A Phase II, randomized, blinded, dose selection study to assess safety and preliminary efficacy of antithrombotic heparin proteoglycan mimetic APAC (antiplatelet, anticoagulant) administered locally to the site of arterio-venous fistula (AVF) surgery to facilitate maturation of hemodialysis (HD) vascular access in patients with end stage kidney disease (ESKD) (MATURATION)

Condition studied

End stage kindey disease

Investigational medicinal product(s)

Eligibility

Primary endpoint

1) Safety and tolerability will be defined by the frequency and severity of adverse events (AE) and serious adverse events (SAE). Specific tolerability endpoints: • Incidence of the treatment-emergent adverse events (TEAEs) specifically localized to the AVF surgical site or systemic findings (graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 6.0), o Local signs and symptoms: e.g. swelling / oedema, erythema, induration/hardness, warmth, pruritus, local bleeding or oozing., o Local complications: e.g. hematoma, seroma, wound failure / dehiscence and surgical site infection., o Change in patient reported pain AVF score (visual analogue pain scale 0-10)., o Systemic findings: e.g. fever or hypersensitivity reaction, hyper perfusion heart failure, inflammation (CRP), hemolysis/bleeding (hemoglobin) and coagulation variables., • AVF-specific vascular access healing and integrity o No complication o Local reaction o Reduction of thrill/bruit meriting investigation and confirmation of poor flow o Aneurysm/Pseudoaneurysm o Thrombosis (confirmed by duplex ultrasound) o Stenosis (confirmed by duplex ultrasound)., 2) Unassisted AVF maturation will be assessed by duplex ultrasound. AVF maturation is defined as: • Average cephalic vein lumen diameter ≥ 4 mm at ≥ 2/3 measurement locations (at 5 cm proximal to anastomosis, at midforearm and at cubital outflow area), and, • Brachial arterial volume blood flow 5 cm proximal to brachial arterial bifurcation ≥ 500 mL/min., 3) Investigator’s assessment of the usability of the AVF for HD: • If AVF has been cannulated for hemodialysis, the assessment will be based on whether AVF allows effective two needle HD., • If AVF has not been cannulated, the assessment will be based on investigator’s evaluation (thrill/bruit, wound healing, and ultrasound measurements)., 4) Recommended APAC dose for Phase III development will be selected based on the safety and tolerability as well as unassisted AVF maturation and AVF usability for HD.

Endpoint detail

1) Assisted AVF maturation is assessed and defined as above at 42 days post-surgery., 2) Other clinical AVF efficacy measures • Proportion of patients with successful 2- needle HD for at least 75 % of the dialysis sessions, including 3 consecutive sessions with a mean Qb (blood flow rate) of 300 mL/min (unless the prescribed Qb is < 300 mL/min) performed during any continuous 30-day period that commences no later than 150 days after AVF surgery., • AVF primary patency (the time from AVF surgery until the first intervention [endovascular or surgical] to maintain or re-establish blood flow or abandonment of the AVF)., • AVF assisted primary patency (the time from AVF surgery until the first intervention [endovascular or surgical] to re-establish blood flow or abandonment of the AVF)., • AVF cumulative patency (the time from AVF surgery until abandonment of the AVF)., • Time to successful cannulation (the time from AVF surgery to successful 2-needle HD for at least 75 % of the dialysis sessions, including 3 consecutive sessions with a mean Qb of 300 mL/min (unless the prescribed Qb is < 300 mL/min) performed during any continuous 30-day period that commences no later than 150 days after AVF surgery)., • Investigator’s assessment of the usability of the AVF for HD at 90 and 180 days post-surgery: o If AVF is in use, the assessment will be based on whether AVF allows effective two needle HD., o If AVF is not being used or has been abandoned due to kidney transplantation, the assessment will be based on investigator’s evaluation (thrill/bruit, wound healing, and ultrasound measurements)., • Number of procedures to restore or maintain patency., 3) Patient reported outcome measures • EQ-5D-5L QoL and vascular access specific quality of life measure (VASQoL) at Screening and days 42 and 180 after surgery.