Acute Kidney InjuryPhase 1Revaki-001NCT02136329
A Study to Determine the Pharmacokinetic Profile, Safety and Tolerability of Sildenafil (REVATIO®) in Cardiac Surgery
A Phase 1 study testing Sildenafil in people with Acute Kidney Injury, run by University of Leicester at 1 site in United Kingdom.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Kidney Injury
- What is being tested?
- Sildenafil
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jun 2013to Dec 2014
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- Patients allergic to any other PDE-5 Inhibitor
- Patients who are participating in another interventional clinical study
- -
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Department of Cardiovascular Sciences.
Leicester, Leicestershire, LE3 9QP
About this study
Official title: A Phase I Study to Determine the Pharmacokinetic Profile, Safety and Tolerability of Sildenafil (REVATIO®) in Cardiac Surgery
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
Read the 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
- Being tested
- Sildenafil
- Medical subject headings
- Acute Kidney Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SildenafilDrug
Also called REVATIO®
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
| Study group | Role | What they receive |
|---|---|---|
| Sildenafil | Experimental | All subjects in groups 1-6 will receive SIldenafil but in escalating doses. Receives: Drug: Sildenafil |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 48 Hours
Secondary outcomes (1)
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.
Measured: 5 Days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2014 (estimated)
- Study startJun 2013
- Primary completionDec 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Kidney InjuryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Leicester
- Sponsor type
- University, hospital or other
- Collaborators
- British Heart Foundation
- Responsible party
- Sponsor
- Investigators
- Gavin Murphy, Prof, Principal investigator, University of Leicester
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02136329
- Sponsor's protocol ID
- 0359
- Acronym
- Revaki-001
- Status last verified
- Dec 2014
- First submitted
- 6 May 2014
- Last updated
- 30 Jan 2020
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study to Determine the Pharmacokinetic Profile, Safety and Tolerability of Sildenafil (REVATIO®) in Cardiac Surgery
- ClinicalTrials.gov ID
- NCT02136329
- Acronym / sponsor ID
- Revaki-001 / 0359
- Conditions
- Acute Kidney Injury
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- University of LeicesterUniversity, hospital or other
- Collaborators
- British Heart Foundation
- Study start
- Jun 2013
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 13 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Sildenafil | Experimental | Drug: SildenafilAll subjects in groups 1-6 will receive SIldenafil but in escalating doses. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SildenafilAlso: REVATIO®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 | Drug | Sildenafil |
Primary outcome
Area under the plasma concentration versus time curve and Plasma Concentration of Sildenafil
Time frame: 48 Hours
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.
1 secondary outcome
Serum creatinine and Biochemical markers of AKI
Time frame: 5 Days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gavin Murphy, Prof principal investigator
University of Leicester
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Sildenafil in people with Acute Kidney Injury, run by University of Leicester at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area under the plasma concentration versus time curve and Plasma Concentration of Sildenafil (time frame: 48 Hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2020.