First-in-human Study to Examine Safety of a New Peritoneal Dialysis Device (WEAKID) in End-stage Kidney Disease Patients

Peritoneal dialysis (PD) is a life-sustaining renal replacement therapy for patients with end-stage kidney disease (ESKD). With PD, waste solutes and excess water are drawn from the blood across the peritoneal membrane lining the abdominal cavity via diffusion and osmosis, respectively, into dialysis fluid (peritoneal dialysate) that is introduced into the abdominal cavity through a permanent tube (peritoneal catheter). The peritoneal dialysate is replaced 4-6 times/day either manually by the patient or automatically by a machine at night while the patient is asleep. PD is a gentle dialysis technique that provides continuous gradual dialysis while the patient is free to move during the day. However, PD has several disadvantages. Removal of waste solutes is inadequate and technique failure rate is high, contributing to poor quality of life and high (co)morbidity and mortality (10-15% per year). The low solute clearance (\~1-7% of that of healthy kidneys (depending on the solute) and lower than that with haemodialysis (HD)) is due to rapid decrease of diffusive transport of solutes during a dwell due to the disappearance of the plasma-to-dialysate concentration gradient across the peritoneal membrane. The limited technique survival (median 3.7 years) is primarily due to the high incidence of recurrent infection of the peritoneal membrane (peritonitis) and exposure of the peritoneal membrane to very high, harmful glucose concentrations needed for osmotic fluid removal.

Both peritonitis and high glucose concentrations cause pathological changes of the peritoneal membrane and eventually ultrafiltration failure necessitating a switch to the more invasive and expensive HD treatment. To reduce the existing shortcomings of conventional PD, a novel continuous flow peritoneal dialysis system with dialysate regeneration (WEAKID) for PD was developed. WEAKID treatment is based on continuous recirculation of peritoneal dialysate via the single lumen peritoneal catheter with regeneration of spent dialysate by means of sorbent technology. The WEAKID nighttime system (weight: \~12 kg) is intended to be used for 8h per day (during the night) on a daily basis. Instead of performing 4-6 exchanges with fresh peritoneal dialysate per day, WEAKID uses one peritoneal dialysate filling which is continuously recirculated and regenerated. The continuous regeneration prevents saturation of the dialysate with toxins and thereby maintains a high plasma to dialysate concentration gradient which enhances diffusive transport of uremic toxins. In addition, the continuous recirculating flow of fluid along the peritoneal membrane is expected to increase the mass transfer area coefficient as observed in previous studies with continuous flow peritoneal dialysis, probably due to reduction of diffusion resistance, renewal of stagnant fluid layers at the tissue surface and an increase of the effective membrane area. Both the high plasma to dialysate concentration gradient and the increase in mass transfer contribute to an enhancement of the clearance. Another advantage of the WEAKID system is that the glucose peak load to peritoneum is lower than with traditional automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD) thanks to the buffering of the sorbents (sorbents adsorb glucose at the start, lowering the initial glucose peak, and release the glucose again at later stage) and the continuous recirculation.

The primary objective of this study is to assess the (short-term) safety of the WEAKID nighttime system in a limited number (n=12) of patients and sessions (6 sessions per patient).

Secondary objectives of this study are:

1. To evaluate the incidence of adverse events (AEs) and device deficiencies (DDs) other than serious adverse device effects (SADEs) and DDs that could have led to a serious adverse event (SAE) 2. To describe the characteristics of WEAKID treatment (i.e. number and duration of sessions, dialysate flow rates) 3. To evaluate the clinical condition and vital signs of the participants during WEAKID treatment 4. To evaluate the effectiveness of ultrafiltration (UF) in relation to glucose concentration during WEAKID treatment 5. To evaluate the efficacy of solute removal and base release of WEAKID treatment 6. To evaluate the evolution of plasma analytes during WEAKID treatment 7. To evaluate the evolution of dialysate effluent analytes of the WEAKID system 8. To evaluate the (technical) device performance of the WEAKID system by the number of device deficiencies, adverse device effects and changes in intraperitoneal pressure 9. To evaluate patient tolerance during WEAKID treatment 10. To evaluate the evolution of uremic symptoms during WEAKID treatment 11. To evaluate the effectiveness of using sorbents for dialysate regeneration and the effectiveness of continuous recirculating flow in relation to the efficacy of solute removal.

The WEAKID system will be tested in a clinical setting on 6 days over a period of 2 weeks. During the first week, the subjects will be treated with the nighttime system without sorbents for 4h (first day) or 8h (second and third day) during daytime. The second week, treatment will consist of the nighttime system with sorbents (also 4h (first day) or 8h (second and third day) during daytime).

This way, exposure to new components of the system is incremental and the effectiveness of the sorbents can be analyzed separately from the effect of continuous recirculating flow dialysis. A peritoneal equilibration test (PET) will be performed at baseline and follow-up. In addition, patients will collect 24h spent peritoneal dialysate and 24h urine followed by venous puncture for blood sampling 3 times prior to WEAKID treatment during standard PD.

• Adverse events (AEs) and device deficiencies (DDs) [Срок оценки: This will be assessed through study completion (four weeks in total per participant)]
• Number of WEAKID treatments [Срок оценки: The number of WEAKID treatments will be assessed for the study treatment period (2 weeks in total per participant)]
• Duration of WEAKID treatments [Срок оценки: This will be assessed for each WEAKID treatment throughout the study treatment period (2 weeks in total per participant)]
• Dialysate flow rates during WEAKID treatment [Срок оценки: This will be assessed during WEAKID treatment throughout the study treatment period (2 weeks in total per participant)]
• Evolution of blood pressure [Срок оценки: This will be assessed during WEAKID treatment at t=0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours (for 8-hour treatment), and 8 hours (for 8-hour treatment) throughout the study treatment period (2 weeks in total per participant)]
• Evolution of heart rate [Срок оценки: This will be assessed during WEAKID treatment at t=0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours (for 8-hour treatment), and 8 hours (for 8-hour treatment) throughout the study treatment period (2 weeks in total per participant)]
• Evolution of body temperature [Срок оценки: This will be assessed during WEAKID treatment at t=0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours (for 8-hour treatment), and 8 hours (for 8-hour treatment) throughout the study treatment period (2 weeks in total per participant)]
• Evolution of oxygen saturation [Срок оценки: This will be assessed during WEAKID treatment at t=0 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours (for 8-hour treatment), and 8 hours (for 8-hour treatment) throughout the study treatment period (2 weeks in total per participant)]
• Ultrafiltration volume [Срок оценки: This will be assessed for every WEAKID treatment throughout the study treatment period (2 weeks in total per participant)]
• Peak glucose concentration in the device effluent [Срок оценки: This will be assessed for every WEAKID treatment throughout the study treatment period (2 weeks in total per participant)]
• Ultrafiltration efficiency [Срок оценки: This will be assessed for every WEAKID treatment throughout the study treatment period (2 weeks in total per participant)]
• Removal of urea by the WEAKID system [Срок оценки: This will be assessed for every WEAKID treatment throughout the study treatment period (2 weeks in total per participant)]