CANagliflozin In DIALysis Patients

Main objective:

The main objective of this exploratory study is to investigate specific tissue distribution of SGLT2 inhibitors in patients on dialysis with-and without residual diuresis and visualize this by the use of 18F- canagliflozin.

Secondary objective:

To investigate 18F- canagliflozin binding in specific regions of interest:

• The proximal tubule of the kidney
• Cardiac tissue
• Vascular tissue
• Brain tissue

To compare whether tissue distribution is different between dialysis patients who have and that do not have residual diuresis.

Study design:

This is an open-label exploratory study. The study will consist of a screening visit and 2 study days, separated by a one-week interval.

Study population:

The trial population will consists of 10 patients ≥18 years of age who are on dialysis for more than 3 months with or without residual diuresis and as exclusion criteria a total cumulative radiation burden above 1mSv per year (from the age of 18 years), a history of hypersensitivity to canagliflozin, any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications or peripheral/cardiovascular disease.

Interventions:

On both study days, a blood sample will be obtained for routine clinical care. A non-diagnostic CT scan will be performed to optimally position the individual participant for the PET scan. In all participants, two 60-minute PET scans will be obtained. On the first study day, following IV radiotracer administration, a baseline 60-minute PET scan will be taken to measure uptake and accumulation of 18F- canagliflozin. On the second study day (approximately 1 week after the first study day), following oral administration of 600 mg canagliflozin, a second IV radiotracer dose will be administered followed by a 60- minute PET scan (post-drug). Venous lines will be placed prior to the PET-scans to inject the dose and for venous sampling. In this study venous sampling was implemented as arterial sampling appeared to be burdensome for both personnel and participants.

Main study endpoint:

The main endpoint of the study is overall drug tissue disposition of SGLT2 in patients on dialysis quantified by images obtained by PET imaging.

Secondary study endpoint:

Receptor occupancy of SGLT2 in the regions of interest (proximal tubule of the kidney, cardiac tissue, vascular tissue, brain tissue) as quantified by images obtained by PET imaging.

Study visits:

Screening visit, study day 1, study day 2.

Sample size:

The sample size planned for this study is 10 participants, allocated n=5 to the residual diuresis group and n = 5 to the non-residual diuresis group. The sample size is based on prior experience of a variability and feasibility study with 18-F canagliflozin in a cohort of 9 patients with T2DM.

Inclusion criteria

• Hemodialysis for more than 3 months (5 also with residual diuresis)
• Age ≥18 years of age
• Willing to sign informed consent

Exclusion criteria

• Mentally incapacitated subjects (i.e. not able to sign informed consent)
• Subjects who participated in a trial with exposure to radiation before, are only allowed to participate if the total cumulative radiation burden in their life does not exceed 1 mSv per year, counting from the age of 18 years.
• Pregnant women and women of child-bearing potential who are not using reliable contraception
• Subjects on diuretics are allowed to participate but the dose should be stable for at least 4 weeks prior to screening
• Subjects already on a SGLT2 inhibitor are allowed to participate, but the drug should be inter-rupted 1 week prior to the first study day till the end of the second study day (as the half-life is 10-13 hours a wash-out of the study drug of at least 7-days should be considered)
• History of hypersensitivity to canagliflozin or another SGLT2 inhibitor
• Severe claustrophobia
• History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.
• Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:

• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
• Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months
• Pancreatic injury or pancreatitis within the last six months
• Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at inclusion visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt
• Use of rifampicin and cholestryramine
• Established peripheral arterial disease
• Active cardiovascular disease: myocardial infarction, angina pectoris, percutaneous translu-minal coronary angioplasty, coronary artery bypass grafting, stroke, or heart failure (NYHA I-IV) admission < 3 months before inclusion
• People using digoxin and/or lithium
• Patients with an active malignancy