Safety and Efficacy of Canagliflozin in Advanced CKD

ESRD Clinical Trial

— SIP-AKiD  

Official title:

Safety and Efficacy of Canagliflozin in Advanced CKD

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05309785
• Other study ID #: 2022-8410
• Status: Recruiting
• Phase: Phase 4
• Start date: November 24, 2022
• Est. completion date: February 1, 2025

Study information

• Verified date: December 2022
• Source: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Contact: Norka Rios
• Phone: 514-934-1934
• Email: norka.rios[@]muhc.mcgill.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 44
• Est. completion date: February 1, 2025
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• CKD Stage 4
• CKD Stage 5
• ESRD

Intervention

Drug:
• Invokana 300 mg and 100 mg tablet
Substudy 1 Patients who fulfill the inclusion criteria and consent to participate will receive canagliflozin 100 mg po daily for 12+2 weeks (phase 1). For participants who have tolerated the drug, canagliflozin will be increased to 300 mg po daily for an additional 12+2 weeks (phase 2) and then stopped. If not tolerated, the dose will be reduced to 100 mg until the end of follow-up. Each phase of 12 weeks is followed by a 2-week window to ascertain surrogate efficacy outcomes. Substudy 2 Patients who fulfill the inclusion criteria and consent to participate will receive canagliflozin 100 mg po daily for 9 days.

Locations

Country	Name	City	State
Canada	McGill University Health Center	Montreal	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
McGill University Health Centre/Research Institute of the McGill University Health Centre

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in urinary excretion of phosphate from baseline	For substudy 1	After =12 weeks of treatment with each dose
Other	Peak plasma concentration (Cmax)	For substudy 2	8 days
Other	Time to peak plasma concentration (tmax)	For substudy 2	8 days
Other	Trough plasma concentration (Cmin)	For substudy 2	8 days
Other	Effective half-life (t1/2)	For substudy 2	8 days
Primary	The 26-week change in albuminuria compared to baseline, as assessed by the UACR.	For substudy 1	26 weeks
Primary	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	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
Secondary	Change in 24-hour ambulatory blood pressure (BP)	For substudy 1	At 12 and 26 weeks
Secondary	Area under the plasma concentration versus time curve (AUC)	For substudy 1	At 12 and 26 weeks
Secondary	Change in 6-minute walk distance from baseline	For substudy 1	At 12 and 26 weeks
Secondary	Change in urinary excretion of sodium from baseline	For substudy 1	At 12 and 26 weeks
Secondary	Neutrophil gelatinase-associated lipocalin (NGAL) levels	For substudy 1	After =12 weeks of treatment with each dose