Safety and Efficacy of Canagliflozin in Advanced CKD

Study Overview
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Brief Summary
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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
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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.

Official Title
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Safety and Efficacy of Canagliflozin in Advanced CKD

Conditions
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ESRD, CKD Stage 4, CKD Stage 5

Intervention / Treatment
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* Drug: Invokana 300 mg and 100 mg tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|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.|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Canagliflozin, Advanced CKD, ESRD, Hemodialysis, Safety, Efficacy, SGLT-2 inhibitor