Safety and Efficacy of Canagliflozin in Advanced CKD (SIP-AKiD)

The study objective is to characterize the pharmacokinetics (PK), pharmacodynamics, and surrogate measures of efficacy for canagliflozin in patients with advanced CKD, including those receiving HD.

As the CV and renoprotective effects of SGLT-2 inhibitors appear to be independent of glycemic control, the investigators hypothesize that canagliflozin will reduce albuminuria in patients with advanced CKD in the same manner as observed in patients with higher eGFR. The investigators also hypothesize that the 300 mg dose will be equally safe as the 100 mg dose but will have greater efficacy, given data which suggests efficacy correlates with drug exposure in patients without CKD.

Given its negligible renal elimination, the investigators hypothesize that exposure to canagliflozin 100 mg at steady state will not exceed the standard bioequivalence boundary of 80-125% in patients receiving HD, compared with published estimates with the 300 mg dose at steady state in individuals with preserved kidney function.

Study Overview

• Status: Recruiting
• Conditions: ESRD; CKD Stage 4; CKD Stage 5
• Intervention / Treatment: Drug: Invokana 300 mg and 100 mg tablet

Detailed Description

Substudy 1:

Patients with eGFR<30 ml/min/1.73m2 and urine albumin to creatinine ratio (UACR)>200 mg/g not receiving dialysis will receive canagliflozin 100 mg po daily for 12 weeks (phase 1). For participants who have tolerated the drug, canagliflozin will be increased to 300 mg po daily for an additional 12 weeks (phase 2) and then stopped. Each phase will be followed by a 2-week window to ascertain surrogate efficacy outcomes.

Substudy 2:

Adult patients on HD for at least 3 months without significant residual renal function will receive canagliflozin 100 mg po daily for 9 days.

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Norka Rios; Phone Number: 514-934-1934; Email: norka.rios@muhc.mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada
      • Recruiting
      • McGill University Health center
      • Contact: Norka Rios; Phone Number: 5149341934

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

(Substudy 1- SIP-AKiD-1):

• adult patients with eGFR <30 ml/min/1.73m2
• urine albumin to creatinine ratio (UACR) >200 mg/g
• not receiving dialysis.

(Substudy 2- SIP-AKiD-2):

• adult patients on hemodialysis for at least 3 months
• without significant residual renal function, defined as a urine output <250 ml/24h.

Exclusion Criteria:

• Age <18 years
• type 1 diabetes
• history of euglycemic ketoacidosis
• known hypersensitivity to SGLT-2 inhibitors
• recurrent severe genital or urinary tract infections
• history of atraumatic amputation, gangrene, or active skin ulcer
• use within the last 48 h of an SGLT-2 inhibitor or a combined SGLT-1 and SGLT-2 inhibitor
• liver disease defined by an ALT > 3.0 times the upper limit of normal [ULN] or total bilirubin >1.5 times the ULN or liver cirrhosis of any stage
• gastrointestinal surgery or gastrointestinal disorder that could interfere with trial medication absorption
• pregnancy
• currently breastfeeding
• any other clinical condition that would jeopardize patient safety while participating in this trial.
• Patients receiving digoxin, phenobarbital, phenytoin, rifampin, or ritonavir will be excluded if these agents cannot be safely discontinued

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The 26-week change in albuminuria compared to baseline, as assessed by the UACR.	For substudy 1	26 weeks
The drug exposure at steady-state with 100 mg, as expressed by the AUC0-24, compared to published estimates with the 300 mg dose in patients with preserved renal function.	For substudy 2	8 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in UACR with 300 mg (at 26 weeks) vs. 100 mg dose (at 12 weeks) vs. baseline	For substudy 1	At 12 and 26 weeks
Change in 24-hour ambulatory blood pressure (BP)	For substudy 1	At 12 and 26 weeks
Area under the plasma concentration versus time curve (AUC)	For substudy 1	At 12 and 26 weeks
Change in 6-minute walk distance from baseline	For substudy 1	At 12 and 26 weeks
Change in urinary excretion of sodium from baseline	For substudy 1	At 12 and 26 weeks
Neutrophil gelatinase-associated lipocalin (NGAL) levels	For substudy 1	After ≥12 weeks of treatment with each dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urinary excretion of phosphate from baseline	For substudy 1	After ≥12 weeks of treatment with each dose
Peak plasma concentration (Cmax)	For substudy 2	8 days
Time to peak plasma concentration (tmax)	For substudy 2	8 days
Trough plasma concentration (Cmin)	For substudy 2	8 days
Effective half-life (t1/2)	For substudy 2	8 days

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Investigators: Principal Investigator: Thomas Mavrakanas, MD, Research Institute of the McGill University Health Center

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2022
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: March 14, 2022
• First Submitted That Met QC Criteria: March 24, 2022
• First Posted (Actual): April 4, 2022

Study Record Updates

• Last Update Posted (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: December 5, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Safety; Efficacy; ESRD; Hemodialysis; Canagliflozin; Advanced CKD; SGLT-2 inhibitor
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Canagliflozin
• Other Study ID Numbers: 2022-8410

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No