CANagliflozin In DIALysis Patients

Обзор

Rationale: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of drugs originally developed for the treatment of diabetes. Cardiovascular outcome trials with these drugs showed also beneficial effects of these agents on heart failure, cardiovascular disease and kidney outcomes. Secondary analyses from these trials demonstrated that these benefits were consistent in patients with or without type 2 diabetes and with or without chronic kidney disease (CKD) with a lower eGFR threshold of 20 mL/min/1.73m2. However, it is not yet clear if these drugs can also be used in patients with severe kidney disease who require dialysis. This is in part explained because SGLT2 inhibitors bind to a transporter which is located in the luminal side of proximal tubes in the kidney. If kidney function is low, and these patients have no or limited filtering capacity, it is possible that the efficacy of these drugs decrease. Notwithstanding, several animal experiments and preliminary clinical data have suggested that these drugs do have kidney and cardiac protective effects in case of severely decreased kidney function. The investigators hypothesize that SGLT2 inhibitors are distributed to several tissues in the body on top of the kidney and therefore the investigators would like to investigate the specific tissue distribution of SGLT2 inhibitors in patients on dialysis with-and without residual diuresis.

Подробное описание

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.

Вмешательства

• Препарат Invokana 300 mg and 100 mg tablet
  A 600 mg dose of canagliflozin (two 300 mg tablets) will be administered orally by the participant

Первичные конечные точки

• Overall drug tissue disposition of SGLT2 in patients on dialysis. [Срок оценки: From enrollment to the second study day, seperated by approximately one-week intervals.]

Вторичные конечные точки (1)

• Receptor occupancy of SGLT2 in the regions of interest. [Срок оценки: From enrollment to the second study day, seperated by approximately one-week intervals.]

Критерии участия

Критерии включения

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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Нидерланды · 1 центр

• University Medical Center Groningen — Groningen

Публикации

• Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295- PMID 30990260
• Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID 32970396
• The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, PMID 36331190
• Juni RP, Al-Shama R, Kuster DWD, van der Velden J, Hamer HM, Vervloet MG, Eringa EC, Koolwijk P, van Hinsbergh VWM. Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction. Kidney Int. 2021 May;99(5):1088-1101. doi: 10.1016/j.kint.2020.12.013. Epub 2020 Dec 23. PMID 33359500
• Uthman L, Homayr A, Juni RP, Spin EL, Kerindongo R, Boomsma M, Hollmann MW, Preckel B, Koolwijk P, van Hinsbergh VWM, Zuurbier CJ, Albrecht M, Weber NC. Empagliflozin and Dapagliflozin Reduce ROS Generation and Restore NO Bioavailability in Tumor Necrosis Factor alpha-Stimulated Human Coronary Arterial Endothelial Cells. Cell Physiol Biochem. 2019;53(5):865-886. doi: 10.33594/000000178. PMID 31724838
• Billing AM, Kim YC, Gullaksen S, Schrage B, Raabe J, Hutzfeldt A, Demir F, Kovalenko E, Lasse M, Dugourd A, Fallegger R, Klampe B, Jaegers J, Li Q, Kravtsova O, Crespo-Masip M, Palermo A, Fenton RA, Hoxha E, Blankenberg S, Kirchhof P, Huber TB, Laugesen E, Zeller T, Chrysopoulou M, Saez-Rodriguez J, Magnussen C, Eschenhagen T, Staruschenko A, Siuzdak G, Poulsen PL, Schwab C, Cuello F, Vallon V, Ri PMID 38152989
• Bakker WM, Heerspink HJL, Berger SP, Wanner C, Badve SV, Arnott C, Abrahams AC, van den Born JC, van Faassen TC, Gaillard CAJM, Gelens MACJ, Gorris JL, Hemmelder MH, Jakulj L, van Kruijsdijk RCM, Kuypers DRJ, van der Meer P, van der Net JB, Nijmeijer HH, Vervloet MG, de Vries APJ, Walsh M, Wang AY, Gansevoort RT; Renal Lifecycle Trial Investigators. Rationale and design of the Renal Lifecycle tria PMID 40053493
• van der Hoek S, Willemsen ATM, Visser T, Heeres A, Mulder DJ, Bokkers RPH, Slart RHJA, Elsinga PH, Heerspink HJL, Stevens J. Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18 F]Canagliflozin in Patients with Type 2 Diabetes. Clin Pharmacol Ther. 2023 Jun;113(6):1295-1303. doi: 10.1002/cpt.2886. Epub 2023 Mar 26. PMID 36897753

Идентификаторы

NCT: NCT07527390 · 20725 · 2025-522742-46-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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