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

Study Overview
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Brief Summary
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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
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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

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

Conditions
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Acute Kidney Injury

Intervention / Treatment
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* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult cardiac surgery patients (>18 years) undergoing cardiac surgery with moderately hypothermic CPB (32-34°C) and blood cardioplegia Identified as representing a high risk group for acute kidney injury using a modified risk score based on the variables of Age, Sex, BMI, Smoking Status, NHYA class, Previous Operations, Peripheral Vascular Disease, Diabetes, Hypertension, Pre-operative Haemoglobin level, Pre-operative eGFR, Operative Priority, Operation Type, Ejection Fraction and Presence of Pre-Operative Critical Events. Female subjects of childbearing potential are not to be pregnant (to be confirmed by urine human chorionic gonadotropin pregnancy test prior to dosing). Women are considered not to be of childbearing potential if they have been surgically sterilised (eg, tubal ligation, oophorectomy or hysterectomy) or are postmenopausal (defined as serum follicle-stimulating hormone level of ≥30 IU/mL) in the absence of hormone replacement therapy and complete absence of menses for at least 24 consecutive months. Exclusion Criteria: Emergency or salvage procedure Ejection fraction <30% CKD Stage 5, defined as eGFR<15ml/min or renal replacement therapy. Administration of potent CYP 3A4 inhibitors within 1 month prior to study participation (e.g. HIV protease inhibitors, imidazole antifungals and erythromycin, please see Appendix 1 for a full list of prohibited medications). Administration of nitrate medicines (e.g. glyceryl trinitrate within 24 hours of surgery. Any ongoing malignancy, or prior malignancy that currently requires treatment. Patients allergic to any other PDE-5 Inhibitor Patients who are participating in another interventional clinical study -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil<br>All subjects in groups 1-6 will receive SIldenafil but in escalating doses. | Drug: Sildenafil<br>* 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<br>* Other names: REVATIO®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve and Plasma Concentration of Sildenafil | There will be Pharmacokinetic sample collection pre and post dose to look at plasma concentration of sildenafil. Sample collection timepoints are post dose at 10 mins, 15 mins, 30 mns, 45 mins 2 hours, 4 hours, 12 hours, 24 hours and 48 hours. | 48 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum creatinine and Biochemical markers of AKI | Serum creatinine measured from blood samples collected pre-operatively and at 6 hours, 24 hours, 48 hours and 96 hours after the operation. Biochemical markers of acute kidney injury measured in urine pre-operatively, 0mins, 6 houts, 24 hours and 48 hours. | 5 Days |