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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.
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.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Invokana 300 mg and 100 mg tablet | Drug | 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. |
|
| 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 |
| 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 |
| 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 |
Inclusion Criteria:
(Substudy 1- SIP-AKiD-1):
(Substudy 2- SIP-AKiD-2):
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Thomas Mavrakanas, MD | Research Institute of the McGill University Health Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McGill University Health Center | Montreal | Quebec | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40952584 | Derived | Elenjickal EJ, Mavrakanas TA, Gritsas A, Suri RS, Marsot A. Population Pharmacokinetic Modeling of Canagliflozin in Advanced Chronic Kidney Disease. Clin Pharmacokinet. 2025 Nov;64(11):1693-1708. doi: 10.1007/s40262-025-01571-8. Epub 2025 Sep 15. |
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| ID | Term |
|---|---|
| D007676 | Kidney Failure, Chronic |
| D051436 | Renal Insufficiency, Chronic |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D000068896 | Canagliflozin |
| D013607 | Tablets |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D006573 | Heterocyclic Compounds, 1-Ring |
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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)
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| 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 |
| 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 |
| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 |
| Heterocyclic Compounds |
| D005960 | Glucosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |