SIP-AKiD: Safety and Efficacy of Canagliflozin in Advanced CKD

Sponsor

McGill University Health Centre/Research Institute of the McGill University Health Centre (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05309785

Collaborator

(none)

Enrollment

Location

30.1

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
ESRD CKD Stage 4 CKD Stage 5	Drug: Invokana 300 mg and 100 mg tablet	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

44 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

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)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)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Safety and Efficacy of Canagliflozin in Advanced CKD

Anticipated Study Start Date :

Aug 1, 2022

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Feb 1, 2025

Outcome Measures

Primary Outcome Measures

The 26-week change in albuminuria compared to baseline, as assessed by the UACR. [26 weeks]
For substudy 1
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. [8 days]
For substudy 2

Secondary Outcome Measures

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	McGill University Health Center Research Institute	Montreal	Quebec	Canada

Sponsors and Collaborators

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 Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Thomas Mavrakanas, Assistant Professor, Junior Scientist, McGill University Health Centre/Research Institute of the McGill University Health Centre

ClinicalTrials.gov Identifier:

NCT05309785

Other Study ID Numbers:

2022-8410

First Posted:

Apr 4, 2022

Last Update Posted:

Apr 4, 2022

Last Verified:

Mar 1, 2022

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Thomas Mavrakanas, Assistant Professor, Junior Scientist, McGill University Health Centre/Research Institute of the McGill University Health Centre

Additional relevant MeSH terms:

Canagliflozin

Study Results

No Results Posted as of Apr 4, 2022