Heme Arginate in Cardiac Surgery Patients

Acute Kidney Injury Clinical Trial

— HACS  

Official title:

Phase II Study of Heme Arginate in Patients Planned for Cardiac Surgery

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02142699
• Other study ID #: SE01047
• Secondary ID: 2014-001021-32
• Status: Not yet recruiting
• Phase: Phase 2
• First received: May 9, 2014
• Last updated: May 15, 2014
• Start date: July 2014
• Est. completion date: November 2014

Study information

• Verified date: May 2014
• Source: University of Edinburgh
• Contact: Fiona AI Duthie, MD
• Phone: 007764946050
• Email: fduthie[@]staffmail.ed.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: National Health ServiceUnited Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

A recent analysis of over 4500 cardiac surgical patients at the Royal Infirmary of Edinburgh has confirmed that acute kidney injury (AKI) is not only a relatively common post-operative complication but is associated with prolonged hospital stay, and increased risk of death. There is currently no specific therapy available except supportive care.

In laboratory studies, heme arginate (HA), a drug licensed for human use, has been shown to upregulate the anti-inflammatory enzyme hemeoxygenase-1 (HO-1) and protect aged mice from acute kidney injury.

This study will bring this research into the human arena. It will aim to evaluate the minimum effective dose of HA and verify its safety in this specific group of patients. This will be the next step in investigating if HA could be a potential protective treatment for reducing AKI in patients about to have cardiac surgery.

Patients who are due to have cardiac surgery and are aged 60 or above will be approached for inclusion in the study. If agreeable, they will be randomly assigned to receive either HA at a dose of 1mg/kg or 3mg/kg. There will be 10 patients in each group.

Blood tests will be taken just before the study drug is given, at 6 hours, 24 hours and 7 days post dose. These samples will be used to examine the effect of HA on HO-1 at different doses, and will verify drug safety. Any adverse effects of the drug will be evaluated, although HA has an excellent safety profile when used as it is currently licensed for acute porphyria. Urine samples will also be collected to assess inflammation and quantify urinary biomarkers of AKI. This will set the scene for a randomised clinical trial of HA in cardiac surgical patients at high risk of AKI.

Description:

AKI is a common condition which carries significant morbidity and mortality and has no current treatment except supportive care.

Cardiac surgery remains the standard of care for the revascularisation of the most severe coronary artery disease despite improvements in percutaneous coronary intervention. The nature of such surgery confers an ischaemic renal insult and it follows on that AKI is a relatively common complication. However, the reported incidence of AKI post cardiac surgery varies widely depending on the diagnostic criteria used. A recent retrospective analysis of 4572 cardiac surgical patients at the Royal Infirmary of Edinburgh over a 5 year period showed that 12.4% developed AKI by AKIN criteria post operatively. This was associated with an increased risk of death and prolonged inpatient stay.

Pre-clinical studies in murine models of ischaemia reperfusion injury (IRI) have demonstrated that the anti-inflammatory enzyme HO-1 is of interest as a potential target for therapeutic intervention. Heme arginate (HA) is a drug licensed for human use, as a treatment for acute porphyria. HA upregulates HO-1, and ameliorates IRI when given before injury in murine models of IRI. In Phase I clinical trials, HA has been shown to upregulate HO-1 and is well tolerated.

This is a single-blinded randomised trial of Heme arginate (HA) in patients who are due to have cardiac surgery. The aim of the study is to investigate the efficacy of HA in HO-1 upregulation and its safety in this patient cohort. This will inform a further clinical trial of HA as a preventative treatment for AKI in patients undergoing cardiac surgery.

Methods

Eligible patients will be those planned for elective cardiac surgery, identified at their Cardiothoracic outpatient clinic assessment, aged 60 or above.

HA (3mg/kg) upregulates HO-1 mRNA up to 2-fold at 24 hours post dose in healthy young volunteers. Power calculations based on an 80% power (at p<0.05) to detect at least 2 fold upregulation of HO-1 protein by western blot necessitate 2 groups of 10 (assuming standard deviation (SD) of ±1.5x). 20 patients will be recruited (10 per group).

Patients who agree to participate will be invited up for a study visit to the Clinical Research Facility at the Royal Infirmary of Edinburgh (RIE). If consent is given, participants will be randomised to receive HA at a dose of either 1 or 3mg/kg (maximum 250mg). Prior to the dose being given, routine observations (including blood pressure, pulse, respiratory rate, oxygen saturations and temperature) will be taken, and the trial team member will perform a routine examination of the cardiac and respiratory systems. An electrocardiogram (ecg) will be done for reference.

Blood samples to assess HO-1 expression in circulating monocytes will be taken prior to the administration of the study drug, and at 24 hours post dose. Samples for routine blood tests including full blood count (FBC), urea and electrolytes (U&E), C-reactive protein (CRP), liver function tests (LFT), and ferritin will be taken alongside those for monocyte isolation, with a further set on day 7. Serum (and urine) will be frozen for batch analysis and monocytes will be isolated by in-house protocols. Routine blood tests will be processed at the biochemistry and haematology laboratories at the RIE as per their usual methods.

Urine samples will be collected before the study drug is given, and at 24 hours and 7 days post dose. Urinalysis will be performed, and microalbuminuria and urinary biomarkers of tubular injury neutrophil gelatinase associated lipocalin(NGAL), interleukin 18(IL-18) & kidney injury molecule 1(KIM-1) will be quantified.

Routine clinical observations will be carried out for 6 hours post dose, at which time the patient will be allowed home in the absence of any adverse events. A second study visit at the Clinical Research Facility will be scheduled for 24 hours post dose (day 1), with a third study visit on day 7.

The second and third study visits will allow reporting of any adverse events, as well as an opportunity to perform routine observations and take further blood samples for HO-1 induction and in order to analyse safety.

All patients will be genotyped for the short or long repeat HO-1 promoter polymorphism (either homozygous or heterozygous) though this has not been shown to affect HO-1 induction by HA in previous studies.

The RIE cardiac surgery unit performs approximately 1000 cases per year, with just less than 80% aged 60 or over from our analysis of 4572 patients. A conservative estimate for time to meet recruitment to the study is 3 months.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: November 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

Age =60

Planned for elective cardiac surgical procedure:

• Aortic valve replacement

• CABG

Exclusion Criteria:

Inability to give informed consent Hypersensitivity to HA Enrolment in other clinical trials Renal replacement therapy Planned for elective cardiac surgical procedure other than CABG or AVR (including combined CABG and AVR) Less than 2 weeks until planned cardiac surgery at time of study drug administration Active infection

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject)

Related Conditions & MeSH terms

• Acute Kidney Injury

Intervention

Drug:
• Heme arginate

Locations

Country	Name	City	State
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh	Midlothian

Sponsors (3)

Lead Sponsor	Collaborator
University of Edinburgh	Medical Research Council, NHS Lothian

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Upregulation of Heme oxygenase-1 protein expression in circulating monocytes		within 3 months of study completion	No
Secondary	Upregulation of heme oxygenase-1 messenger ribonucleic acid (mRNA) in circulating monocytes		within 3 months of completion	No
Secondary	Urinary biomarkers of acute kidney injury	Samples will be collected pre dose and at 24 hrs and 7 days to determine the effect (if any) of Heme arginate on levels of urinary biomarkers of AKI in order to inform future interventional trials	within 3 months of completion of study	No
Secondary	Safety	This will be a composite outcome measure consisting of multiple routine measures of safety including adverse event reporting, and the biochemical and haematological data collected (eg renal function, liver function tests, full blood count)	at final study visit ie 7 days post dose (or at the resolution of any ongoing adverse event if this lasts longer than 7 days)	Yes
Secondary	Heme oxygenase-1 (HO-1) Genotype	Patients will have their genotype for HO-1 gene recorded (for the long (L) or short (S) promoter region)- therefore they will be either LL, LS or SS. The study is not powered to detect any difference but will inform future studies.	within 3 months of study completion	No