Effect of Canagliflozin on Ultrafiltration & Fibrosis in Patients on Peritoneal Dialysis

Phase 2Not Yet RecruitingNCT06913647

McGill University Health Centre/Research Institute of the McGill University Health Centre30 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Change in D4/D0

Change in the ratio of intraperitoneal glucose at 0 and 4h post infusion (D4/D0 ratio) in a standardized PET with canagliflozin, compared with placebo.

Time frame: 5 and 10 weeks from baseline

Secondary Outcomes

Change in ultrafiltration

Change in ultrafiltration, as assessed by the volume of drain after a 4h dwell with 2 L of a 2.5% dextrose solution minus the volume infused, with canagliflozin compared with placebo.

Time frame: 5 and10 weeks from baseline

Change in sodium dip/ sieving

Change in sodium dip/ sieving, calculated as the absolute difference in dialysate sodium at 0 and 1h post infusion in a standardized PET, with canagliflozin compared with placebo.

Time frame: 5 and 10 weeks from baseline

Change in small solute clearance

Change in small solute clearance, as assessed by the dialysate-to-plasma (D/P) creatinine and urea at the end of a 4h-dwell, with canagliflozin compared with placebo.

Time frame: 5 and10 weeks from baseline

Canagliflozin levels in the dialysate

Canagliflozin levels in the dialysate at 5 and 10 weeks, as assessed by mass spectrometry

Time frame: 5 and10 weeks from baseline

Change in small and middle solute clearance

Change in small and middle solute clearance using weekly Kt/V urea, weekly creatinine clearance, clearance of β2-microglobulin, and modifications in PD prescription.