Canagliflozin in Advanced Renal Disease With MRI Endpoints (CARe-MRI)

This is a phase II, proof of concept, placebo-controlled, randomized clinical trial, assessing the effect of canagliflozin on cardiac structure and function in patients with advanced renal disease, including those on maintenance dialysis.

Our primary aim is to determine the effect of canagliflozin on cardiac structure and function in patients with advanced chronic kidney disease (CKD), compared with placebo. We hypothesize that canagliflozin will improve left ventricular (LV) hypertrophy in patients with advanced CKD. Our secondary aims are to describe the effect of canagliflozin on other cardiac magnetic resonance imaging parameters and surrogate markers of efficacy in this population.

Study Overview

• Status: Not yet recruiting
• Conditions: ESRD, CKD Stage 4, CKD Stage 5
• Intervention / Treatment: Drug: Canagliflozin 300Mg Tab; Drug: Placebo

Detailed Description

Patients with advanced renal disease, including those on maintenance dialysis, will be randomized to receive canagliflozin 300 mg orally once daily or matching placebo for one year. For patients who are not yet on renal replacement therapy, the study medication will be continued when they transition to dialysis or when they get a kidney transplant.

The prescription of all other medications, including dialysis prescription for dialysis-dependent patients, will be left to the treating physician's discretion. We will discourage changes to medications during follow-up unless deemed clinically necessary. All medications changes will be recorded at each visit.

Symptoms and adverse events will be monitored closely. Participants who experience adverse events classified as severe and probably or definitely related to the study medication will be withdrawn. Patients who develop intercurrent illnesses, are hospitalized, or have surgery (urgent or elective) will temporarily discontinue the drug.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Efrosyne Tsirella, Research Assistant; Phone Number: 37836 514-934-1934; Email: efrosyne.tsirella@muhc.mcgill.ca
• Study Contact Backup: Name: Norka Rios, Research Nurse; Phone Number: 35207 514-934-1934; Email: norka.rios@muhc.mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• advanced CKD, defined as an estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73m2 not yet on dialysis OR incident hemodialysis or peritoneal dialysis patients (i.e., who were started on dialysis in the last 6 months)*

  * For patients who were not previously followed in a CKD clinic and for whom it is not clear whether dialysis was initiated after an acute deterioration in renal function that is potentially reversible, at least 90 days of dialysis will be required prior to enrolment. This criterion only applies to patients for whom baseline eGFR prior to the acute event was ≥ 20 ml/min/1.73m2 or was unknown. The average creatinine values over the last 12 months will be used to calculate baseline eGFR.

• LV hypertrophy, defined as LV mass > 130 g/m2 in men and 100 g/m2 in females OR hospitalization for heart failure or atherosclerotic cardiovascular (CV) disease in the last 12 months OR type 2 diabetes OR UACR > 200 mg/g on a morning spot urine collection (this criterion is not applicable to patients who are on dialysis and have a urine output < 500 ml per day).

Exclusion Criteria:

• type 1 diabetes,
• history of euglycemic ketoacidosis,
• known hypersensitivity to sodium-glucose cotransporter-2 (SGLT-2) inhibitors,
• hemodynamic instability (defined as current use of parenteral inotropic agents),
• systolic BP < 90 mmHg,
• severe liver cirrhosis (Child-Pugh class C stage),
• acute hepatitis (defined as an alanine aminotransferase > 2.0 times the upper limit of normal [ULN] or total bilirubin >1.5 times the ULN),
• recurrent severe genital or urine infections,
• patients receiving digoxin, phenobarbital, phenytoin, rifampin, or ritonavir if these agents cannot be safely discontinued (due to inhibition of the P-glycoprotein mediated efflux of digoxin by canagliflozin or induction of Uridine 5'-diphospho-glucuronosyltransferase enzymes by the other agents),
• cardiac MRI-incompatible cardiac devices (cardiac pacemaker, implanted cardiac defibrillator, internal pacing wires, Swan-Ganz catheter, aneurysm clips),
• claustrophobia,
• cochlear implants,
• metallic body in the eyes,
• pregnancy or breastfeeding,
• and any other medical condition considered to be a contra-indication by the study physician.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo tablet	Drug: Placebo; Patients will get 1 pill of placebo daily for one year.
Active Comparator: Canagliflozin (Invokana) 300 mg tablet	Drug: Canagliflozin 300Mg Tab; Patients will get 1 pill of Canagliflozin 300 mg daily for one year.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular mass to volume ratio (LVMV) from baseline to 12 months, as assessed by cardiac MRI compared with placebo	Assessed on cardiac magnetic resonance imaging (MRI)	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death from any cause		12 months
Difference in distance in the 6-minute walk test at 12 months from baseline		12 months
Difference in dyspnea score at 12 months from baseline	Using the 7-point Likert scale and Visual analog scale questionnaire.	12 months
Difference in quality of life at 12 months from baseline	Using the Kansas City Cardiomyopathy questionnaire.	12 months
Change in urine albumin to creatinine ratio (UACR) from baseline (only for patients not yet on maintenance dialysis) at 6 and 12 months		6 months and 12 months
Change in iron profile		6 months and 12 months
Change in tubular injury biomarkers	For patients not yet on maintenance dialysis.	6 months and 12 months
Change in dose of erythropoietin-stimulating agents at 12 months from baseline		12 months
Changes in left ventricular (LV) and atrial volumes from baseline to 12 months compared with placebo	Assessed on cardiac MRI	12 months
LV strain parameter changes from baseline to 12 months compared with placebo	Long-axis fractional shortening on cardiac MRI	12 months
Changes in myocardial edema and fibrosis from baseline to 12 months compared with placebo	Use of magnetic resonance imaging T2 and T1 maps, respectively (software cvi42).	12 months
Change in myocardial oxygenation reserve from baseline to 12 months compared with placebo	Use of oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) sequences.	12 months
Composite of major adverse cardiovascular events	Cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure.	12 months
Progression to kidney failure (only for patients not yet on maintenance dialysis).	Initiation of maintenance hemodialysis, peritoneal dialysis, or renal transplantation.	12 months
Change in N-terminal pro b-type natriuretic peptide (NT-proBNP)		6 months and 12 months
Change in 24-hour ambulatory blood pressure at 12 months from baseline		12 months
Composite of serious adverse events	Severe hyperkalemia (>6 mmol/l), acute kidney injury (≥ stage 2 using the AKIN criteria), and euglycemic ketoacidosis.	12 months

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Heart and Stroke Foundation of Canada
• Investigators: Principal Investigator: Thomas Mavrakanas, MD, Research Institute of the McGill University Health Center

Study record dates

Study Major Dates

• Study Start (Estimated): March 30, 2024
• Primary Completion (Estimated): March 30, 2028
• Study Completion (Estimated): March 30, 2029

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 27, 2023

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Canagliflozin, Advanced CKD, ESRD, Hemodialysis, Peritoneal dialysis, Cardiac MRI, SGLT-2 inhibitors
• Additional Relevant MeSH Terms: Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Canagliflozin
• Other Study ID Numbers: 2024-10313

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No