Canagliflozin for Chronic Kidney Disease

(SIP-AKiD Trial)

Recruiting at 1 trial location

Overseen By Norka Rios

Age: 18+

Sex: Any

Trial Phase: Phase 4

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

Must not be taking: SGLT-2 inhibitors

Disqualifiers: Type 1 diabetes, Liver disease, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

44 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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. If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Canagliflozin for chronic kidney disease?

Research shows that Canagliflozin, a drug used for type 2 diabetes, can reduce the risk of kidney problems and improve kidney outcomes in patients with diabetes. It works by helping the kidneys remove excess sugar from the body, which may also benefit kidney health. ^{1 2 3 4 5}

Is canagliflozin generally safe for humans?

Canagliflozin, used for type 2 diabetes, has some rare but serious side effects like acute pancreatitis and severe ketoacidosis (a dangerous condition with high acid levels in the blood). It can also cause mild urinary tract infections and low blood pressure, especially in older adults. ^{1 2 3 6 7}

How is the drug canagliflozin unique for treating chronic kidney disease?

Canagliflozin is unique because it works by inhibiting a protein in the kidneys called SGLT2, which helps reduce blood sugar levels by increasing the amount of sugar excreted in urine. This mechanism not only helps manage diabetes but also offers protective benefits for the kidneys, making it a novel option for chronic kidney disease. ^{1 2 3 5 8}

Research Team

Thomas Mavrakanas, MD

Principal Investigator

Research Institute of the McGill University Health Center

Eligibility Criteria

Adults with advanced chronic kidney disease (CKD) can join this trial. For one part, they need an eGFR <30 ml/min/1.73m2 and high urine albumin but not on dialysis. Another part is for those on hemodialysis for at least 3 months without much remaining kidney function. People under 18, with type 1 diabetes, recent SGLT-2 inhibitor use, severe liver disease, certain medication use that can't be stopped, or who are pregnant/breastfeeding cannot participate.

Inclusion Criteria

My kidney function is low, with an eGFR under 30.

I have been on hemodialysis for at least 3 months.

I produce less than 250 ml of urine in 24 hours.

Exclusion Criteria

currently breastfeeding

I am under 18 years old.

I frequently have severe genital or urinary infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Patients with eGFR<30 ml/min/1.73m2 and UACR>200 mg/g not receiving dialysis will receive canagliflozin 100 mg po daily

12 weeks

Treatment Phase 2

For participants who have tolerated the drug, canagliflozin will be increased to 300 mg po daily

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Substudy 2 Treatment

Adult patients on HD for at least 3 months without significant residual renal function will receive canagliflozin 100 mg po daily

9 days

Treatment Details

Interventions

• Canagliflozin

Trial Overview The trial tests Canagliflozin's effects in CKD patients including those on hemodialysis (HD). It aims to see if the drug reduces protein in urine and has cardiovascular/kidney protection benefits as seen in less severe cases. Two doses of Canagliflozin (100 mg and 300 mg) will be compared for safety and effectiveness.

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+

Findings from Research

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, 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 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 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, 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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization. [2022]

2. Belgium pubmed.ncbi.nlm.nih.gov

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

3. India 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. [2020]

4. United States 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. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Severe Ketoacidosis Associated with Canagliflozin (Invokana): A Safety Concern. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. [2022]