Clinical Validation of a Continuous flow Peritoneal Dialysis System with Dialysate Regeneration

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 APD and 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.

Primary objective:
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
1. To evaluate the incidence of AE*s and DD*s other than SADE*s and DD*s that
could have led to an 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.

First-in-human, prospective, open-label, non-randomized, three-center,
single-arm study (proof of concept).

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.

Patients might experience discomfort due to the need to come to the hospital on
11 days, regular venous puncture for blood sampling (max. twice daily, total
volume of ~100 mL during the study period of 4 weeks), 24h PD fluid collection
(3 days at home), 24h urine collection (3 days at home, daily during WEAKID
treatment days), and possibly due to (unknown) undesirable effects related to
treatment with the WEAKID system (e.g. abdominal discomfort).

WEAKID aims to improve the existing shortcomings of conventional PD by offering
enhanced clearance, effective ultrafiltration at lower glucose concentrations,
and by reducing the number of (time-consuming) exchanges and number of
(dis)connections of the peritoneal catheter and thereby the risk of
peritonitis. As a result of the lower risk of peritonitis and reduced glucose
exposure, WEAKID may preserve the integrity of the peritoneal membrane and
prolong technique survival. Although WEAKID was found safe in preclinical
testing and the risk-evaluation concluded that all risks were reduced to an
acceptable level, treatment with the WEAKID system may theoretically have
undesirable effects/risks including abdominal discomfort or even (mechanical)
irritation of the peritoneum due to the rapid cycling of peritoneal dialysate
into- and out of the peritoneal cavity, peritonitis due to bacterial
contamination, disturbance of acid-base balance, and disturbance of fluid and
electrolyte balance. WEAKID may also include risks which are unknown, i.e.
which were not identified on a theoretical ground or during the risk
evaluation. These risks include infrequent events which can only be identified
during prolonged exposure of a sufficiently large population and effects which
only manifest after prolonged treatment with the WEAKID system.
Risks have been minimized to the greatest extent feasible by taking appropriate
measures. Accordingly, the structured risk analysis showed that all risks,
after appropriate measures, were minimized to an acceptable level. The
preclinical biological evaluation showed no evidence of cytotoxicity in vitro
or acute and subchronic systemic toxicity in vivo (see IB). The following
measures are taken to minimize risk to patients during the study:
(1) the study is designed to minimize risk to patients (e.g. the small sample
size minimizes the number of patients at risk, the eligibility criteria reduce
risks to patients, the consecutive treatment of at least the first two patients
at each site allows for a thorough safety evaluation by the study team before
the next patients receive WEAKID treatment, patients* clinical condition and
biochemistry and haematology will be closely monitored in a clinical setting).
(2) All AE's and DD's that might have led to an (S)AE will be documented and
assessed by the (local) investigational study team, and all reportable events
(SADE's and DD's that might have led to an SAE if appropriate action had not
been taken) will be reported to the sponsor within 3 calendar days after
awareness. In case of a reportable event which indicates imminent risk of
death, serious injury, or serious illness and that requires prompt remedial
action, any next WEAKID treatment will be postponed. WEAKID treatments will be
resumed once the sponsor 1) has discussed the event with the Medical Monitor
and DSMB, 2) decided that it is safe to continue, and 3) decided whether the
concerning subject must be withdrawn from the study or not. In case the sponsor
decides that a (temporary) halt of the study is required, the MREC and the NCA
shall be informed as applicable, and restart of the study (after appropriate
measures have been taken to prevent such an event from happening again) shall
only occur after the MREC approved the restart.
(3) Dialysate flow rate will be reduced if necessary to prevent abdominal
discomfort or pain.
(4) To prevent peritonitis, all disconnections of the peritoneal catheter and
sampling procedures will be performed under strict hygienic operating
procedures by trained personnel.
(5) In case of hypervolemia due to insufficient ultrafiltration it can be
decided to (temporary) discontinue WEAKID treatment and resume conventional PD
to remove excess fluid.
(6) Study personnel will receive appropriate training on use of the WEAKID
system and study procedures.
(7) The WEAKID system is equipped with sensors and alarms to detect device
deficiencies.
(8) Pregnancy testing will be performed in all female patients <55 years and
reliable contraception will be recommended to prevent the possibility of fetal
exposure to unknown teratogenic effects of WEAKID treatment.