DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



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

Information source: University of Leicester
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Kidney Injury

Intervention: Sildenafil (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: University of Leicester

Official(s) and/or principal investigator(s):
Gavin Murphy, Prof, Principal Investigator, Affiliation: University of Leicester

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

Clinical Details

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome: Area under the plasma concentration versus time curve and Plasma Concentration of Sildenafil

Secondary outcome: Serum creatinine and Biochemical markers of AKI

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

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Adult cardiac surgery patients (>18 years) undergoing cardiac surgery with moderately hypothermic CPB (32-34°C) and blood cardioplegia 2. 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. 3. 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: 1. Emergency or salvage procedure 2. Ejection fraction <30% 3. CKD Stage 5, defined as eGFR<15ml/min or renal replacement therapy. 4. 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). 5. Administration of nitrate medicines (e. g. glyceryl trinitrate within 24 hours of surgery. 6. Any ongoing malignancy, or prior malignancy that currently requires treatment. 7. Patients allergic to any other PDE-5 Inhibitor 8. Patients who are participating in another interventional clinical study

-

Locations and Contacts

Department of Cardiovascular Sciences., Leicester, Leicestershire LE3 9QP, United Kingdom
Additional Information

Starting date: June 2013
Last updated: June 12, 2015

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017