ESRD, CKD (Chronic Kidney Disease) Stage 5D
Conditions
Keywords
SGLT-2 inhibitors, Canagliflozin, Ultrafiltration failure, Peritoneal fibrosis, Peritoneal dialysis
Brief summary
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.
Detailed description
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.
Interventions
Canagliflozin 300 mg once daily
Sponsors
McGill University Health Centre/Research Institute of the McGill University Health Centre
Canadian Institutes of Health Research (CIHR)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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.
Intervention model description
This is a phase II, proof-of-concept, placebo-controlled, double-blind, cross-over randomized clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in D4/D0 | 5 and 10 weeks from baseline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in ultrafiltration | 5 and10 weeks from baseline | 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. |
| Change in sodium dip/ sieving | 5 and 10 weeks from baseline | 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. |
| Change in small solute clearance | 5 and10 weeks from baseline | 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. |
| Canagliflozin levels in the dialysate | 5 and10 weeks from baseline | Canagliflozin levels in the dialysate at 5 and 10 weeks, as assessed by mass spectrometry |
| Change in small and middle solute clearance | 26 weeks from baseline | Change in small and middle solute clearance using weekly Kt/V urea, weekly creatinine clearance, clearance of β2-microglobulin, and modifications in PD prescription. |
| Change in effluent biomarker levels | 26 weeks from baseline | Change in effluent biomarker levels at 26 weeks from baseline. The panel of biomarkers includes interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), cancer antigen-125 (CA-125), plasminogen activator inhibitor-1 (PAI-1), and decoy recptor-2 (eDcR2), assessed by using enzyme-linked colorimetric immunoassays. |
| Change in residual kidney function | 26 weeks from baseline | Change in residual kidney function, as assessed by the 24h urine output and 24h native urea and creatinine clearance |
| Change in blood pressure | 26 weeks from baseline | Change in 24h-ambulatory blood pressure measurements at 26 weeks from baseline |
| 6-minute walk test | 26 weeks from baseline | Change in distance in the 6-minute walk test at 26 weeks from baseline |
| Change in dyspnea score | 26 weeks from baseline | Change in dyspnea score using the 7-point Likert scale and Visual analog scale questionnaire at 26 weeks from baseline |
| Change in quality of life | 26 weeks from baseline | Difference in quality of life using the Kidney Disease Quality of Life questionnaire at 26 weeks from baseline |
| Major adverse cardiovascular events | 26 weeks from baseline | Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure |
| Death from any cause | 26 weeks from baseline | Death from any cause |
| Safety outcomes | 26 weeks from baseline | Safety outcomes, including serious adverse events and any adverse events |
Countries
Canada
Contacts
CONTACTEfrosyne Tsirella
CONTACTNorka Rios
PRINCIPAL_INVESTIGATORThomas A. Mavrakanas, MD, MSc.
Research Institute-McGill University of Health Centre
Outcome results
None listed