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)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Aplagon Oy
- 入组人数
- 20
- 试验地点
- 3
- 主要终点
- 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)
研究概览
简要总结
- To evaluate safety and tolerability of APAC at 42 days post-surgery.
- To investigate the effect of APAC on unassisted AVF maturation at 42 days post-surgery or at initiation of HD, if earlier, compared to control group treated with Standard of Care (SoC).
- To evaluate the effect of APAC on the usability of AVF for HD at 42 days post-surgery or at initiation of HD, if earlier, compared to control group treated with SoC.
- To determine the recommended APAC dose for Phase III development at 42 days post-surgery.
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Male or female, age of at least 18 years.
- •The patient must not participate in any other investigational clinical trial during the study.
- •Ability to understand and comply with the requirements of the entire study and to communicate with the study team.
- •Written informed consent using a document that has been approved by the Ethics Committee (EC).
- •If female and of childbearing potential (premenopausal and not surgically sterile) must have a negative pregnancy test at screening and be willing to use highly effective contraception from the time of screening until D42 post AVF-surgery. Highly effective contraception methods of birth control are those that achieve a failure rate of less than 1% per year when used consistently and correctly (as per the Clinical Trial Coordination Group [CTCG] Recommendations related to contraception and pregnancy testing in clinical trials, Version 1.2, 07 Mar 2024).
- •Males must be willing to use a condom and their partners that can be of childbearing potential must use highly effective contraception to prevent pregnancy 2 weeks following study drug administration.
- •Males must refrain from sperm donation from the time of the screening to 2 weeks following study drug administration.
- •Life expectancy of at least 6 months.
- •Diagnosis of ESKD (eGFR < 15 mL/min).
- •Planned creation of a new distal radio-cephalic anastomosis proximal to the carpal joint, not allowing snuff box, to be constructed with the end of the cephalic vein to the side of the radial artery.
- •RRT is anticipated to be required within the subsequent 6 months or has already started via a contralateral central venous catheter within 6 months prior to the signing of the inform consent form.
- •Contemporary pre-operative ultrasound vein and arterial mapping per local practice, confirming anatomy suitable for AVF creation, as confirmed by the operating surgeon.
- •Luminal diameter of distal radial artery and cephalic vein ≥ 2 mm and distal radial artery compressible under ultrasound pressure.
- •One or more of the following adverse factors to successful maturation of an AVF: Anatomical factors: • Wrist: artery < 2.5 mm, vein < 3 mm • Elbow: artery < 4 mm, vein < 4 mm • Poor arterial quality due to calcification Technical factors: • Depth: distance of the cephalic vein to skin predominantly > 5 mm • Length of vein for cannulation < 6 cm Patient factors: • Age > 65 years • Female • Type 1 or type 2 Diabetes mellitus • Peripheral arterial occlusive disease or other diagnosed vasculopathy • Body Mass Index (BMI) > 29 kg/m2
- •The patient must agree not to undergo far-infrared therapy during the study.
排除标准
- •Known allergy to heparin, history of heparin-induced thrombocytopenia (HIT), or protamine sulphate (antidote of heparin).
- •Scheduled living-donor kidney transplantation within 60 days.
- •Previous AVF is not allowed in the side (ipsilateral) of the planned AVF.
- •Active malignancy (hematological or solid tumor) or treatment for malignancy within the previous 12 months with the exception of the following cancers if they have been completely resected: basal or squamous cell skin cancer.
- •Peritoneal dialysis treatment with an elective transition to hemodialysis.
- •Presence of any significant medical condition that might significantly confound the collection of safety and efficacy data in this study, including unstable cardiovascular disease, mechanic heart valve replacement (vitamin K antagonist indicated), atrial fibrillation, recent < 3 months of thrombotic episode, acute infection or an active autoimmune, including antiphospholipid syndrome, or any generalized inflammatory disease.
- •Treatment with more than one antithrombotic within the previous 10 days prior to signing informed consent.
- •Treatment with any investigational drug within the previous 30 days or investigational antibody therapy within the previous 90 days prior to signing informed consent.
- •Anemia (hemoglobin ≤ 90 g/L) or clinically significant abnormalities in platelet and white blood cell counts.
- •Body Mass Index (BMI) ≥ 40 kg/m
- •Requirement for vein transposition or superficialization to ensure successful dialysis.
结局指标
主要结局
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)
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 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 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 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.
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).
• 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
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.
• 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.
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).
• 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.
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.
次要结局
- 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.
研究者
Clinical Study Director
Scientific
Aplagon Oy