A Randomized, Open Label, Cross-over Feasibility Study for Heparin-free Hemodialysis With the Dialyzer With Endexo™ in End-Stage Renal Disease (ESRD) Subjects
Phase: NA
Conditions: Chronic Kidney Diseases, Patient Requiring Heparin Free Dialysis Treatments
Sponsor: Fresenius Medical Care North America

 
 
 
 
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FRESENIUS MEDICAL CARE  
RENAL THERAPIES GROUP (RTG), LLC 
 
 
TITLE: 
 
 
 
A Randomized, Open Label, Cross-over 
Feasibility Study for Heparin-free Hemodialysis 
with the Dialyzer with EndexoTM in End-Stage 
Renal Disease (ESRD)Subjects  
 
PROTOCOL NUMBER: 
 
 
Endexo-002 
 
INVESTIGATIONAL PRODUCTS (IP): Dialyzer with EndexoTM, Fresenius Medical  
 
 
 
 
 
Care North America 
 
 
 
 
 
 
 
 
 
SPONSOR:  
 
 
 
Fresenius Medical Care RTG, LLC  
 
 
 
Medical Department, Clinical Research 
 
 
 
920 Winter Street 
 
 
 
Waltham, MA 02451–1457 
 
ORIGINAL PROTOCOL:  
 
Version 1.0 [11AUG2020]  
 
                                                                 NCT04511338 
 
 
 
 
 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
Date:11AUG2020 
 
 
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PROTOCOL SYNOPSIS 
Title 
A Randomized, Open label, Cross-over Feasibility Study for Heparin-free 
Hemodialysis with the Dialyzer with EndexoTM in End-Stage Renal Disease (ESRD) 
Subjects  
Protocol Number 
Endexo-002 
Study Type 
Feasibility study 
Investigational 
Product (IP) 
Dialyzer with Endexo, Fresenius Medical Care North America 
Proposed 
Indication 
The dialyzer with Endexo used with either the CombiSet® bloodline1 or the Streamline® 
bloodline2, and Citrasate® dialysate are intended for heparin-free hemodialysis 
treatments of patients with acute or chronic renal failure when conservative therapy is 
judged to be inadequate.  
The dialyzers with Endexo must be used in conjunction with dialysis machines 
equipped with ultrafiltration control and are to be used only as directed by a physician. 
 
1 Fresenius Medical Care North America 
2 B. Braun Medical Inc. 
Study Objective(s) 
The primary objective of this study is to explore the feasibility of heparin-free 
hemodialysis (HFHD) with two extracorporeal dialysis circuits (A, B) in ESRD 
subjects maintained on conventional hemodialysis (HD) with Citrasate dialysate and 
regularly prescribed heparin. 
Circuit (A): dialyzer with Endexo and CombiSet bloodline 
Circuit (B): dialyzer with Endexo and Streamline bloodline 
 
The secondary objective is to collect and summarize adverse events with both dialysis 
circuits. 
Study Design 
This is a randomized, open-label, cross-over study with subjects on thrice-weekly (in-
center) hemodialysis. The study consists of a Screening Period, two Study Periods (1 
and 2), a Washout Period and a Follow-up Visit. A study design diagram is presented in 
Appendix I. 
After screening, chronic kidney disease subjects on thrice weekly conventional HD with 
Optiflux dialyzer (F160NR and F180NR), standard of care (SOC) bloodline, Citrasate 
dialysate, and regularly prescribed heparin dose will be assigned randomly to one of the 
treatment sequences: AB or BA. 
• 
Circuit (A) includes the dialyzer with Endexo and the CombiSet bloodline. 
• 
Circuit (B) includes dialyzer with Endexo and the Streamline bloodline 
Each sequence includes two study periods (Period 1 and Period 2) and a Washout 
period. 
• 
Period 1 and Period 2 consist of 5 HD sessions per period (5 Visits per period): 
The 1st HD session with the regularly prescribed Heparin dose, the 2nd HD 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
Date:11AUG2020 
 
 
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session with 50% of the prescribed Heparin dose, and the 3rd, 4th and 5th HD 
sessions with 0% Heparin (heparin-free). 
• 
The Washout period is performed between Period 1 and Period 2. It consists of 
3 conventional HD sessions (3 Visits). 
 
The tables below provide a summary for study periods and HD visits: 
Table 1: 
Summary of Study Periods 
Randomization 
Period 1 
(Five Visits: 
1,2,3,4,5) 
Washout 
Period*** 
(Three Visits: 
6,7,8) 
Period 2 
(Five Visits: 
9,10,11,12,13) 
Sequence AB 
A* 
B** 
Sequence BA 
B** 
A* 
*Circuit A: dialyzer with Endexo + CombiSet bloodline 
**Circuit B: dialyzer with Endexo + Streamline bloodline 
***Conventional HD 
 
Table 2: 
Summary of HD Visits during Periods 1 and 2 
Period 1 and Period 2 
(Circuit A or B) 
Visit 1 and Visit 9 
Regularly prescribed Heparin dose 
Visit 2 and Visit 10 
50% of the regularly prescribed Heparin dose 
Visit 3 and Visit 11 
0% Heparin (Heparin-free) 
Visit 4 and Visit 12 
0% Heparin (Heparin-free) 
Visit 5 and Visit 13 
0% Heparin (Heparin-free) 
 
 
Table 3: 
Summary of the Washout Period 
Washout Period 
Visits 6, 7, and 8 
Conventional HD 
Study Population 
The study population will consist of ESRD subjects who are a minimum of 22 years of 
age and have been prescribed in center thrice weekly HD for at least 180 days prior to 
the date of signed informed consent. 
Total Number of 
Subjects 
12–16 eligible subjects will be enrolled 
Total Number of 
Sites 
1–2 (United States) 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
Date:11AUG2020 
 
 
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Estimated Duration 
of Study 
Each subject will participate in the study for approximately 10 weeks. 
• 
Screening Period up to 4 weeks. 
• 
Two Study Periods (Period 1 and Period 2) including 5 HD sessions per period  
(approximately 2 weeks per subject per period).  
• 
A Washout Period includes 3 HD sessions  
(1 week) between the Study Periods 1 and 2.  
• 
A Follow-up Visit within one week of the subject’s last study HD session. 
After the subject’s last study HD session, the subject will resume HD as 
prescribed by his/her physician. 
Inclusion Criteria 
A subject who signed the ICF must meet all the following inclusion criteria in order to 
be eligible for enrollment in the study: 
1. Must be an adult, defined as having had a 22nd birthday on or before the date of 
signed informed consent 
2. Has been prescribed in center thrice weekly HD for at least 180 days prior to 
the date of signed informed consent 
3. Has been on Conventional HD for at least 30 days prior to the date of signed 
informed consent. Conventional HD includes: Optiflux dialyzer (F160NR or 
F180NR), SOC bloodline, Citrasate dialysate, and regularly prescribed heparin 
dose.  
4. Has a prescribed HD treatment duration ≥ 180 minutes (3 hours) and ≤ 270 
minutes (4.5 hours) at the time of signed informed consent 
5. Has a well-established functional permanent vascular access (AVF, AVG) that 
can allow a blood flow of at least 250 mL/min 
6. Has been on a regularly prescribed heparin dose for HD and has had no change 
in heparin prescription within 14 days prior to the date of signed informed 
consent  
7. Has the following most recently available laboratory results within 45 days 
prior to the date of signed informed consent: 
a. Single pool Kt/V (spKt/V) ≥ 1.2 
b. Hemoglobin ≥ 9 g/dL 
c. Platelet count ≥ 100,000/mm3   
8. A female of childbearing potential must have a negative serum 
pregnancy test at the time of screening and agree to use an acceptable 
method of contraception during the study 
Exclusion Criteria 
A subject who signed the ICF is excluded from the study if any of the following criteria 
are met: 
1. Known allergic reactions to Endexo 
2. Known heparin contraindications 
3. Hospitalization within 30 days prior to the date of signed informed consent  
4. Presence of active malignancy, congestive heart failure New York Heart 
Association (NYHA) Class III or IV (see Appendix III), or liver cirrhosis 

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5. Is receiving or has received chemotherapy/radiation 
therapy/immunotherapy/plasmapheresis therapy within 90 days prior to the date 
of signed informed consent 
6. Is receiving oral or/and intravenous (IV) antibiotics or has used oral or/and IV 
antibiotics within 14 days prior to the date of signed informed consent 
7. Is currently enrolled in or has completed any other investigational product study 
within 30 days prior to the date of signed informed consent 
8. Is receiving anticoagulants including vitamin K antagonists 
9. Is receiving a glycoprotein platelet inhibitor 
10. Is receiving more than one anti-platelet medication 
11. Is receiving systemic heparin therapy for prevention or treatment besides heparin 
prescribed for dialysis 
12. Requiring blood and other labile blood products (for e.g., fresh frozen plasma, 
platelets) transfusion during HD treatments 
13. Has history of clotting or bleeding disorders 
14. Has history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the participant’s ability to follow the 
requirements of the study and participate for the full duration of the study, 
or is not in the best interest of the subjects to participate, in the opinion of 
the investigator. 
Study Endpoints 
Primary endpoint: 
• 
The number and percent (%) of successful heparin-free HD* sessions for each 
subject in each circuit 
 
*Definition of a successful HD Session: 
A successful HD session must meet all the following criteria: 
1. Absence of complete HD circuit occlusion (Grade 4) rendering dialysis 
impossible 
2. Absence of the need to replace dialyzers or bloodlines due to clotting 
3. Absence of saline flushes to maintain blood flow through the circuit during the 
HD session 
4. Absence of any additional heparin beyond what is allowed per study visits 
5. Single pool Kt/V (spKt/V) ≥ 1.2 
 
Secondary endpoint: 
• 
Adverse events and device-related adverse events 
 
Additional Assessments: 
• 
Number and percentage of dialyzers and bloodlines for each clotting grade 
using the visual inspection clotting grade scale (Appendix II) 
• 
HD treatment duration or time to complete circuit occlusion (Grade 4) 
• 
Blood volume processed per dialysis session 

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Date:11AUG2020 
 
 
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• 
The volume, the time of saline administered and the reason for administration 
per subject per HD session (other than for circuit priming or rinse back) 
• Urea Reduction Ratio (URR) and spKt/V for all HD sessions 
Exploratory 
Assessment 
 
Pictures of the arterial and venous end caps of the dialyzer with Endexo, arterial and 
venous drip chambers for CombiSet bloodline and venous chambers, arterial and 
venous pods for Streamline bloodline will be taken by the study sites at the end of 
each HD session. 
 
Data Collection 
The data listed below will be collected in the study: 
1. Demographics 
2. Medical History, historical laboratory values and Concomitant Medications 
3. Physical Exam, Vital Signs, Body Measurements (height, weight) 
4. Adverse events, serious adverse events, and device deficiencies 
5. HD Treatment parameters: 
a. Initial HD Prescription 
b. Data collection during dialysis treatment: 
 
Blood flow rate (Qb), dialysate flow rate (Qd), arterial pressure (AP), 
venous pressure (VP), at initiation of the HD sessions and every 
30 ± 15 minutes 
 
KECN recorded at initiation of the HD sessions and every 30 ± 15 
minutes 
c. HD Treatment Data: 
 
Treatment Time (Td), mean Qb, mean Qd, mean AP and VP, mean 
ultrafiltration volume and rate, and blood volume processed 
 
Mean KECN 
d. Volume, time and the reason for saline flushes administration (other than for 
circuit priming or rinse back) 
e. HD Treatment-related Medications (total heparin units given [bolus + 
maintenance]) when applicable  
f. Duration of blood flow cessation during hemodialysis treatment estimated 
as the difference between the Ultrafiltration (UF) clock and the Remaining 
Time on Dialysis (RTD) clock.  
6. Thrombus scoring at the end of each HD session: 
a. Visual thrombus scoring of dialyzer end caps, and bloodline drip 
chambers and pods will be performed (Grade 1–4) and recorded by site 
staff (the investigator or a designee). For further details, see Appendix 
II. 
b. Digital pictures of the dialyzer end caps, and bloodline drip chambers 
and pods will be taken by site staff.  
7. 
Laboratory Assessments: 
a. At screening: 
 
Serum pregnancy test for females of childbearing potential 

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Date:11AUG2020 
 
 
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b. Periods 1 and 2: 
 
Pre- and post-hemodialysis for Visits (1–5) and (9–13): 
­ Complete Blood Count with differential (CBC with diff), Blood 
Urea Nitrogen (BUN), and Albumin 
 
Pre- and post-hemodialysis for Visits 1,3, 9 and 11: 
- 
β2 Microglobulin (B2M), C-Reactive Protein (CRP),   
                                      Interleukin-6 (IL-6) and Ferritin 
Sample Size 
Determination 
For this feasibility study, we proposed to enroll 12–16 eligible subjects. The sample size 
was not calculated based on any estimates or comparisons. 
Statistical Methods 
Analysis for primary endpoint: 
The descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) will be presented for the number and percent of successful heparin-free HD 
sessions for each circuit. The frequency for subjects with possible successful heparin-
free sessions (0, 1, 2, or 3) will be displayed for each circuit. 
 
Analysis for secondary endpoints: 
The number and percent of subjects with adverse events, and the number of adverse 
events will be presented for each circuit by system organ class and preferred term using 
MedDRA. The device-related adverse events will be listed for each circuit. 
 
Additional assessments: 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will 
be presented for continuous endpoints for each circuit. Frequency and percent will be 
presented for categorical endpoints for each circuit. 
 
Safety 
Monitoring/Safety 
Oversight 
All adverse events (AE) and serious adverse events (SAE) regardless of relatedness to 
the Investigational Product (IP) will be captured from the time the subject signs the ICF 
until the subject completes or withdraws from the study. 
The site investigator must inform the Sponsor of every SAE, within 24 hours of 
becoming aware of the occurrence. 
The study medical monitor will evaluate and monitor safety of the subjects during the 
study. 
If the Sponsor determines that an unanticipated adverse event or serious adverse event 
presents an unreasonable risk to the subjects, the Sponsor will terminate the study as 
soon as possible. 
 
 
 

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APPENDIX I: Study Design Endexo-002 
 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
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Appendix II: Clotting scales 
During Period 1 and 2, an investigator or designee is to perform thrombus scoring on dialyzer 
arterial and venous end caps, and bloodline drip chambers and pods at the end of 
dialyzer/bloodline use. All observers will be trained on the scoring prior to study start. The same 
observer should perform the evaluations as much as possible throughout the study. After use, the 
observer is to select one of the 4 possible grades as described in the tables below (The pictures in 
the tables are for reference only. The observer must assign the grade based on the description, 
not the pictures). 
The following areas of the circuits need to be scored: 
Dialyzer with Endexo: 1) arterial end cap and 2) venous end cap 
CombiSet bloodline: 1) arterial chamber and 2) venous chamber 
Streamline bloodline: 1) venous Chamber, 2) arterial pod and 3) venous pod 
 
a) 
Dialyzer arterial and venous end caps 
Thrombus scoring is to be performed at the end of dialyzer use for every dialyzer used in the study. 
Visual inspections of the dialyzer arterial and venous end caps will be done after the rinseback process 
has been completed by the clinical staff. This graded scoring method has been adopted from Dorsch et al.2 
and Laville et al.3 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Good, clear dialyzer; no 
detectable clotting 
Overall light redness; 
minimal clot formation 
Overall moderate 
redness; clot formation 
but nonobstructive and 
dialysis still possible 
Complete occlusion of 
the dialyzer rendering 
dialysis impossible  
 
 
 
 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
Date:11AUG2020 
 
 
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b) 
Bloodline Drip Chambers and Pods 
This graded scoring method has been adopted from Islam et al. 
 
 
 
 
 
 
 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
Date:11AUG2020 
 
 
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Appendix III: New York Heart Association Functional Classification 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest.  If any physical activity is undertaken, discomfort 
increases. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL NUMBER: Endexo-002                                                                            Version Number:1.0 
 
 
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References 
1U.S. Department of Health and Human Services, Food and Drug Administration Guidance for Industry 
and Food and Drug Administration Staff. Investigational Device Exemptions (IDEs) for Early Feasibility 
Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies. Document issued on: 
October 1, 2013 
2Dorsch et al. A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation 
during maintenance hemodialysis--the membrane study BMC Nephrology 2012 Jun 28;13:50. doi: 
10.1186/1471-2369-13-50. 
3Laville et al. Results of the HepZero study comparing heparin-grafted membrane and standard care show 
that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis. Kidney Int. 2014 Dec 
;86(6):1260-7. doi: 10.1038/ki.2014.225. Epub 2014 Jul 9. 
 
4Islam MS, Hassan ZA, Chlamin F, Vido S, Berrada M, Verhelst D, Donnadiau P, Moranna O, Esnault V. 
Vitamin E-coated and heparin-coated dialyzer membranes for heparin-free hemodialysis: A multicenter, 
randomized, crossover trial. AJKD, 2016.