This is a phase II, proof-of-concept, placebo-controlled, double-blind, cross-over randomized clinical trial, assessing the effect of canagliflozin on peritoneal membrane function in patients on PD.

The primary aim of this trial is to determine the short-term effects of canagliflozin, an SGLT-2 inhibitor, on glucose absorption by the peritoneal membrane and on ultrafiltration, as assessed by a standardized peritoneal equilibrium test. The secondary aims are to determine the effect of canagliflozin on solute clearance and on effluent biomarkers of inflammation, angiogenesis, and fibrosis at 26 weeks. We hypothesize that canagliflozin will prevent glucose absorption by the peritoneal membrane, as compared with placebo, and will attenuate the development of inflammation, angiogenesis, and fibrosis of the peritoneal membrane, as assessed by relevant biomarkers in the dialysate.

Patients with kidney failure on peritoneal dialysis who meet the study inclusion criteria will be randomized at a 2:2:1 ratio to one of the following arms:

(i) canagliflozin 300 mg once daily for 5 weeks (double-blind), followed by matching placebo once daily for 5 weeks (double-blind), followed by canagliflozin 300 mg once daily for 16 weeks (open label).

(ii) placebo once daily for 5 weeks (double-blind), followed by canagliflozin 300 mg once daily for 5 weeks (double-blind), followed by canagliflozin 300 mg once daily for 16 weeks (open label).

(iii) standard of care, with no active treatment, for 26 weeks (open label). Four in-person and one phone study visits have been scheduled: baseline visit, week 5, week 10, week 18 (phone visit), and week 26. A standardized peritoneal equilibration test (PET) will be performed at each of the in-person visits. There will also be two safety assessments at weeks 2 and 7, which will consist of blood tests. Patients who develop intercurrent illnesses or are hospitalized may temporarily discontinue the study drug if deemed appropriate by the treating physician.

Inclusion Criteria:

• Adult patients with kidney failure on PD (both incident and prevalent) who are on a stable prescription of dextrose-based solutions for at least 3 months.
• Only high or high-average transporters, as classified by PET, will be included.

Exclusion Criteria:

• History of euglycemic ketoacidosis
• Known hypersensitivity to canagliflozin
• Active peritonitis or tunnel infection
• Kidney transplant scheduled in the next 6 months
• Severe liver cirrhosis (Child-Pugh class C stage)
• Recurrent severe genital or urine infections
• Patients receiving digoxin, phenobarbital, phenytoin, rifampin, or ritonavir if these agents cannot be safely discontinued
• Pregnancy or breastfeeding

An anonymized dataset may be shared with other investigators in the future after the publication of primary results of this clinical trial. Any request for data sharing will have to be approved by the clinical trial steering committee after having examined the data sharing proposal. A data use agreement will be required through the Contracts Office of the Research Institute of McGill University Health Center.

The data may become available twelve months after the end of the study.

Any request for data sharing will have to be approved by the clinical trial steering committee after having examined the data sharing proposal. A data use agreement will be required through the Contracts Office of the Research Institute of McGill University Health Center.

The cross-over part of the study for the assessment of the primary outcome will be blinded (first 10 weeks for arms 1 & 2). Canagliflozin pills will be encapsulated. For placebo, cellulose will be used to fill identical capsules.