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Clinical validation of miniature wearable dialysis machine

Periodic Reporting for period 2 - WEAKID (Clinical validation of miniature wearable dialysis machine)

Reporting period: 2018-07-01 to 2019-06-30

Problem:
Despite being life-saving, existing dialysis techniques have major shortcomings. In conventional peritoneal dialysis (PD) and hemodialysis (HD) blood purification and water removal are inadequate: performance <10% (of healthy kidneys). This contributes to severe health problems (cardiovascular morbidity ~10-30x higher) and high mortality (15‐20% per year). Quality of life is poor. Due to inadequate removal of phosphate and potassium, patients need phosphate and potassium binding drugs. The daily pill burden is one of the highest reported in any chronic disease state (>25/day for 25% of the patients). A strict diet is required, potentially compromising the nutritional status.
PD has advantages over HD. Patients can perform PD at home instead of going to a center 3-4x/week. Although lower in performance, PD results in more stable toxin concentrations in contrast to the saw-tooth pattern in intermittent HD, which aggravates toxicity. Residual renal function, associated with a survival benefit, is better preserved with PD than with HD. PD is a blood free system using a relatively simple access to the abdomen, which is less complex than the HD vascular access. Costs for PD (~50k€/patient/year) are ~40% lower than those for in-center HD.
Still, PD is not popular. Drawbacks are: low blood purification low, time-consuming exchange procedures and high risk of peritonitis (infection). Patients switch to HD after median 3.7 years, because of recurrent peritonitis or deterioration of the peritoneal membrane, due to exposure to high dialysate glucose concentrations (generating osmotic gradient for fluid extraction).

Importance for society:
WEAKID offers a new treatment modality, expected to have significant medical and economic impact. Currently ~80% of patients are treated by HD in a center. Since WEAKID overcomes the main problems of PD, we expect WEAKID to enhance popularity of PD. The improved technique durability may cause a shift from in-center HD to home-based WEAKID therapy, at considerably reduced cost. Better blood purification is expected to improve health and well-being, allowing patients to stay active with social and economic quality of life.

Objectives:
WEAKID (Wearable Artificial Kidney) aims to clinically validate a new method for PD, prove patient acceptability and gain accreditation for the system to be used by patients. WEAKID is based on continuous flow PD using (currently standard) single lumen fluidic access (abdomen). Peritoneal dialysate is continuously circulated and refreshed by a wearable sorption unit, removing toxins from the dialysate. The technology has been demonstrated in preclinical research and is suited both for wearable dialysis (16 hours/day) and portable dialysis (8 hours/night). WEAKID enhances blood purification 2-3 fold with only one dialysate exchange per day (vs 4-6/day with standard PD), reducing peritonitis risk. High (toxic) dialysate glucose concentrations (conventional PD) are no longer required for fluid extraction, slowing down functional deterioration of the peritoneal membrane. Data are continuously logged to a remote monitoring webportal.

Objectives:
- Validating the WEAKID wearable/portable dialysis system in a clinical setting and preparing it for CE-marking.
- Demonstrating the clinical efficacy and safety of the system in an early feasibility first-in-human trial and a pilot crossover trial in PD patients.
The partners effectively cooperated and contributed to timely fulfilment of the deliverables during the first year. The clinical trials and documentation were prepared and the device prototype was built and tested. However, in M10 the Technical Committee decided to change the device technology, because new advanced cytotoxicity tests during the accreditation procedure had revealed adverse effects even though extensive prior biocompatibility testing had been reassuring.
This was a foreseen risk and a mitigation plan was set up including a system modification for the device and related updates in the treatment plan. This required repeating a substantial part of the ISO10993 evaluation including subchronic toxicity testing (rodent study) and in vivo large animal tests (pig). It took 9 months to prove safe and sound patient benefit.

The system technology update comprises a wearable sorbent based device for both day and night, which is combined with a dialysate reservoir during the night only. After repeating the extensive test program, in vitro and in vivo, with the updated technology, it now meets the predefined system requirements: approx. 2-3 fold increase in uremic toxin clearance, 40% lower glucose concentrations and 2-3-fold fewer connections than conventional PD. The system has proven to be safe at a pleasantly low-risk level while offering high performance and ease of use at the same time.

The stringent peritoneal dialysate endotoxin requirements presented another challenge and a
new subcontractor for the sterilization process had to be found. They agreed on realizing the small series needed for the trial at this high level of sterilization after which the technology update was completed successfully and the original WEAKID program was resumed.

Preparations for the clinical trials were completed earlier on. Some documents (e.g. Investigator’s Brochure and IMDD) have been updated with the results of the renewed verification tests. Device and documentation are now ready for the accreditation procedure by the technical department and the Medical Ethics Committee.

The mitigation plan included a revised planning of Deliverables and Milestones.
However the delay due to mitigation actions was not accepted by the EC and activities are currently on hold.
At present, only a small percentage of dialysis patients uses PD. As WEAKID eliminates the main drawbacks of current PD, it may increase popularity of PD and may cause a shift in the dialysis world from HD to PD which will significantly reduce costs (~40k€/patient/year). The WEAKID system is expected to be 2-3 times as effective as current PD thanks to the technique of continuous refreshment of peritoneal dialysate. This prevents concentrations of toxins to build up in the peritoneal cavity (1) and enables to maintain a high diffusion gradient across the peritoneal membrane (2). Glucose concentrations can be low, because there is no static dwell time and a constant osmotic gradient across the peritoneal membrane is maintained (low osmotic stress). Existing PD systems use high glucose concentrations that eventually leads to deterioration of the peritoneal membrane, as chronic exposure to high glucose concentrations is toxic. As conventional PD is only effective for median 3.7 years, WEAKID has been developed with long peritoneal membrane survival in mind. Both types of existing dialysis, HD and PD, save lives but also require patients to take many supplementary drugs and live with chronic health issues. WEAKID will improve this situation significantly. By de-skilling the administration of dialysis, treatment can be offered to anyone with the competence to exchange cartridges and follow simple hygiene regimes. The embedded sensors and remote monitoring (webportal) capability of WEAKID further reduce the need for patients to be regularly treated in a clinical setting. Patients will be provided with information on their condition and medical professionals can directly monitor their health and device performance.
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