and past medical history, while WHO (World Health Organisation) Drug 
Dictionary will be used for that of concomitant medications. The medical coding will follow the 
Medical Coding Plan, which specifies in detail the contents of medical coding entries, dictionary 
version, dictionary update, coding review, etc.  
9.9 External Data Management  
The external data for this study are test results from the central laboratory and will be managed 
according to the External Data Transmission Agreement.  
9.10 Blind Review  
Before locking the clinical study database, the Sponsor’s representative, PI, statistical analyst 
and data management specialist blindly review the data, jointly review the questionable data, 
divide the statistical analysis population according to the clinical study protocol and sign the 
decision on the division of the statistical analysis population.  
9.11 Database Locking  
After all the queries are answered and the data in the database are confirmed to be complete and 
accurate, the database will be locked by the database management specialist with the joint 
approval of the Sponsor’s representative, PI, statistical analyst and data management specialist.  
9.12 Submission and Archiving of Data Management Documents  
After the database is locked, the data administrator shall write Data Management Report based 
on the actual implementation of the project, and complete the submission and archiving of paper 
and electronic documents according to the project document management requirements.  
The data management specialist submits the data to the statistical analyst. The statistical analyst 
will perform statistical analysis according to SAP.  
10. Feasibility Analysis  
10.1 Analysis of the Possibility of Success  
(1)  
This study will be conducted in accordance with the study protocol developed in 
accordance with the Declaration of Helsinki (the 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013), the Good Clinical Practice for Medical Devices (GCP) (CFDA, 
NHFPC Order No. 25), the Provisions for Medical Device Registration (CFDA Order No. 
4) and other relevant regulations.  
(2)  
The Ethics Committee of the initiating unit is responsible for reviewing the ethics and 
scientificity of the study protocol. The Ethics Committee of each clinical study institution 
reviews the feasibility of the study, the qualification and experience of the investigators, 
and the equipment and conditions. Patients will be recruited volunteers who understand 
the objectives of the study and have adequate compliance with the study protocol. By 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 43 of 74 
 
signing the ICF, the rights and interests of the patients will be fully guaranteed, which 
provides a guarantee for the completion of the clinical study.  
(3)  
Before the start of this study, the Sponsor or its designee will conduct unified training on 
the investigational medical device, study protocol and study-related data, unified 
recording method and evaluation criteria for the relevant personnel participating in this 
clinical study.  
(4)  
Theranova 400 has been marketed in 44 countries or regions around the world with more 
than 3.5 million devices used, and some clinical efficacy and safety data have been 
accumulated. Moreover, its composition structure and technical standards comply with 
the requirements of relevant national and indusstudy standards, and all the technical 
requirements for product safety and performance have passed the relevant tests by 
Guangdong Medical Device Quality Supervision and Inspection Institute.  
(5)  
The participating units of this clinical study are qualified as national clinical study 
institutions for drugs/medical devices, and have rich clinical study experience and good 
quality control system.  
(6)  
All the staff participating in this study have received unified training and have a high 
standard of GCP regulations, which can ensure that all the original data such as 
observation results and laboratory tests in the clinical study are carefully recorded and 
verified, and finally ensure that all the conclusions drawn after the completion of the 
clinical study are derived from the real original data.  
In summary, the success of this clinical study is highly controllable.  
10.2 Analysis of the Possibility of Failure  
(1)  
Failure to strictly implement the clinical study protocol, failure to operate, inspect and 
evaluate in accordance with the specifications, failure to reach approximately 308 valid 
cases and other factors may cause the failure of this study, but these factors are still 
controllable.  
(2)  
The patients enrolled in this study are patients with chronic kidney failure requiring 
HD/HDF treatment. The patient may have other complications. The improvement of 
various indicators after treatment is related to the patient's underlying diseases and 
treatment compliance, not completely dependent on the investigational product. During 
this study, the investigator will complete the relevant examinations according to the 
requirements of the protocol, strictly implement the inclusion and exclusion criteria of 
cases and carry out the treatment in strict accordance with the requirements of the 
protocol, avoiding the inclusion of patients who cannot finish the expected treatment and 
have poor compliance, so as to reduce the interference factors as far as possible.  
(3)  
The investigators participating in this clinical study shall be trained in product knowledge 
and operating procedures by the personnel designated by the Sponsor to ensure that the 
treatment operators are skilled. During the operation, the occurrence of AEs will be 
closely observed and a detailed treatment plan will be developed to prevent the 
occurrence of AEs.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 44 of 74 
 
In conclusion, this clinical study is less likely to fail.  
11. Quality Control of Clinical Study  
11.1 Site Quality Control  
In order to ensure the quality of the study, the PIs participating in the study jointly discuss and 
develop the clinical study protocol before the study is officially initiated.  
The Sponsor or person who’s assigned shall organize the trainings on relevant laws and 
regulations, study protocol, principle of the investigational medical device, scope of application, 
product performance and treatment instructions for the personnel participating in the clinical 
study prior to the initiation of the clinical study, so as to improve each participant's understanding 
of relevant laws and regulations, study protocol and investigational medical device and to master 
and strictly implement the clinical study protocol to ensure the study quality.  
It is necessary to ensure the accuracy, consistency, completeness and credibility of the data 
collected during the study. All the observed results and abnormal findings in clinical studyies 
shall be timely and carefully verified and recorded to ensure the reliability of data. During the 
clinical study, the study site and central laboratory should provide laboratory qualification 
certificates (such as inter-laboratory quality assessment certificate) for regular quality control.  
11.2 Monitoring  
The CRA approved by the Sponsor shall perform regular and irregular monitoring during the 
study. The CRA shall fulfill the responsibilities specified in GCP and be responsible for 
monitoring whether the study personnel follow the study protocol and accurately record the study 
results; During each monitoring, the CRA must compare the eCRFs with original CRFs and 
inform the investigator of any omissions or errors. Moreover, the CRA should also verify that all 
AEs are recorded and that SAEs or device deficiencies are reported and recorded within the 
required time. The CRA should submit a written report to the Sponsor in a timely manner after 
monitoring.  
11.3 Audit and Inspection  
The study site must also be subject to audits by auditors appointed by the Sponsor in accordance 
with GCP requirements. The auditors conduct systematic and independent inspection on clinical 
study-related activities and documents to evaluate and determine whether the study is conducted 
in accordance with the study protocol, standard operating procedures and relevant regulatory 
requirements, and whether the study data are recorded in a timely, true, accurate and complete 
manner. The audit does not directly involve the personnel conducting the clinical study.  
The regulatory authority may inspect the documents, facilities, records and other aspects related 
to the clinical study.  
12. Ethical Review and Informed Consent  
12.1 Ethical Considerations  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 45 of 74 
 
(1)  
Ethical review and informed consent are the main measures to ensure the rights and 
interests of patients. The parties participating in this study shall assume corresponding 
ethical responsibilities according to their responsibilities in the study.  
(2)  
This clinical study conforms to the ethical principles in the Declaration of Helsinki (the 
64th WMA General Assembly, Fortaleza, Brazil, October 2013) and GCP and other 
relevant regulations, and the clinical protocol has been designed with full consideration 
of the rights and interests of patients.  
(3)  
The Ethics Committee of a medical device clinical study institution shall be composed 
of at least 5 members, including medical professionals and non-medical professionals, of 
which there shall be members of different genders. At least one of the non-medical 
professional members is a legal worker and one is a person other than the site. The 
members of the Ethics Committee shall have the qualification or experience in assessing 
and evaluating the science, medicine and ethics of the clinical study. All the members 
shall be familiar with the ethical guidelines and relevant regulations for medical device 
clinical studys and abide by the articles of association of the Ethics Committee.  
(4)  
Before the start of the study, the study protocol, ICF, patient recruitment procedures, and 
other written documents provided to the patients should be reviewed and approved by 
the Ethics Committee. Any amendment to the above documents should be re-approved 
by the Ethics Committee. The investigator may start screening a patient only after the 
written approval of consent has been given by the Ethics Committee.  
12.2 Informed Consent  
Before a patient participates in the study, the investigator should fully explain the details of the 
clinical study to the patient or the guardian of the patient with no or limited civil capacity, 
including known and foreseeable risks and possible AEs.   
The patient or his/her guardian shall sign and date the ICF upon the investigator’s full and 
detailed explanation, and the investigator shall also sign and date the ICF. For the incapacitated 
patients, if the Ethics Committee agrees in principle and the investigator believes that the 
patients' participation in the clinical study is in their own interests, they may participate in the 
clinical study upon the signature of their guardians before the study. If either the patient or his/her 
guardian cannot read, a witness should be present in the process of being informed. If important 
information or unexpected clinical effect involving the investigational medical device is found, 
the investigator and Sponsor should modify the Informed Consent Form. After the revised 
Informed Consent Form is approved by the Ethics Committee, the affected patients or their 
guardians should sign for confirmation again. A copy of the signed and dated Informed Consent 
Form shall be kept by the investigator and patient, respectively.  
By signing the Informed Consent Form, the patient agrees the CRA/Auditor/Ethics 
Committee/regulatory authorities to verify the obtained original data of the clinical study to 
determine the reliability of such data.  
13. Provisions for Reporting Adverse Events and Product Complaints  
13.1 Adverse Events   

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 46 of 74 
 
13.1.1 Definition of Adverse Events  
Table 1. Adverse Event Term Definitions 
Adverse Event 
(AE) 
An AE is any untoward medical occurrence in a clinical study and which 
does not necessarily have to have a causal relationship with the 
investigational medical device Chinese medical device GCPArticle 93  
Serious Adverse 
Event (SAE) 
An SAE is any untoward medical occurrence in the clinical study that is 
life-threatening or leads to serious deterioration in health including:  
Fatal illness or injury;  
Persistent impairment of any body structure or body function;  
Hospitalization or prolongation of existing hospitalization;  
Medical or surgical intervention to preclude permanent impairment to any 
body structure or body function;  
Fetal distress, fetal death, or congenital abnormalities, congenital defects 
and other events.  
Chinese medical device GCP Article 93 
Device 
Deficiency (DD) 
DDs refer to unreasonable risks of medical devices under normal use 
during the process of clinical trial that may endanger human health and 
life safety, such as label error, quality problem and fault.  
Chinese medical device GCP Article 93 
 
13.1.2 Safety Reporting  
All AEs observed by the study personnel or reported by the patient during the course of the study 
will be documented from the time of signing the ICF (i.e., enrollment) through the final 
assessment visit (i.e., End of Study Visit). All device deficiencies (DD) observed by the study 
personnel or reported by the patient during the treatment period will be documented. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered medical history and not recorded as an AE or SAE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as an AE or 
SAE in the eCRF.  
 
If a definitive diagnosis has been medically established by the physician caring for the patient or 
by the investigator, this diagnosis should be recorded as the AE or SAE. If a definitive diagnosis 
has not been medically established, the signs and symptoms should be recorded as the AEs or 
SAEs. Once the diagnosis is confirmed, the eCRF should be updated from signs and symptoms 
to the diagnosis. 
 
If a patient is given a diagnosis and also experiences a complication of the diagnosis (e.g., 
myocardial infarction with congestive heart failure), both the diagnosis and the medical 
complication should be collected and recorded as separate events. 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 47 of 74 
 
Adverse events or SAEs that change in severity will be documented only once with the highest 
degree of severity.  
 
An elective procedure/surgery that occurs during the course of the study but is being performed 
for a documented pre-existing condition and was pre-planned prior to study entry will not qualify 
as an AE or SAE. If, however, the pre-existing condition unexpectedly deteriorates during the 
study requiring the procedure/surgery to be performed earlier than planned, the condition for 
which the procedure/surgery is being performed will qualify as an AE or SAE (refer to Table 1).  
 
Laboratory and vital sign abnormalities qualify as AEs if medical intervention is required to treat 
or address the abnormality, if the patient must be discontinued from the study due to the 
abnormality, or if the investigator determines the value is clinically significant. 
 
For all AEs associated with patients, a full description of the event should be recorded in the 
eCRF including the date and time of onset (when the signs and symptoms of the event began), 
outcome, seriousness, severity, event description, actions taken, and causal relationship of the 
AE or SAE. Investigators should review and reference the severity (refer to Table 2) and 
causality definitions (refer to Table 3) when determining relationship of the AE or SAE to the 
study device and procedure. The investigator may also discuss the event(s) with the Sponsor’s 
Medical Monitor or designee. 
 
For all AEs associated with users or other persons (not the study patient), a full description of 
the event should be recorded on the paper AE form and sent via email to Sponsor designee and 
Baxter Global Patient Safety Medical Device Vigilance 
. 
 
All AEs and SAEs should be actively solicited and documented in the eCRFs, no matter how 
common they are for a patient and regardless of the causality assigned by the investigator. 
Additionally, any AE and SAEs voluntarily reported by the patient should be recorded in the 
eCRF and verified by the investigator or designee with the relevant source documents.  
 
The outcome/resolution of all AEs and SAEs will be determined by the investigator and 
documented in the eCRF. Investigators will follow all unrelated AEs and SAEs until resolution, 
stable, or the end of the study, whichever occurs first, and follow all study device-related and 
procedure-related AEs and SAEs until resolution or stable, including following the patient after 
the end of the study if necessary. Outcomes and other relevant information obtained after the end 
of the study will be reported via the paper AE form and sent via email to Baxter Global Patient 
Safety Medical Device Vigilance 
. 
 
For the outcome categories that can be used in the eCRF by the investigator refer to Table 4. 
 
During the study period, if a patient experiences an AE which is considered causally related to a 
Baxter medicinal/drug product (not the study medical device or comparator), the event shall be 
forwarded by the investigator or designee within 24 hours of becoming aware of the AE to Baxter 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 48 of 74 
 
Global Patient Safety 
for assessment as per 
Baxter’s process for case processing of spontaneous reports. 
 
Table 2. Severity Assessment * 
Criterion 
Definition 
Mild 
Transient, mild, no influence on daily life and activities, no special measures or treatment 
required. 
Moderate 
Slight influence on daily life and activities, and measures or treatment should be taken 
when necessary. 
Severe 
Seriously affecting daily life and activities, special measures or treatment must be taken, 
and hospitalization is required when necessary, which may be life-threatening. 
*Severity assessment based on the Chinese medical device GCP 
 
Table 3. Causality Assessment * 
Classification 
Causality Criteria 
Causal 
Association 
Definitely 
Related 
The AE occurs in a temporal sequence consistent with the use of the 
medical device, and the AE is consistent with the known type of AE 
of the device. The improvement occurred after stopping the use of the 
device, and the AE could not be explained by other reasons. 
YES 
Probably Related 
The AE occurs in a temporal sequence consistent with the use of the 
medical device, and the AEis consistent with the known type of AE of 
the device. Improvement after discontinuation of the device, the 
patient's clinical status, or other modes of treatment may also 
contribute to the AE. 
YES 
Possibly Related 
The AE occurs in a temporal sequence consistent with the use of the 
medical device, and the AE is consistent with the known type of AE 
of the device. The AE may also occur due to the patient's clinical 
status or other treatment. 
YES 
Possibly 
Unrelated 
The AE does not occur in a temporal sequence consistent with the use 
of the medical device, and the AE is not consistent with the known 
type of AE of the device. The patient's clinical status or other 
treatment modality may have contributed to the AE. 
NO 
Definitely 
Unrelated 
The AE does not occur in a temporal sequence consistent with the use 
of the medical device, the AE is not consistent with the known type of 
AE of the device, and the AEs does not disappear after stop using the 
device. The AE may be caused by the patient's clinical status or other 
NO 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 49 of 74 
 
Table 3. Causality Assessment * 
treatment methods. The AE is resolved when the disease status is 
improved or other treatment methods are stopped. The AE occurs 
when other treatment methods are reused. 
Unable to Judge 
It cannot be assessed with the above rationale. 
YES 
*Causality assessment based on the Chinese medical device GCP 
 
Causality: Performed by a medical professional and is a determination of whether there is a 
reasonable possibility that a medical device/procedure is etiologically related to/associated with 
an AE. Causality assessment includes, for example, assessment of temporal relationships, 
underlying disease, presence (or absence) of a more likely cause, and physiologic plausibility. 
Investigator shall provide an alternative etiology for SAEs that are definitely unrelated or 
possibly unrelated to use of study medical device. If the alternative etiology is unknown, 
investigator shall document “unknown.” 
For AEs with causal relationship (Definitely Related, Probably Related, Possibly Related or 
Unable to Judge) to Theranova 400, the AE must also be reported as a device deficiency to the 
Sponsor. 
Table 4. Outcome Conclusion * 
Symptoms disappear (with or without sequelae, record sequelae). 
The symptoms were improved. 
Persistent symptoms. 
Death (direct cause of death and time of death are recorded). 
Unknown (record reason). 
*Outcome conclusion based on the Chinese medical device GCP 
13.1.2.1 Adverse Events, Serious Adverse Events and Device Deficiency Reporting  
The principal investigator shall: 
a. Record every AE, SAE and DD including assessment and full description of each event.  
 
b. Report to the Sponsor or designee within 5 business days of awareness, all non-serious AEs. 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 50 of 74 
 
c. Report to the Sponsor or designee within 24 hours of awareness, all SAEs and DDs. Each SAE 
should be documented on a separate SAE eCRF. Each DD should be documented on a separate 
DD eCRF. In addition, SAEs should be reported to Sponsor or designee in written form. 
 
d. Report to the Ethics Committee, SAEs and DDs, if required by national or local regulations or 
by the Ethics Committee. 
 
e. Supply the Sponsor or designee, upon Sponsor’s or designee’s request, with any additional 
information related to the safety reporting of a particular event.  
 
f. After study completion, report any SAEs within 24 hours after awareness on the paper AE form 
to the Sponsor 
 
13.1.2.2 Pregnancy Reporting  
If a female study patient or a study patient’s partner becomes pregnant during the study 
patient’s participation in the trial, the pregnancy must be reported by investigator to Sponsor 
designee and Baxter Global Patient Safety Medical Device Vigilance 
within one business day of awareness using the 
Pregnancy Report Form. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, ectopic pregnancy) irrespective of relatedness to the 
study medical device or procedure are considered SAEs, and the reporting time period is the 
same as it is for SAEs. 
13.2 Product Complaints  
A Product Complaint (PC) includes any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, usability, safety, effectiveness, 
or performance of a product after it is released for distribution or related to a service that affects 
the performance of such product. A complaint may involve the possible failure of the product 
itself, its packaging, or its labeling (i.e., product label, package insert, or any instructions for use).  
 
Reports of off-label use (in the absence of a device allegation or associated AE) are considered 
use error and need to be reported as complaints.  
 
When a product complaint is encountered with a Post-Marketed Baxter product, the information 
should be reported to Baxter by the investigator to 
within 24 hours 
of awareness of the event using the Product Complaint form. This should also include AEs with 
a positive causal relationship to a Post-Marketed Baxter device. 
 
When a DD for the pre-marketed investigational device (Theranova dialyzer) is encountered, the 
information should be reported on the DD eCRF form and analysed by Baxter PMS (via 
). Product complaints reported for the comparator product will be 
collected based on each study site’s established PC reporting processes and sent to the product 
manufacturer. Baxter will not analyze comparator-related PCs. 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 51 of 74 
 
13.3 Safety Reporting to Authorities and Ethics Committee 
It is the responsibility of the investigator to report any SAEs and DDs to Ethics Committee, 
according to national or local regulatory requirements. Sponsor or designee will report applicable 
AEs and DDs to regulatory authorities according to written guidelines, including timelines.  
14. Determination, Deviation and Amendment of Clinical Study Protocol  
14.1 Determination of the Clinical Study Protocol  
The clinical study protocol shall be reported to the Ethics Committee of the clinical study 
institution for review and approval after discussion, and filed at the provincial regulatory 
authority in the place where the Sponsor or its designee is located in accordance with the 
requirements in CFDA Announcement [2015] No. 87. The clinical study can only be conducted 
after filing.  
14.2 Deviations from the Clinical Study Protocol  
The investigator should strictly follow the clinical trial protocol and should not intentionally 
deviate from the protocol or materially change the protocol. However, in the event of an 
emergency that requires emergency treatment, such as when the patient is at immediate risk, a 
written report may be made afterwards.  
If the investigator unintentionally fails to follow the clinical study protocol, the investigator 
should timely report to the competent medical device clinical study administration, and notify 
the Sponsor and the Ethics Committee in time.  
For any protocol deviation, the investigator must record the reason, date and in major / minor 
deviation deviation in the original documents.  
Protocol deviations include but are not limited to:  
(1)  
The selected patients do not meet the inclusion criteria or meet the exclusion criteria;  
(2)  
Failure to perform or accurately perform the treatment specified in this clinical study 
protocol, such as:  
1) 
The actual QB of the patient is less than 220 mL/minute for a duration of more than 
30 minute or for a total duration of more than 60 minute at themid-week treatment 
day dialysis session;  
2) 
The actual dialysis time of the patient is less than 210 minute at themid-week 
treatment day dialysis session;   
(3)  
Failing to report AEs within the time limit specified in the clinical study protocol.  
The investigator should classify the severity of protocol deviations as follows:  
(1)  
Major protocol deviation: Protocol deviations that affect the study data and results, or 
jeopardize the rights, safety or health of the patients.  
(2)  
Minor protocol deviations: Protocol deviations that will not affect the study data and 
results or jeopardize the rights, safety or health of patients.  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 52 of 74 
 
Protocol deviations will be reviewed and evaluated on an ongoing basis by the Sponsor and 
appropriate corrective and preventive actions will be taken as necessary, including but not limited 
to: Notify, re-train the site or investigator, terminate the qualification of the study site, and report 
to local drug regulatory authority and national health regulatory authority.  
14.3 Amendments to the Clinical Study Protocol  
The clinical study protocol must be strictly implemented after being approved by the Ethics 
Committee. If it is necessary to supplement or revise the study protocol after the start of the study, 
the investigator and the Sponsor should make revisions upon negotiation and submit the revised 
study protocol to the Ethics Committee again for approval before implementation. Amendments 
to the clinical study protocol should be documented in detail, including: the specific contents of 
and reasons for the amendments, the letter of submission to the Ethics Committee for re-approval 
and the approval document of the Ethics Committee, etc.  
15. Direct Access to Source Data and Documents  
Source data and documents are defined in GCP as follows:  
Source data refer to all information in original records and their approved copies of clinical 
findings, observations and other activities in a clinical study that can be used for reconstruction 
and evaluation of the clinical study.  
Source documents are printed, visible, or electronic documents that contain source data.  
Original medical records and laboratory test data of patients. The investigator should truthfully 
and accurately record and preserve the source data and documents related to the clinical study. 
The regulatory authority, CRA and inspector can directly access the source data and documents 
of this clinical study for inspection, monitoring and verification.  
16. Finance and Insurance  
See the Clinical Study Agreement for details. In this study, insurance will be purchased in 
accordance with the requirements of GCP.  
17.  Assessments Covered in the Clinical Study Report   
The investigator shall verify or validate the safety and efficacy of the investigational medical 
device according to the design requirements of the Clinical Study Protocol, and complete the 
Clinical Study Report. The Clinical Study Report shall comply with the relevant requirements of 
GCP and be consistent with the Clinical Study Protocol, with its contents including but not 
limited to:  
（1） General information;  
（2） Abstract;  
（3） Introduction;  
（4） Clinical study objectives;  
（5） Clinical study methods;  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 53 of 74 
 
（6） Clinical study content;  
（7） General clinical data;  
（8） Investigational medical device and control medical device or control diagnosis and 
treatment method;  
（9） Statistical analysis methods and evaluation methods adopted;  
（10） Clinical evaluation criteria;  
（11） Organizational structure of clinical study;  
（12） Ethical statement;  
（13） Clinical study results;  
（14） Adverse events identified in the clinical study and treatment;  
（15） Analysis and discussion of clinical study results, especially indications, scope of 
application, contraindications and precautions;  
（16） Clinical study conclusions;  
（17） Existing problems and suggestions for improvement;  
（18） List of study personnel;  
（19） Other situations requiring explanation;  
（20） Comments from the investigator and the competent medical device clinical study 
administration.  
18. Confidentiality  
This clinical study protocol contains trade secrets that are privileged or strictly confidential and 
may not be disclosed without legal permission. It is only exposed to the investigators of the 
clinical study, and no further distribution is allowed. This disclosure policy applies to all other 
confidential information that will be provided in the future.  
In case that the parties terminate the cooperation, each party shall still have the obligation to 
keep the technical secrets and trade secrets of the product agreed in this clinical protocol known 
to or obtained by the other party confidential, that is: Not to be disclosed to or known by any 
third party. However, the disclosure caused by submitting the information to the competent 
product approval authority, filing authority and/or experts for review and discussion 
demonstration shall be excluded.  
18.1 Trade Secrets 
The technical secrets and trade secrets of the product as agreed herein refer to: ① Clinical data 
and trial data; ② Product specification, technical requirements and test methods; ③ All 
relevant technical data and literatures.  
19. Agreement on Publishing Study Results  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 54 of 74 
 
The ownership of all the data and study results of this clinical study shall be in accordance with 
GCP.  
Any trial-related information (including this research plan) shared by the sponsor is proprietary 
information and should be kept confidential. The data generated during this clinical study 
belongs to the sponsor. Whether it is now or in the future, sponsors can decide to use the data for 
presentations or publications or submit them to regulatory agencies. In addition, the sponsor 
reserves the right to review and approve the research data before any publication or any 
presentation may release proprietary information. 
20. Responsibilities Assumed by Each Party  
20.1 Responsibilities of Clinical Study Institutions and Investigators  
Clinical study institutions and investigators shall strictly fulfill their responsibilities in GCP and 
carry out this clinical study in accordance with this study protocol and clinical study agreement.  
Before a clinical study, the competent medical device clinical study administration shall 
cooperate with the Sponsor in submitting an application to the Ethics Committee and submitting 
the relevant documents as required. The investigator shall truthfully explain the details of the 
investigational product to the patients, and give the patients sufficient time to consider whether 
to participate in the clinical study before the study; Faithfully record the side effects and AEs 
and product complaints. In case of any AE, it is necessary to timely make clinical judgment, take 
measures and truthfully and timely report them level by level to protect the rights and interests 
of patients; After the clinical study, the clinical study personnel shall sign, and the competent 
medical device clinical study administration shall sign, date and sign, and issue the clinical study 
report to the investigator. Keep the patient data and the data provided by the implementer 
confidential.  
The investigator should strictly follow the clinical study protocol, and should not deviate from 
the protocol or materially change the protocol without the approval of the Sponsor and the Ethics 
Committee, or failing to obtain the approval from the NMPA as required.. However, in the event 
of an emergency that requires immediate removal, such as when the patient is at immediate risk, 
a written report may be made afterwards.  
The investigator should ensure that the clinical study data are accurately, completely, clearly and 
timely recorded in the eCRF. Any change of data should be signed and dated by the investigator, 
and original records should be kept, which should be clear and identifiable.  
The clinical study institution and investigator should accept the monitoring and verification by 
the Sponsor and the supervision by the Ethics Committee, and provide all required records 
related to the study. Where drug regulatory authorities and health regulatory authorities send 
inspectors to carry out verification, clinical study institutions and investigators shall cooperate.  
20.2 Sponsor’s Responsibilities  
The Sponsor should strictly perform the responsibilities specified in GCP, including but not 
limited to:  
The Sponsor is responsible for organizing the development and revision of the Investigator’s 
Brochure, clinical study protocol, Informed Consent Form, eCRF and other relevant documents, 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 55 of 74 
 
and organizing the training necessary for the clinical study.  
The Sponsor shall ensure that all investigators conducting clinical studies strictly follow the 
clinical study protocol, and timely point out and correct the failure of clinical study institutions 
and investigators to comply with relevant laws and regulations, this Practice and clinical study 
protocol; In case of serious situation or continuous failure to change, the study shall be 
terminated and reported to the food and drug regulatory authority of the province, autonomous 
region or municipality directly under the central government where the clinical study institution 
is located and China Food and Drug Administration.  
The Sponsor shall bear the treatment cost and corresponding economic compensation for the 
patients who suffer from injury or death due to the clinical study, except for the damage caused 
by the faults of medical institution and its medical staff in the diagnosis and treatment.  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 57 of 74 
 
 
  
  
  
  
 
 
 
 
 
  
  
 
  
  
  
  
  
  
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
 
 
  
  
 
 
  
  
  
  
  
  
  
  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 58 of 74 
 
3)  
 
  
  
  
  
 
 
 
 
 
  
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
 
  
  
  
  
  
  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 61 of 74 
 
 
  
  
  
  
  
  
  
  
  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 62 of 74 
 
Appendix 4
  
  
  
 
  
  
  
 
 
  
  
 
 
 
 
  
  
 
 
 
  
  
  
 
 
 
  
 
 
  
 
  
  
  
  
  
 
 
 
  
  
  
 
  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 63 of 74 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
  
  
  
  
 
 
 
 
 
 
  
  
  
 
 
  
  
  
  
 
  
  
  
 
 
  
 
 
 
 
  
  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 64 of 74 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
 
  
  
  
 
  
 
 
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 65 of 74 
 
 
  
 
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
  
  
  
 
  
  
  
  
 
  
 
 
 
 
 
 
 
  
 
  
  
  
  
  
  
  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 66 of 74 
 
  
 
  
  
 
 
  
 
 
 
 
 
  
 
 
  
 
  
  
 
  
  
 
 
  
  
  
 
  
 
 
 
  
  
  
  
 
  
 
  
  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 67 of 74 
 
  
  
 
  
  
 
  
  
 
  
  
  
  
 
  
 
  
 
 
  
 
 
 
  
  
 
  
 
  
 
 
  
 
  
  
  
  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 68 of 74 
 
 
  
  
  
 
 
  
 
  
 
  
  
  
 
 
  
 
 
 
 
  
 
  
  
  
 
  
  
  
 
  
  
  
  
 
 
   
  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 69 of 74 
 
 
 
 
 
  
  
 
 
 
  
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
 
  
   
  
  
  
  
  
  
  
 
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 70 of 74 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 71 of 74 
 
Appendix 5
  
 
 
  
  
  
  
 
 
  
  
  
 
  
  
  
 
 
  
 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
  
  
  
  
 
 
 
  
  
 
  
(V)  
Depletion syndrome  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 72 of 74 
 
 
 
 
  
22. References  
[1] 
National Health Commission. Standard Operating Procedures for Blood Purification 
(2021). November 2021.  
[2]   Ma L, Zhao S: Risk factors for mortality in patients undergoing hemodialysis: a 
systematicreview and meta-analysis. Int J Cardiol 2017;238: 151–158. 3. Ronco C, Clark 
WR: Haemodialysis membranes. Nat Rev Nephrol 2018; 14: 394–410. 
[3]    Vanholder R, De Smet R, Glorieux G, Argile´s A, Baurmeister U, Brunet P, et al. Review 
on uremic toxins: Classification, concentration, and interindividual variability. Kidney 
Int. 2003; 63(5):1934–43. 
[4]    USRDS report. Epidemiology of kidney disease in the United States.; 2020. 
[5]    Moradi H, Sica DA, Kalantar-Zadeh K: Cardiovascular burden associated with uremic 
toxins in patients with chronic kidney disease. Am J Nephrol 2013; 38: 136–148. 
[6]    Ok E, Asci G, Toz H, Ok ES, Kircelli F, Yilmaz M, Hur E, Demirci MS, Demirci C, 
Duman S,Basci A, Adam SM, Isik IO, Zengin M, Suleymanlar G, Yilmaz ME, Ozkahya 
M; Turkish Online Haemodiafiltration Study: Mortalityand cardiovascular events in 
online haemodiafiltration (OL-HDF) compared with highflux dialysis: results from the 
Turkish OLHDF Study. Nephrol Dial Transplant 2013;28: 192–202. 
[7]   Lamy T, Henri P, Lobbedez T, Comby E, Ryckelynck JP, Ficheux M. Comparison 
between on-line highefficiency hemodiafiltration and conventional high-flux 
hemodialysis for polyclonal free light chain removal. Blood Purif. 2014; 37(2):93–8.  
[8]    Mazairac AH, Blankestijn PJ, Grooteman MP, Penne EL, van der Weerd NC, den Hoedt 
CH, Buskens E, van den Dorpel MA, ter Wee PM, Nube MJ, Bots ML, de Wit GA; 
CONTRAST investigators: The cost-utility ofhaemodiafiltration versus haemodialysis in 
the Convective Transport Study. Nephrol Dial Transplant 2013; 28: 1865–1873. 
[9]    Kirsch AH, Rosenkranz AR, Lyko R, Krieter DH. Effects of hemodialysis therapy using 
dialyzers with medium cut-off membranes on middle molecules. Contrib Nephrol. 
2017;191:158–167. 
[10]  Sebastian Koball , Christina Westphal, Silvius Frimmel. Comparison of changes in 
albumin binding capacity during hemodiafiltration or hemodialysis with middle cut off 
membranes.The International Journal of Artificial Organs. 2020: 1-5. 
[11]  Alexander H. Kirsch et al. Performance of hemodialysis with novel medium cut-off 
dialyzers. Nephrol Dial Transplant (2017) 32: 165–172  
[12] 
Alexander H. Kirsch et al. Effects of Hemodialysis Therapy Using Dialyzers with 
Medium Cut-Off Membranes on Middle Molecules. Ronco C (ed): Expanded 
Hemodialysis – Innovative Clinical Approach in Dialysis. Contrib Nephrol. Basel, 
Karger, 2017, vol 191, pp 158–167  

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 73 of 74 
 
[13] 
Weiner et al. Efficacy and Safety of Expanded Hemodialysis with the Theranova 400 
Dialyzer. A Randomized Controlled Study. Clin J Am Soc Nephrol 2020; 15 (9) 1310-
1319  
[14] 
Kirsch AH, et al. Performance of hemodialysis with novel medium cut-off dialyzers. 
Nephrol Dial Transplant 2017; 32(1): 165-72.  
[15] 
Kirsch AH, Lyko R, Nilsson LG, et al. Performance of hemodialysis with novel medium 
cut-off dialyzers. Nephrol Dial Transplant. 2016  
[16] 
Meyer et al., Hemodialysis-induced release of hemoglobin limits nitricoxide 
bioavailability and impairs vascular function, J Am Coll Cardiol.2010 Feb. 2; 55(5): 454-
9. 
[17] 
Guidelines for Technical Review of Disposable Dialyzer Registration (SYJBXH [2013] 
No. 3), January 4, 2013  
[18] 
Bergström J, Wehle B. No change in corrected ß2-microglobulin concentration after 
cuprophane haemodialysis [letter]. Lancet. 1987; 1:628-629.  
[19] 
Kamyar Kalantar-Zadeh, et al. Normalized Protein Nitrogen Appearance Is Correlated 
With Hospitalization and Mortality in Hemodialysis Patients With Kt/V Greater Than 
1.20. Journal of Kidney Nutrition, Vol 13, No 1 ( January), 2003: pp 15-25  
[20] 
Gambro Dialysatoren GmbH. Instructions for Use of Hollow Fiber Dialyzers with 
Medium Cut-off Volume. December 15, 2020.  
[21]  Study 1407-001. Comparison of the Clinical Performance of 2 THERANOVA 400 
Dialyzer Prototypes in Hemodialysis Mode with the Performance of a High-Flux 
Dialyzer in Hemodialysis Mode and a High-Flux Dialyzer in High-volume 
Hemodiafiltration Mode – A Pilot Study. 
[22]  Tim Friedea, Meinhard Kieser. Blinded sample size re-estimation in superiority and 
noninferiority trials: bias versus variance in variance estimation. Pharmaceutical 
Statistics 2013;12(3):141-6. 
 
 

Gambro dialysatoren GmbH     
Protocol Number: BXU561424  
 
Protocol version number and date: V1.1, Amendment 1.1  30 May 2022 
Page 74 of 74 
 
Investigator’s Statement  
I agree:  
1.  
To conduct this clinical study in strict compliance with Declaration of Helsinki, current 
laws and regulations of China, and the requirements of the clinical study protocol.  
2.  
To accurately record all data required into the eCRF and complete the final report of the 
clinical study on time.  
3.  
The investigational medical device is only used in this clinical study. The receipt and use 
of the study device will be completely and accurately recorded and the records will be 
kept during the clinical study.  
4.  
To allow the CRA and inspector authorized or designated by the Sponsor and supervision 
department to conduct inspection, verification and examination on the clinical study.  
5.  
To strictly perform the clinical study contract and articles of agreement signed by all 
parties.  
I have already read the clinical trail protocol, including above Statement and fully agree all 
requirements above.  
 
 
Comments of the Sponsor  
Signature (Seal) 
Date 
 
Comments of the Investigator  
Signature 
Date 
 
Comments of the Medical Device Clinical Study Institution  
Signature (Seal) 
Date