Clinical trial NCT05309785: Safety and Efficacy of Canagliflozin in Advanced CKD
Official title: Safety and Efficacy of Canagliflozin in Advanced CKD
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: ESRD
CKD Stage 4
CKD Stage 5
Keywords: Canagliflozin
Advanced CKD
ESRD
Hemodialysis
Safety
Efficacy
SGLT-2 inhibitor
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2022-04-04
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: We will conduct a single center, prospective, single-arm, open-label interventional study in 2 cohorts.

Substudy 1: patients with advanced CKD, not yet on HD (N=36) Substudy 2: patients receiving HD (N=8)
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: The 26-week change in albuminuria compared to baseline, as assessed by the UACR.
timeFrame: 26 weeks
measure: 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.
timeFrame: 8 days
Secondary outcomes:
measure: Change in UACR with 300 mg (at 26 weeks) vs. 100 mg dose (at 12 weeks) vs. baseline
timeFrame: At 12 and 26 weeks
measure: Change in 24-hour ambulatory blood pressure (BP)
timeFrame: At 12 and 26 weeks
measure: Area under the plasma concentration versus time curve (AUC)
timeFrame: At 12 and 26 weeks
measure: Change in 6-minute walk distance from baseline
timeFrame: At 12 and 26 weeks
measure: Change in urinary excretion of sodium from baseline
timeFrame: At 12 and 26 weeks
measure: Neutrophil gelatinase-associated lipocalin (NGAL) levels
timeFrame: After ≥12 weeks of treatment with each dose
Other outcomes:
measure: Change in urinary excretion of phosphate from baseline
timeFrame: After ≥12 weeks of treatment with each dose
measure: Peak plasma concentration (Cmax)
timeFrame: 8 days
measure: Time to peak plasma concentration (tmax)
timeFrame: 8 days
measure: Trough plasma concentration (Cmin)
timeFrame: 8 days
measure: Effective half-life (t1/2)
timeFrame: 8 days
Locations:
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
Study officials:
affiliation: Research Institute of the McGill University Health Center
name: Thomas Mavrakanas, MD
role: PRINCIPAL_INVESTIGATOR
References: