Canagliflozin for Kidney Disease

(CARe-MRI Trial)

Overseen By Efrosyne Tsirella, Research Assistant

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Must not be taking: Digoxin, Phenobarbital, Phenytoin, others

Disqualifiers: Type 1 diabetes, Hepatitis, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

92 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests canagliflozin, a medication, to determine its potential to improve heart health in individuals with severe kidney disease. Researchers aim to discover if canagliflozin can reduce heart muscle thickening, a common issue in those with kidney problems. The trial compares canagliflozin to a placebo (a pill with no active drug) to assess effectiveness. Suitable participants include those with advanced chronic kidney disease who also have heart issues or type 2 diabetes. As a Phase 2 trial, this research focuses on evaluating canagliflozin's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications like digoxin, phenobarbital, phenytoin, rifampin, or ritonavir if they cannot be safely discontinued. For other medications, the protocol does not specify, so it's best to discuss with the study team.

Is there any evidence suggesting that canagliflozin is likely to be safe for humans?

Research shows that canagliflozin is generally safe for people with kidney and heart problems. Studies have found that the drug safely lowers the risk of kidney failure and heart issues. People with various levels of kidney function, including those with severe kidney disease, have typically tolerated the drug well. Even in older adults, no major safety problems have been reported.

These findings suggest that canagliflozin might be safe for those considering participation in a clinical trial for kidney disease. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for kidney disease?

Researchers are excited about canagliflozin for kidney disease because it works differently from standard treatments like ACE inhibitors or ARBs. Most treatments focus on managing blood pressure or blood sugar levels, but canagliflozin targets the kidneys directly. It works by blocking a protein called SGLT2, which helps to reduce kidney damage by lowering excess sugar reabsorption and improving kidney function. This unique approach not only helps protect the kidneys but also may provide additional heart benefits, making it a promising option for those with kidney disease.

What evidence suggests that canagliflozin might be an effective treatment for advanced chronic kidney disease?

Research has shown that canagliflozin, which participants in this trial may receive, may help treat kidney disease, especially in people with type 2 diabetes. Studies have found that this medication can lower the risk of kidney failure and heart problems. In one study, patients taking canagliflozin had a 32% lower risk of reaching end-stage kidney disease. This finding suggests that canagliflozin might improve kidney health in people with severe kidney disease. While the main focus is on its potential heart benefits for those with kidney disease, the evidence for its kidney benefits remains promising. ^{1 2 6 7 8}

Who Is on the Research Team?

Thomas Mavrakanas, MD

Principal Investigator

Research Institute of the McGill University Health Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced chronic kidney disease (CKD) not yet on dialysis or who started dialysis in the last 6 months. Participants must have severe reduction in kidney function, heart muscle thickening, recent hospitalization for heart issues, type 2 diabetes, or significant protein in urine. Those recently starting dialysis need a stable course of at least 90 days.

Inclusion Criteria

I've been on dialysis for at least 90 days and my kidney function was not severely low before it worsened suddenly.

I have a heart condition, diabetes, or specific kidney issues not related to dialysis.

My kidney function is very low, and I either just started dialysis or haven't yet.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive canagliflozin 300 mg orally once daily or matching placebo for one year

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Canagliflozin

Trial Overview

The study tests if Canagliflozin improves heart muscle thickness and function compared to a placebo in people with severe CKD. It's randomized: participants are put into the Canagliflozin group or placebo group by chance.

How Is the Trial Designed?

Group I: Canagliflozin (Invokana) 300 mg tablet Active Control 1 Intervention

Group II: Placebo tablet Placebo Group 1 Intervention

Canagliflozin is already approved in European Union, United States for the following indications:

Approved in European Union as Invokana for:

• Type 2 diabetes mellitus
• Cardiovascular risk reduction

Approved in United States as Invokana for:

• Type 2 diabetes mellitus
• Cardiovascular risk reduction
• Diabetic kidney disease

Who Is Running the Clinical Trial?

McGill University Health Centre/Research Institute of the McGill University Health Centre

Lead Sponsor

Trials

476

Recruited

170,000+

Heart and Stroke Foundation of Canada

Collaborator

Trials

131

Recruited

72,600+

Published Research Related to This Trial

Canagliflozin is effective in improving glycemic control in adults with type 2 diabetes, specifically by inhibiting SGLT2 to increase urinary glucose excretion, with a focus on patients having a baseline eGFR of 45 mL/min/1.73 m² or higher.

The safety analyses conducted during the clinical development of canagliflozin provided a comprehensive understanding of its impact on renal function, allowing for informed dosing recommendations in patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. Khurana, M., Vaidyanathan, J., Marathe, A., et al.[2022]

Canagliflozin, an SGLT2 inhibitor, effectively lowers blood sugar levels and HbA1c by promoting glucose excretion in urine, with an average HbA1c reduction of 0.75% when used alongside other diabetes treatments.

While canagliflozin is generally safe, it can cause genital infections and urinary tract infections, and caution is advised for elderly patients and those with renal insufficiency, as its efficacy decreases with lower kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Canagliflozin (Invokana): kidney SGLT2 cotransporter inhibitor for treating type 2 diabetes]. Scheen, AJ.[2018]

Canagliflozin, an SGLT-2 inhibitor, showed potential in improving kidney function in rats with non-diabetic chronic kidney disease (CKD) induced by adenine, significantly reducing inflammation and oxidative stress markers.

The drug did not cause any significant adverse effects, suggesting it may be safe for further investigation in human trials for CKD treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats. Ali, BH., Al Salam, S., Al Suleimani, Y., et al.[2020]

Canagliflozin, a sodium-glucose co-transporter 2 inhibitor for type 2 diabetes, can cause acute pancreatitis, a very rare side effect occurring in less than 1% of patients, as demonstrated in a case of a 50-year-old male who developed diabetic ketoacidosis after 4 days of treatment.

The case highlights the importance of monitoring for serious side effects like acute pancreatitis when prescribing canagliflozin, emphasizing the need for more detailed guidelines on patient selection for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute pancreatitis in the use of canagliflozin: A rare side-effect of the novel therapy for type 2 diabetes mellitus. Srivali, N., Thongprayoon, C., Cheungpasitporn, W., et al.[2020]

Canagliflozin significantly improved glycemic control in patients with type 2 diabetes and stage 3 chronic kidney disease, reducing HbA1c levels compared to placebo after 26 weeks.

The treatment was generally well tolerated, with similar rates of adverse events compared to placebo, although there were slightly higher instances of urinary tract infections and other osmotic diuresis-related effects at the higher dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Yale, JF., Bakris, G., Cariou, B., et al.[2022]

Canagliflozin, an SGLT-2 inhibitor introduced for type 2 diabetes, shows potential for type 1 diabetes treatment due to its insulin-independent mechanism of action.

However, it carries serious risks, including severe metabolic acidosis and euglycemic diabetic ketoacidosis, which require immediate recognition and treatment to prevent life-threatening complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern. Gelaye, A., Haidar, A., Kassab, C., et al.[2022]

In a large retrospective cohort study involving over 55,000 patients with type 2 diabetes, canagliflozin was associated with a significantly lower risk of hospital admission for heart failure compared to DPP-4 inhibitors, GLP-1 receptor agonists, and sulfonylureas.

Canagliflozin showed similar risks for major cardiovascular events (like heart attacks and strokes) when compared to these other diabetes medications, indicating its safety profile in terms of cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. Patorno, E., Goldfine, AB., Schneeweiss, S., et al.[2022]

Canagliflozin significantly reduces the risk of cardiovascular events and kidney outcomes in individuals with type 2 diabetes, showing a consistent relative effect across different KDIGO risk categories based on kidney function and albumin levels.

Higher KDIGO risk categories experienced greater absolute reductions in cardiovascular outcomes, suggesting that patients with more severe kidney disease may benefit more from canagliflozin treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program. Neuen, BL., Ohkuma, T., Neal, B., et al.[2021]

Canagliflozin, an SGLT2 inhibitor, effectively lowers blood glucose levels in patients with type 2 diabetes by increasing urinary glucose excretion, showing significant improvements in glycemic control over 26-52 week trials.

It has a low risk of causing hypoglycemia and is generally well tolerated, although it may lead to urinary tract infections and increased urination; its effects on cardiovascular risk are still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin: a review of its use in patients with type 2 diabetes mellitus. Plosker, GL.[2021]

Citations

1.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1811744

Canagliflozin and Renal Outcomes in Type 2 Diabetes and ...

In conclusion, among patients with type 2 diabetes and kidney disease, those in the canagliflozin group had a lower risk of kidney failure and cardiovascular ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7217416/

Renal, Cardiovascular, and Safety Outcomes of Canagliflozin ...

Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating ...

3.

jnj.com

jnj.com/media-center/press-releases/invokana-canagliflozin-significantly-reduces-the-risk-of-renal-failure-in-patients-with-type-2-diabetes-and-chronic-kidney-disease-in-the-landmark-phase-3-credence-study

INVOKANA® (canagliflozin) Significantly Reduces the Risk ...

INVOKANA® reduced the risk of end-stage kidney disease by 32 percent (HR: 0.68; 95% CI: 0.54 to 0.86; p=0.0015). Furthermore, INVOKANA® showed a ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02065791

NCT02065791 | Evaluation of the Effects of Canagliflozin ...

The goal of this study is to assess whether canagliflozin has a renal and vascular protective effect in reducing the progression of renal impairment ...

5.

invokanahcp.com

invokanahcp.com/dkd-benefit/

DKD Benefit | INVOKANA® (canagliflozin) HCP

INVOKANA® reduced the relative risk of the primary composite outcome of end-stage kidney disease, doubling of serum creatinine, and renal or CV death.

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39781601/

A combined analysis from the CANVAS Program and ...

Canagliflozin reduced cardiovascular and kidney outcomes, regardless of age, with no additional safety concerns identified in older patients.

7.

invokanahcp.com

invokanahcp.com/safety-profiles/

Safety Profile | INVOKANA® (canagliflozin) HCP

INVOKANA® 100 mg has a proven safety profile in adult patients with DKD and T2D who have an eGFR as low as 30.

8.

ahajournals.org

ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035901

Cardiovascular and Renal Outcomes With Canagliflozin ...

The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55–0.90) and ...