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
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Locations and Contacts
Department of Cardiovascular Sciences., Leicester, Leicestershire LE3 9QP, United Kingdom
Additional Information
Starting date: June 2013
Last updated: June 12, 2015
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