NCT02136329

A Study to Determine the Pharmacokinetic Profile, Safety and Tolerability of Sildenafil (REVATIO®) in Cardiac Surgery

A Phase I Study to Determine the Pharmacokinetic Profile, Safety and Tolerability of Sildenafil (REVATIO®) in Cardiac Surgery

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 36 (actual)
• Sponsor: University of Leicester · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The objectives of the study are the following: * To evaluate the pharmacokinetic profile of Sildenafil in cardiac surgery patients at risk of acute kidney injury * To determine the safety and tolerability of Sildenafil in cardiac surgery patients at risk of acute kidney injury

Detailed description

Acute kidney injury occurs in up to one third of all patients following cardiac surgery. It is manifested by an acute decline in kidney function and results in significant increases in postoperative complications as well as an almost fourfold increase in the risk of postoperative death. Our understanding of the underlying processes is poor and recent systematic reviews have concluded that there is no effective treatment. Experimental studies have demonstrated that preservation of endogenous Nitric Oxide (NO) bioavailability is reno-protective in response to a variety of injurious stimuli. Endogenous NO activity is increased by administration of the phosphodiesterase type 5 (PDE-5) inhibitor sildenafil citrate. This is used clinically in the treatment of erectile dysfunction (Viagra®, Pfizer) and more recently, pulmonary hypertension and acute right ventricular failure (Revatio®, Pfizer). We have developed a preclinical swine model of extracorporeal circulation (cardiopulmonary bypass) mediated acute kidney injury that shows significant homology to that which occurs in post cardiac surgery patients. Administration of intravenous sildenafil prevents acute kidney injury in this model in association with an increase in NO bioavailability. There is a recognized clinical need for developing prevention and treatment strategies for AKI and results obtained in this preclinical study indicate that Sildenafil is suitable for further development as a potential prevention strategy for post cardiac surgery AKI. Prior to conducting a safety and efficacy trial however we intend to first establish a dose of Sildenafil that is tolerated by cardiac surgery patients and compare the pharmacokinetics of this dose to the effective dose identified in our preclinical work. We therefore propose to evaluate the pharmacokinetic profile, safety and tolerability of sildenafil in 36 patients undergoing cardiac surgery, in an open label, dose escalation Phase I study. This study will inform the design of a subsequent randomized Phase IIb trial that will determine efficacy and safety

Conditions

• Acute Kidney Injury

Interventions

Type	Name	Description
DRUG	Sildenafil	The active study drug, Revatio®, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE5). Sildenafil citrate is designated chemically as 1-\[\[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo \[4,3-d\] pyrimidin-5-yl)-4-ethoxyphenyl\] sulfonyl\]-4-methylpiperazine citrate. The active study medication is supplied in single use glass vials and as a clear, colourless, sterile, ready-to-use solution containing 10 mg (12.5 mL) of sildenafil. Each mL of solution contains 1.124 mg sildenafil citrate, 50.5 mg dextrose and water for injection. Sildenafil is manufactured under Good Manufacturing Practice (EU-GMP) by Pfizer Inc

Timeline

• Start date: 2013-06-01
• Primary completion: 2014-12-01
• Completion: 2014-12-01
• First posted: 2014-05-13
• Last updated: 2020-01-30

Locations

1 site across 1 country: United Kingdom