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Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study.

ABSTRACT: INTRODUCTION:Acute kidney injury (AKI) after cardiac surgery is common and results in increased morbidity and mortality. One possible mechanism for AKI is ischaemia-reperfusion injury caused by the extracorporeal circulation (ECC), resulting in an opening of the mitochondrial permeability transition pore (mPTP) in the kidneys, which can lead to cell injury or cell death. Ciclosporin may block the opening of mPTP if administered before the ischaemia-reperfusion injury. We hypothesised that ciclosporin given before the start of ECC in cardiac surgery can decrease the degree of AKI. METHODS AND ANALYSIS:Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS) study is an investigator-initiated double-blind, randomised, placebo-controlled, parallel design, single-centre study performed at a tertiary university hospital. The primary objective is to assess the safety and efficacy of ciclosporin to limit the degree of AKI in patients undergoing coronary artery bypass grafting surgery. We aim to evaluate 150 patients with a preoperative estimated glomerular filtration rate of 15-90?mL/min/1.73?m2. Study patients are randomised in a 1:1 ratio to receive study drug 2.5?mg/kg ciclosporin or placebo as an intravenous injection after anaesthesia induction but before start of surgery. The primary end point consists of relative P-cystatin C changes from the preoperative day to postoperative day 3. The primary variable will be tested using an analysis of covariance method. Secondary end points include evaluation of P-creatinine and biomarkers of kidney, heart and brain injury. ETHICS AND DISSEMINATION:The trial is conducted in compliance with the current version of the Declaration of Helsinki and the International Council for Harmonisation (ICH) Good Clinical Practice guidelines E6 (R1) and was approved by the Regional Ethical Review Board, Lund and the Swedish Medical Products Agency (MPA). Written and oral informed consent is obtained before enrolment into the study. TRIAL REGISTRATION NUMBER:NCT02397213; Pre-results.

SUBMITTER: Ederoth P

PROVIDER: S-EPMC5168697 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study.

Ederoth Per P Grins Edgars E Dardashti Alain A Brondén Björn B Metzsch Carsten C Erdling André A Nozohoor Shahab S Mokhtari Arash A Hansson Magnus J MJ Elmér Eskil E Algotsson Lars L Jovinge Stefan S Bjursten Henrik H

BMJ open 20161215 12

<h4>Introduction</h4>Acute kidney injury (AKI) after cardiac surgery is common and results in increased morbidity and mortality. One possible mechanism for AKI is ischaemia-reperfusion injury caused by the extracorporeal circulation (ECC), resulting in an opening of the mitochondrial permeability transition pore (mPTP) in the kidneys, which can lead to cell injury or cell death. Ciclosporin may block the opening of mPTP if administered before the ischaemia-reperfusion injury. We hypothesised tha ...[more]

PMID: 27979834

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Project description:Objective:To investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod-a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator-in patients with SLE. Methods:This multicentre, double-blind, placebo-controlled study was conducted in two parts. In part A, patients with SLE were randomised 1:1:1:1 to receive oral cenerimod 0.5, 1 or 2?mg, or placebo once daily for 12 weeks. Following an interim safety review of part A, additional patients were randomised 3:1 for part B and received cenerimod 4?mg or placebo once daily for 12 weeks. Endpoints included changes in total lymphocyte count, SLE Disease Activity Index-2000 (SLEDAI-2K) score (modified (mSLEDAI-2K) to exclude leucopenia), biomarker anti-double-stranded DNA (anti-dsDNA) antibodies, pharmacokinetic assessments and treatment-emergent adverse events (TEAEs). Results:Part A included 49 patients (1:1:1:1 receiving cenerimod 0.5, 1 or 2?mg, or placebo) and part B included 18 patients (13 cenerimod; 5 placebo). Cenerimod caused a statistically significant dose-dependent reduction in total lymphocyte count from baseline to end of treatment (EOT). Compared with placebo at EOT, cenerimod 4?mg had an estimated treatment effect on change from baseline in mSLEDAI-2K score of -2.420 (p=0.0306), and on anti-dsDNA antibodies of -64.55?U/mL (p=0.0082), suggesting clinical and biological improvement in these exploratory efficacy analyses. Trough plasma concentrations were dose proportional and reached steady-state conditions after 4 weeks of once daily dosing. All groups reported similar, non-dose-related frequencies of TEAEs (cenerimod 0.5?mg: 41.7%; 1?mg: 41.7%; 2?mg: 46.2%; 4?mg: 38.5% and placebo: 58.8%). A small, dose-related, non-clinically relevant decrease in heart rate was only observed in the first 6?hours after initiation. Conclusions:With an acceptable safety profile, the efficacy findings suggest that cenerimod has the potential to treat patients with SLE. Further investigation in larger patient populations with longer treatment duration is warranted.

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Dataset Information

Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study.

Publications

Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS): a study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study.

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