Comparison of the Human Acellular Vessel (HAV) With Fistulas as Conduits for Hemodialysis

Study Overview
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Brief Summary
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The main purpose of this study is to compare the Human Acellular Vessel (HAV) with arteriovenous fistula (AVF) when used for hemodialysis access

Detailed Description
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This is a Phase 3, prospective, multicenter, open-label, randomized, two-arm, comparative study. Subjects who sign informed consent will undergo study-specific screening assessments within 45 days from the day of informed consent. Eligible study subjects will be randomized to receive either an HAV or AVF. The randomization will be stratified by upper arm or forearm placement based on the investigator's determination of where the study access (SA) should be located. Subjects will be followed to 24 months post SA creation at routine study visits regardless of patency status. After 24 months, AVF subjects with a patent SA will be followed (while the SA remains patent) for up to 5 years (60 months) post SA creation at routine study visits. After 24 months, HAV subjects will be followed (regardless of SA patency) for 5 years (60 months) post SA creation at routine study visits.

Official Title
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A Phase 3 Study to Compare the Efficacy and Safety of Humacyte's Human Acellular Vessel With That of an Autologous Arteriovenous Fistula in Subjects With End Stage Renal Disease

Conditions
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Renal Failure, End Stage Renal Disease, Hemodialysis, Vascular Access

Intervention / Treatment
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* Biological: Human Acellular Vessel (HAV)
* Procedure: Arteriovenous fistula (AVF)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with end-stage renal disease (ESRD), receiving HD via DC and are suitable for the creation of an AVF or implantation of AVG for HD access. Subjects who plan to undergo HD at a dialysis unit of a participating dialysis provider for at least the first 6 months after SA creation. Subjects aged at least 18 years at Screening. Suitable anatomy for creation of a forearm or upper arm AVF and for implantation of straight or looped HAV in either the forearm or upper arm. Hemoglobin ≥8 g/dL and platelet count ≥100,000 /mm3. International Normalized Ratio (INR) ≤ 1.5. Female subjects must be either: Of non-childbearing potential, which is defined as post-menopausal (at least 1 year without menses prior to Screening) or documented surgically sterile or post hysterectomy (at least 1 month prior to Screening). Or, of childbearing potential, in which case: i. Must have a negative urine or serum pregnancy test at Screening, and ii. Must agree to use at least one form of the following birth control methods for the duration of the study: Established use of oral, injectable or implanted hormonal methods of contraception. Placement of an intrauterine device or intrauterine system. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/ gel/ film/ cream/ suppository. Subject, or legal representative, able to communicate effectively with investigative staff, competent and willing to give written informed consent, and able to comply with entire study procedures including all scheduled follow-up visits. Life expectancy of at least 2 years. Exclusion Criteria: Subjects who are optimal candidates for radiocephalic AVF as indicated by meeting ALL of the following criteria: No previous failed AVF. Cephalic vein diameter on ultrasound of more than 3.5mm. Radial artery diameter on ultrasound of more than 3mm. Vein depth of less than 0.5cm from the skin. Normal Allen's test indicating that ulnar artery flow to the hand is sufficient. No calcification in the wall of the distal radial artery. Sufficient length of the proposed fistula outflow vein to provide an adequate (at least 6 cm) cannulation segment. No evidence of iatrogenic injury to target artery or vein. Uncontrolled diabetes; a. HbA1c >10% (at Screening). History or evidence of severe peripheral arterial disease in the extremity selected for implant. Known or suspected central vein stenosis or obstruction on the side of planned SA creation, unless corrected prior to randomization. Planned AVF creation that requires more than one stage to complete. (e.g. basilic vein transposition AVF performed in 2 stages). Planned AVF creation by means other than suture or vascular anastomotic clips (e.g. endovascular surgery or other anastomotic creation devices). Treatment with any investigational drug or device within 60 days prior to study entry (Day 0) or ongoing participation in a clinical trial of an investigational product. Cancer that is actively being treated with a cytotoxic agent. Documented hyper-coagulable state. Bleeding diathesis. Active clinically significant immune-mediated disease, not controlled by maintenance immunosuppression. Low dose glucocorticoid therapy (e.g. 5-10mg prednisone [Deltason]) is acceptable. High dose glucocorticoid therapy for treatment of autoimmune flare, or other inflammatory diseases is excluded. Patients using glucocorticoids for immunosuppression post-transplant to prevent against transplanted allograft rejection in the period post allograft failure are excluded. The following examples of immunosuppressive agents (or the like) are exclusionary for enrollment in this clinical trial: tacrolimus or FK506 [Prograf] mycophenolate mofetil [Cellcept], cyclosporine [Sandimmune or Gengraf] sirolimus [Rapamune] (this only includes systemically administered, drug eluting stents are acceptable) Anticipated renal transplant within 6 months. History of heparin-induced thrombocytopenia. Venous outflow from SA cannot be located more centrally than the venous outflow of any previous failed access in that extremity. Active local or systemic infection (white blood cells [WBC] > 15,000 cells/mm3 at Screening). If the infection resolves, the subject must be at least one week post resolution of that infection before SA creation. Known serious allergy or intolerance to aspirin and alternative antiplatelet therapy. Pregnant women, or women intending to become pregnant during the course of the trial. Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of the SA. Previous enrollment in this study or any other study with HAV. Employees of Humacyte and employees or relatives of an investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Acellular Vessel (HAV)<br>The HAV is a tissue-engineered vascular conduit (6mm diameter) for hemodialysis access in patients with end-stage renal disease. It will be surgically implanted in the forearm or upper arm on Study Day 0. | Biological: Human Acellular Vessel (HAV)<br>* Surgical implantation of the HAV and subsequent use of the implanted vascular conduit for hemodialysis vascular access.<br>* Other names: Humacyl;|
| Active Comparator: Arteriovenous fistula (AVF)<br>The comparator is an autologous arteriovenous fistula created in the forearm or upper arm on Study Day 0. | Procedure: Arteriovenous fistula (AVF)<br>* Surgical creation of an autologous arteriovenous fistula and subsequent use of the implanted vascular conduit for hemodialysis vascular access.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with functional patency at 6 months post study access (SA) creation | Co-primary endpoint #1: Proportion of subjects with functional patency at 6 months post study access (SA) creation The definition of functional patency is: Dialysis with 2 needles for ≥75% of dialysis sessions over a continuous 4-week period and either: (1) 4 consecutive sessions during the 4-week period in which 2 needles are used and the mean dialysis machine blood pump speed is ≥300 mL/min, or (2) a measured spKt/Vurea is ≥ 1.4 or urea reduction ratio >70% during any session in which 2 needles are used within the 4-week period. SpKt/Vurea is calculated from pre and post-treatment serum urea nitrogen concentrations, body weight, and dialysis session duration. The functional patency ascertainment period will take place between the 1st day of Week 21 (Day 140) and the last day of Week 26 (Day 181) after AVF creation or HAV placement. The endpoint is met when the functional patency criteria are satisfied within any consecutive 4 week period within this ascertainment period. | 6 months post SA creation | 
| Proportion of subjects with secondary patency of SA at 12 months post SA creation. | Co-primary endpoint #2: Proportion of subjects with secondary patency of SA at 12 months post SA creation. The SA maintains secondary patency until it is abandoned, irrespective of interventions to maintain or restore patency. Abandonment is defined as AVF or HAV that can no longer be used for 2-needle, prescribed dialysis as it may be unable to provide adequate flows and/or is deemed unsafe for the subject, and the associated problem cannot be corrected by any intervention, including medical, surgical, or radiological interventions or rest. | 12 months post SA creation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to loss of secondary patency (abandonment). |  | 12, 24, and 60 months post SA creation | 
| Incidence rate of HD access related interventions over the period from SA creation until SA abandonment or 12 months post SA creation |  | 12 months post SA creation | 
| Incidence rate of infections related to any HD access in situ over the period from SA creation until 12 months post SA creation, irrespective of SA abandonment. |  | 12 months post SA creation | 
| Proportion of subjects with unassisted functional patency at 6 months post SA creation. |  | 6 months post SA creation | 
| Incidence rate of HD access-related interventions over the period from SA creation until SA abandonment or the conclusion of the suitability ascertainment period (6 months). |  | 6 months post SA creation | 
| Time to loss of primary unassisted patency |  | 12, 24, and 60 months post SA creation | 
| Proportion of HD sessions completed via DC (1 or 2 lines) over the period from SA creation until 12 months post SA creation, irrespective of SA abandonment. |  | 12 months post SA creation | 
| Number of days with DC in situ catheter contact time over the period from SA creation until 12 months post SA creation, irrespective of SA abandonment |  | 12 months post SA creation | 
| Histopathological remodeling of HAV and AVF - based on histological examination of SA samples explanted for clinical reasons |  | 12, 24, and 60 months post SA creation | 
| Incidence rate of HD access-related infections over the period from SA creation until SA abandonment. |  | 12, 24, and 60 months post SA creation | 
| Incidence rate of clinically significant aneurysm or pseudoaneurysm over the period from SA creation until SA abandonment |  | 12, 24, and 60 months post SA creation | 
| Incidence rate of SA site infections (CDC definition) over the period from SA creation until SA abandonment. |  | 12, 24, and 60 months post SA creation | 
| Frequency and severity of AEs. |  | 12, 24, and 60 months post SA creation |