Online-Only Supplement: Intravenous amino acid therapy for ... · printed OR written on to a blank form to create a permanent record of calculations. It is the site investigator's

© University of Sydney 2018.

Online-Only Supplement:

Intravenous amino acid therapy for kidney protection in cardiac surgery patients:

A pilot randomised controlled trial

Gordon S. Doig and PU Hong (蒲虹) For the Cardiac Surgery Nephro-Protective Trial Investigators

The Cardiac Surgery Nephro-Protective Trial

North Shore Heart Research Foundation Grant ID: 2012_1

Australian and New Zealand Clinical Trials Registry Number: 12612000134820 Corresponding Author: Dr. Gordon S. Doig, Royal North Shore Hospital, Intensive Care Unit, St. Leonards, NSW Australia 2065 [email protected] www.EvidenceBased.net/cardiac 13 September 2018

http://www.anzctr.org.au/ACTRN12612000134820.aspx�

mailto:[email protected]�

Cardiac Surgery Nephro-Protective Trial: Online Supplement

©University of Sydney 2018. 2

© 2018 Gordon S Doig, University of Sydney. All rights reserved. This publication is protected by copyright. No part of it may be reproduced for commercial purposes or distributed electronically without prior written permission of the publisher. Reproduction for personal or educational use is acceptable.



Table of Contents

Table of Contents ....................................................................................................................... 3

The Cardiac Surgery Nepro-Protective Trial Investigators: ....................................................... 4

ADDITIONAL DETAILED METHODS ............................................................................................. 5

See Appendix 1 for complete eligibility criteria. ........................................................................ 5

See Appendix 3 for copy of grant submitted to request funding. ............................................. 5

Study run-in phase ..................................................................................................................... 5

Study intervention tools and procedures .................................................................................. 5 Study Intervention: Amino Acid Supplementation ............................................................................................. 5

eFigure 1. Cardiac Nephro-Protect web calculator ................................................................... 7

Study cardiacCALC web tool and Synthamin 17 EF infusion protocol (https://www.EvidenceBased.net/cardiacCalc) ........................................................................ 8

IMPORTANT CHANGES TO METHODS AFTER COMMENCEMENT ............................................. 8

Intra-operative management ..................................................................................................... 9

eFigure 3: Estimated Glomerular Filtration Rate (CKD-EPI Cystain C) by study day, percent change from pre-surgery baseline. .......................................................................................... 11

eFigure 4: Blood urea (mmol/L) by study day.......................................................................... 12

eTable 1: Covariate adjusted analysis for duration of renal dysfunction. ............................... 13

eTable 2: Covariate adjusted analysis for duration of AKI ....................................................... 13

eTable 3: Patient characteristics on day of initiating RRT ....................................................... 14

Appendix 1: Eligibility Criteria .................................................................................................. 15 Inclusion Criteria ............................................................................................................................................... 15 <Exclusion criteria continued next page.> ........................................................................................................ 15 Exclusion Criteria .............................................................................................................................................. 16 Note: The Exclusion criteria are continued over two pages: ............................................................................ 16 Exclusion Criteria continued ............................................................................................................................. 17

Appendix 2: Maximum Creatinine Table. ................................................................................ 18 Age and Gender adjusted maximum allowable creatinine for enrolment. ...................................................... 18



The Cardiac Surgery Nepro-Protective Trial Investigators: Management Committee: Gordon S. Doig (Chair), Elizabeth Sweetman (Co-Chair), John Brereton, Carol Pollock, Rinaldo Bellomo, Fiona Simpson, Philippa Heighes, and Douglas Chesher. Protein Dosing Sub-Committee: Gordon Doig (Chair), Rinaldo Bellomo, Fiona Simpson. Data Quality and Management: Jennifer L. Hannam (Northern Clinical School Intensive Care Research Unit, University of Sydney, Australia). Statistical analysis: Gordon S. Doig. Independent Data and Safety Monitoring Committee: Dr Bruce Cooper, Nephrology, Royal North Shore Hospital, NSW. Participating Site: (Royal North Shore Hospital) John Brereton, Andy Wang, Katrina Mann, Kristy Fiala, Stephen Siu, Simon Bird, Liz Yarad, Anne O’Connor, Frances Bass and Naomi Hammond. Visiting Research Fellow: Dr. PU Hong (蒲虹), Department of Critical Care Medicine, Sichuan Provincial People's Hospital, Chengdu, PRC.



ADDITIONAL DETAILED METHODS See Appendix 1 for complete eligibility criteria. Appendix 1 is located at the end of this document. See Appendix 3 for copy of grant submitted to request funding. Appendix 3 is located at the end of this document. Study run-in phase After attendance at the start-up meeting, a formal run-in phase will be undertaken at each participating centre. The run-in phase will allow the site investigators and research coordinators to educate the participating centre on study protocols and procedures and will provide the team with valuable experience in identifying truly eligible patients. Study intervention tools and procedures Study Intervention: Amino Acid Supplementation Once a patient has been enrolled into the study, if they are randomised to receive Amino Acid Supplementation, the study web site will automatically calculate the required infusion rate for the study Synthamin 17 EF. Otherwise, the study web site will notify you that the patient is to be managed using standard care. The goal of the active intervention arm is to achieve a target total protein intake of 2.0gm/kg/day from all sources of protein throughout the duration of ICU and hospital stay. Total protein intake will be calculated using protein from enteral nutrition, parenteral nutrition and study Synthamin 17 EF. Enteral nutrition and parenteral nutrition delivery rate will not be adjusted by the study web site calculator. Only study Synthamin 17 EF infusion rates will be adjusted (increased or decreased) to achieve the target total protein intake. At time of randomisation, the patient's current (or planned) protein intake from enteral nutrition and parenteral nutrition will be entered into the study web site. The study web site will calculate the appropriate dose rate for the study Synthamin 17 EF. Calculations will be based on the following principles: Protein intake for overweight (BMI > 25) patients will be based on their ideal body weight (ideal BMI set at 23). Regardless of actual protein intake from other sources, active intervention arm study patients will receive a maximum Synthamin 17 EF infusion of 42 mL/hr, which will provide a minimum of 100g protein/day. If total protein intake (from EN plus PN plus study Synthamin 17 EF) exceeds 2.5 gm/kg/day the study web site will recommend reducing the study Synthamin 17 EF infusion such that a target of 2.0 gm/kg/day is achieved.



If a patient changes to a different type of EN or PN, with a different protein content, the study web site can be used to re-calculate study Synthamin 17 EF rates. The Cardiac Nephro-Protect web calculator is located at: https://www.evidencebased.net/cardiacCalc The calculator is reproduced on the next page (eFigure 1).



eFigure 1. Cardiac Nephro-Protect web calculator



Study cardiacCALC web tool and Synthamin 17 EF infusion protocol (https://www.EvidenceBased.net/cardiacCalc) The cardiacCALC study web tool will calculate study Synthamin 17 EF infusion rates based on a patient’s current protein intake from Enteral and Parenteral nutrition and the patient’s weight. Protein intake calculations for overweight (BMI > 25) patients will be based on their ideal body weight (ideal BMI set at 23). The majority of patients will commence study Synthamin 17 EF at an infusion rate of 42 mL/h, which will provide 100g protein per day (approximately 1 g/kg/day). If a patient weighs less than 50Kg, the initial infusion will be less than 42 mL/h. The protocol will reduce the initial Synthamin 17 EF infusion to a lower rate only if total protein from EN, PN and study Synthamin 17 EF reaches 2.5g/kg. If total protein from EN, PN and study Synthamin 17 EF reaches 2.5g/kg, the Protocol will reduce the patient’s study Synthamin 17 EF infusion rate such that a total protein intake of 2.0g/kg from EN, PN and study Synthamin 17 EF is achieved. The cardiacCALC study web tool will be used to conduct all calculations. Results can be printed OR written on to a blank form to create a permanent record of calculations. It is the site investigator's responsibility to ensure that the appropriate study Synthamin 17 EF infusion rates, as calculated by the cardiacCALC web tool are effectively communicated to, and achieved by, the bedside health care team. If a patient switches to a different Brand of EN or a different type of PN, or if EN or PN is started or discontinued, the cardiacCALC study web tool should be used to calculate a new study Synthamin 17 EF infusion rate. The cardiacCALC study web tool is not password protected. It can be accessed by the bedside nurse on the weekend / at night if required. IMPORTANT CHANGES TO METHODS AFTER COMMENCEMENT On 3rd March 2014, the primary eligibility criteria was changed from pre-surgical eGFR < 60 ml/min/1.73m2 to eGFR < 90 ml/min/1.73m2. After recruitment of 12 patients, we initiated a sub-study to assess more sensitive urinary markers of renal function that we believed would allow us to detect smaller, but still potentially meaningful, differences in renal function in patients with less diminished kidney function at time of enrolment.



Intra-operative management After routine monitoring and establishment of arterial blood pressure monitoring, general anesthesia was induced with midazolam, propofol, fentanyl, and vecuronium or pancuronium, maintained with sevoflurane or isoflurane, at the discretion of the anesthetist. Ventilation with oxygen in air (fraction of inspired oxygen 0.5 to 1.0) was controlled with lung protection strategies aiming for a tidal volume <= 7mls/kg ideal body weight and respiratory rate titrated to a end-tidal CO2 of 35 to 45mmHg, allowing for permissive hypercarbia during periods of hypoventilation/apnoea to allow for surgical access. A central venous catheter, pulmonary artery catheter, and transesophageal echocardiography probe were place and used for hemodynamic and cardiac function monitoring after anesthesia induction. Depth of anaesthesia was monitored with entropy. Isoflurane or sevoflurane was used as the maintenance anesthetic agent before, during and after cardiopulmonary bypass. Surgery was performed with standard cardiopulmonary bypass technique: mean pressure of 60 mmHg via roller pump, Hartmann’s priming solution, hollow fibre oxygenator, no hemofiltration and cooling to 30°C nasopharyngeal. Flow was adjusted according to calculated index of 2.4 L/min/m2 body surface area and pressure was adjusted with conventional pharmacological pressors (metaraminol and noradrenaline) and dilators with regard to mixed venous oxygen, temperature, pH and lactate on thirty minutely blood gas estimation. Myocardial protection was with St Thomas’ blood cardioplegia at 14°C administered twenty minutely. Cardiopulmonary bypass was weaned following rewarming to 36.5°C nasopharyngeal in the presence of normal rhythm.



eFigure 2: Mean total protein intake from study intervention, EN and PN whilst in the study ICU/HDU.

Legend, eFigure 2: Sx: Surgery; Error bars indicate 95% confidence intervals around differences between groups at each time point. Note: Total protein intake differs significantly between groups on each first three study days (P < 0.001).



eFigure 3: Estimated Glomerular Filtration Rate (CKD-EPI Cystain C) by study day, percent change from pre-surgery baseline.

Legend, eFigure 3: CKD-EPICystatin C: Glomerular filtration rate estimated from Cystatin C using the equations developed by Stevens et al (1); Sx: Surgery; Note: P = 0.35 for between group difference from repeated measures ANOVA. Error bars indicate 95% confidence intervals around differences between groups at each time point.



eFigure 4: Blood urea (mmol/L) by study day.

Legend, eFigure 3: Sx: Surgery; Note: P = 0.0283 for between group difference from repeated measures ANOVA infusion (8.35 ± 8.33 vs. 11.39 ± 8.98 mmol/L). Error bars indicate 95% confidence intervals around differences between groups at each time point.



eTable 1: Covariate adjusted analysis for duration of renal dysfunction.

Covariate Regression Parameter

Standard Error

P-value Covariate adjusted

Relative Risk

Study group Amino Acid Supplement vs. Standard Care

-0.1537 0.7587 0.8395 0.8576

Baseline creatinine µmol/L 0.0388 0.0111 0.0005 1.04

Peripheral vascular disease yes vs. no 1.7511 0.7016 0.0126 5.76

Baseline eGFR < 30 yes vs. no 1.8926 0.8180 0.0207 6.63

CABG: coronary artery bypass graft. eTable 2: Covariate adjusted analysis for duration of AKI

Covariate Regression Parameter

Standard Error

P-value Covariate adjusted

Relative Risk

Study group Amino Acid Supplement vs. Standard Care

-3.7114 0.7720 <0.0001 0.0244

Baseline renal dysfunction Creatinine > 168 µmol/L -1.6963 0.7323 0.0205 0.1834

Chronic Kidney Disease Yes / no 1.1957 0.5507 0.0299 3.306

Baseline eGFR < 30 yes vs. no 3.6859 0.5780 <0.0001 39.88



eTable 3: Patient characteristics on day of initiating RRT

Standard Care

1 patient

Amino Acid Supplement

4 patients p-value

Creatinine, mean (SD) µmol/L

257 191 (88) N/A

Fluids administered, mean (SD), All fluids, mL/24 h 656 2211 (1443) N/A

Total urine output, mean (SD) mL/24 h,

65 671 (205) N/A

Oliguria, n (%) < 100mL over 6 consecutive hours.

1 (100%) 2 (50%) N/A

Potassium, mean (SD) mmol/L

4.8 4.6 (0.2) N/A

Urea, mean (SD) mmol/L

12.2 25.9 (19.1) N/A

Urea > 30 mmol/L, n (%) 0 (0%) 2 (50%) N/A

* RRT: renal replacement therapy; SD: standard deviation

Reference List

1. Stevens LA, Coresh J, Schmid CH et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis 2008;51:395-406.



Appendix 1: Eligibility Criteria Inclusion Criteria Patients with eGFR < 90 mL/min/1.73m2 who are scheduled to undergo on-pump valve replacement or on-pump coronary artery bypass graft surgery expected to require longer than one hour on-pump will be considered eligible. Unless at least one of the Exclusion Criteria listed below is met, these patients will be approached to provide informed consent to participate. Patients who provide informed consent to participate will be randomly allocated to receive a study intervention, unless at least one Exclusion Criteria listed below is met. <Exclusion criteria continued next page.>



Exclusion Criteria Patients will be considered ineligible to enrol or randomise for the trial if any of the following exclusion criteria are met at the time of screening: (Answer NO to all questions to enrol)

Note: The Exclusion criteria are continued over two pages: 1) Was the actual on-pump time surgical time less than 1 hour?

[Time of any procedures performed off-pump do not contribute towards ‘on-pump’ surgical time.] 2) The Patient does not have a working central venous access line through which the study intervention could be delivered? 3) The patient is not able to tolerate at least 1L of fluid volume per day? [The study intervention may involve the delivery of up to one litre of amino acids per day. This volume of amino acids can replace equivalent volumes from other fluids being received.]

4) The patient is currently less than 18 years old?

5) Is the patient receiving an NSAID, with specific emphasis on COX-2 inhibitors during their ICU or hospital stay? [‘Receiving' means that it is currently known that the patient will receive the NSAID or COX-2 inhibitor during their ICU and hospital stay. If the patient does NOT plan to continue receiving one of these drugs daily, they may be enrolled. COX-2 inhibitors include Celecoxib, Paracoxib, Etoricoxib. NSAIDS include > 160mg Aspirin or any dose of Ibuprofen, Naproxen, Piroxicam, Indomethacin, Meloxicam, Mefenamic Acid, Diclofenac, Prioxicam, Ketoprofen, Tiaprofenic Acid, Ketorolac.] 6) Is the patient currently enrolled into a clinical trial evaluating a nitric oxide (NO) inhibitor? 7) Is the patient receiving Acetazolamide, which is a diuretic that works on the proximal tubule? 8) Is the patient's current known eGFR < 20 mL/min/1.73m2? [See Appendix 2: Maximum Creatinine Table to translate serum creatinine into eGFR.] 9) Is the patient currently known to have severe Acute Kidney Injury, defined as:

• Current serum creatinine (SCr) increased 3 times pre-acute illness value OR • SCr >350 μmol/L with recent increase greater than 44 μmol/L?

[Note: If pre-acute illness creatinine values are unknown, assume upper limit of normal: 90 μmol/L for females and 110 μmol/L for males.] Continued on next page.....



Exclusion Criteria continued Patients will be considered ineligible for the trial if any of the following exclusion criteria are met at the time of screening: (Answer NO to all questions)

10) Is the patient receiving or scheduled to begin dialysis / renal replacement therapy? 11) Has the patient ever had a kidney transplant? 12) Is the patient expected to receive palliative care only and is not expected to survive ICU or hospital discharge? 13) Is the patient moribund and not expected to survive 24 hours? 14) Is the patient brain dead or suspected to be brain dead? 15) Has the patient been taking Nardil (phenelzine) within the last 6 weeks? [Nardil (phenelzine) is an uncommonly used anti-depressant. It may be used in people who are resistant to other treatment for major depression or anxiety disorders. Because of its unique side-effect profile, and explicit drug interactions (meperidine, epinephrine, norepinephrine), a history of Nardil (phenelzine) use is usually found clearly documented in the patient's charts.] 16) Has the patient previously been enrolled and randomised into this study? 17) Does the patient have a documented contraindication to the study intervention (IV amino acids), as listed on the TGA product licensing document? TGA Product Licensing Contraindications, Synthamin 17 EF: (Answer NO to all questions) 17A. Is the patient known to be pregnant or currently breastfeeding? 17B. Does the patient have severe liver disease (Biopsy proven cirrhosis, or documented portal hypertension with a known past history of either upper GI bleeding attributed to portal hypertension or of hepatic failure leading to encephalopathy / coma)? 17C. Does the patient have a documented hypersensitivity (known allergy) to one or more of the included amino acids? [Known allergies will be clearly documented in the Patient's Charts. See Product Details for complete list of Ingredients.] 17D. Does the patient have a documented inborn error of amino acid metabolism? [Ex. Phenylketonuria (PKU), Maple Syrup Urine Disease. These disorders are actively screened for during childhood. If present, they will be clearly documented in the patient's charts and will likely be accompanied by strict directions to consult a Dietitian prior to providing nutritional support. Other less common inborn errors include: atypical phenylketonuria, hereditary tyrosinaemia, biotinidase deficiency, methylmalonic aciduria, glutaric acidemia, methylglutaconic acidemia.] <End of exclusion criteria>



Appendix 2: Maximum Creatinine Table. Age and Gender adjusted maximum allowable creatinine for enrolment. See Exclusion Criteria 8.

Females Age (years) 18 19

serum Creatinine (µmol/L) 284 282 Age (years) 20 21 22 23 24 25 26 27 28 29

serum Creatinine (µmol/L) 279 277 274 272 270 268 266 265 263 261 Age (years) 30 31 32 33 34 35 36 37 38 39







serum Creatinine (µmol/L) 214 214 213 213 213 212 212 211 211 211 Age (years) 100 101 102 103 104 105 106 107 108 >109

serum Creatinine (µmol/L) 210 210 209 209 209 208 208 208 207 203

Males Age (years) 18 19

serum Creatinine (µmol/L) 368 365 Age (years) 20 21 22 23 24 25 26 27 28 29








serum Creatinine (µmol/L) 277 277 276 276 275 275 274 274 273 273 Age (years) 100 101 102 103 104 105 106 107 108 >109

serum Creatinine (µmol/L) 272 272 271 271 270 270 269 269 269 264



Appendix 3: Grant submitted to Heart Research Foundation <begin next page>

Page 1 of 24

NORTH SHORE HEART RESEARCH FOUNDATION RESEARCH GRANT Application for 2012 funding

PROJECT SUMMARY

Project Title:

Nephro-protective effects of L-amino acids in cardiac surgery patients: A pilot randomised controlled trial

The title should be precise & informative to workers outside your field. This information may be used for publicity purposes Principal Investigator / 1st Named Co-Principal Investigator :

A/Prof Gordon S. Doig and Dr. John Brereton

See also following pages for additional information required Brief Project Title: Preventing kidney injury after cardiac surgery: A pilot project.

Abbreviated title to be used for correspondence, identification etc Amount Requested: $144,168 over 3 years

Awards of up to $50,000 p.a. are available for up to 3 years

Commercial-in-Confidence Material: YES NO

If YES, indicate any special security measures that may be required

KEYWORDS:

List up to 6 keywords that refer to your project. These will assist the Committee to assign appropriate assessors. You may use NHMRC keywords or other words appropriate to your topic (eg health outcomes; program evaluation)

1. Acute Kidney Injury 1st Keyword – describe your broad research area

2. Cardiac Surgery 2nd Keyword – describe your broad discipline area

3. Nutrition

4. Critical illness 5. Renal replacement therapy 6.

Page 2 of 24

INVESTIGATOR DETAILS

PRINCIPAL INVESTIGATOR / CO-PRINCIPAL INVESTIGATOR Complete a separate form for the Principal and each Co-Principal Investigator (see also (2) following) Name: A/Prof Gordon Doig Title First Name Last Name

Position: Head, Northern Clinical School Intensive Care Research Unit and Associate Professor in Intensive Care

Current Appointment : Permanent. Indicate if permanent/temporary; full-time/part-time. If temporary, give details

Discipline: Intensive Care Department/Section: Medicine Postal Address: Royal North Shore Hospital Intensive Care Unit, Pacific Hwy, St Leonards, NSW Phone: 9926 8656 Fax: 9439 8418 Mobile: 0425 287 010 E-mail Address: [email protected] Time to be spent on this project : Indicate the amount of time to be spent on this project in average days/month 5 days per month Previous RNSH or NSHRF Grants : List the project numbers, names & publications arising or all previous NSH research grants held since 2006. nil Other Research Grants (currently & previously held since 2006). Provide project title, funding body & level of funding for each year the project was funded 2011-2012 Sydney Medical School Cardiothoracic Surgery Research Grant Scheme Investigators: Doig GS and Sweetman EA. Subject: A systematic review and meta-analysis of outcomes attributable to off-pump coronary artery

bypass surgery without aortic manipulation compared to on-pump coronary artery bypass surgery.

Funding: $24,000 2010-2015 National Health & Medical Research Council Enabling Grant Investigators: Bellomo R, Myburgh J, Finfer SR, Cooper DJ, Lipman J, Doig GS and Hillman K. Subject: ANZICS Centre for Clinical Trials. Funding: $2,500,000 2010-2014 National Health & Medical Research Council Project Grant Investigators: Doig GS, Simpson F, Caterson I, Davies AR, McLean A, Bellomo R, Chesher D, Ferrie S,

Harrigan P, Nair P and Nalos M. Subject: Management of refeeding syndrome in critical illness: An AuSPEN endorsed multicentre

clinical trial. Funding: $1,308,800 2010-2013 National Health & Medical Research Council Project Grant Investigators: Doig GS, Bellomo R, Davies AR, Simpson F, Reade M, Pollock C, Chesher D, Harrigan P,

Devarajan, P, Botha J and Sweetman EA. Subject: Nephro-protective effects of L-amino acids in critically ill patients: A multi-centre randomised

controlled trial. Funding: $829,300

Page 3 of 24

2010-2012 Baxter Health Care Pty Ltd, Investigators: Doig GS, Simpson F, Sweetman EA and Bellomo R. Subject: The effects of amino acid supplementation in critically ill patients at high risk of clinically

significant renal dysfunction: Product support for a multi-centre randomised controlled trial. Funding: $142,920 2010 Fresenius Kabi Deutschland GmbH. Investigators: Doig GS and Simpson F. Subject: Provision of parenteral nutrition to support a Level I RCT of early parenteral nutrition. Funding: $110,000 2009 Research Infrastructure Block Grant, Northern Clinical School, University of Sydney, Investigators: Doig GS, Pollock C and Simpson F. Subject: Redundant Array of Inexpensive Drives (RAID) to facilitate secure and redundant data storage

for Northern Clinical School web-based clinical trials. Funding: $2,539 2009-2010. Sydney Medical School Cardiothoracic Surgery Research Grant Scheme, Investigators: Doig GS and Sweetman EA. Subject: A systematic review and meta-analysis of outcomes attributable to off-pump coronary artery

bypass surgery without aortic manipulation. Funding: $20,000 2009-2010 Baxter Health Care Pty Ltd, Investigators: Doig GS, Simpson F, Sweetman EA and Bellomo R. Subject: Background work in preparation for a multi-centre randomised controlled trial: The effects of

amino acid supplementation in critically ill patients at high risk of clinically significant renal dysfunction.

Funding: $20,000. 2008 Research Infrastructure Block Grant, Northern Clinical School, University of Sydney, Investigators: Doig GS and Pollock C. Subject: Robust, redundant server cluster to support Northern Clinical School web-based clinical trials. Funding: $20,000 2006-2010 National Health & Medical Research Council Project Grant, Investigators: Doig GS, Cooper DJ, Finfer SR, Simpson F, Solano T, Peake S and Davies A. Subject: Early parenteral nutrition vs. standard care in the critically ill patient: A Level I randomised

controlled trial. Funding: $1,812,750 2006-2010 Fresenius Kabi Deutschland GmbH. Investigators: Doig GS and Simpson F. Subject: Provision of parenteral nutrition to support a Level I RCT of early parenteral nutrition. Funding: $418,900 2006-2009 Fresenius Kabi Deutschland GmbH. Investigators: Simpson F and Doig GS. Subject: The clinical utility of body composition spectroscopy (using the BodyScout monitor) in the

critically ill: An add-on study to a Level I RCT. Funding: $10,000 in equipment 2006 Research Infrastructure Block Grant, Northern Clinical School, University of Sydney, Investigators: Doig GS, Finfer SR, Piper R and Raper R. Subject: Critical care research network upgrade. Funding: $30,000 Expected Commitments for 2012 - List the project details and time required on each Nephro-Protective Trial (NHMRC Project Grant) = 7 days per month (30% of time). Refeeding Syndrome Trial (NHMRC Project Grant) = 7 days per month (30% of time).

Page 4 of 24

TRACK RECORD For each principal investigator a brief CV (maximum ½ page) should be attached for track record evaluation. Track records will be assessed relative to opportunity. Brief Track Record: A/Prof Gordon Doig A/Prof Gordon S. Doig completed his Research Fellowship in Critical Care Medicine (WJ Sibbald, University of Western Ontario, London, Canada) in 1996 and his PhD in Epidemiology and Biostatistics (JM Robertson, University of Western Ontario, London, Canada) in 1999. He received the US Society of Critical Care Medicine's In-Training Fellow Award for his work in sepsis in 1996 and was awarded the Foundation Visitor's Medal from the ANZ Faculty of Intensive Care in 1998 for his contributions to evidence-based critical care. In 1999 he was invited to China as a Short Term Consultant for the WHO and in 2000, he was the Year 2000 Royal Perth Hospital Visiting Professor. In 2001 he was recruited from Canada to the Royal North Shore Hospital, Sydney. GSD has been a Chief Investigator on 45 grants totaling over $20 million dollars, many of which were awarded by Major National and National-level funding agencies. He currently manages an active funding base of over $4 million. He was a member of the management committee of the 7,000 patient NHMRC funded Saline vs. Albumin Fluid Evaluation (SAFE) study, which was published in the NEJM and was also a member of the management committee of the 21,000 patient NHMRC funded Medical Early Response Intervention Trial (MERIT) trial, which has been published in the Lancet. Currently, he is CI-A on three active NHMRC Project Grants supporting multi-centre clinical trials. GSD is an Associate Editor for the peer-review methodological journal Trials and reviews more than 30 submissions a year for JAMA, BMJ and ten other leading specialty journals. He has reviewed Project Grant submissions for the NHMRC Large Scale Clinical Trials Grant Review Panel, served as an external reviewer for other NHMRC Panels and reviewed grants for the Canadian Institutes of Health Research. In addition to being the Primary Supervisor of 4 PhD students, GSD has published 103 research papers in leading specialty and general journals, 3 research books, and 15 book chapters. He has delivered 13 invited plenary lectures, 81 invited talks and has organised and conducted 20 workshops at International and National level meetings. GSD’s track record of involvement in successful collaborative research projects leading to key publications clearly indicates that he is capable of successfully managing and completing a trial of the scope proposed in this submission.

Page 5 of 24

PROJECT DETAILS

Please provide details of your project, addressing the following : 1. SIMPLIFIED DESCRIPTION: More than 7,000 Australians undergo cardiac surgery each year with up to one third of these patients developing new onset Acute Kidney Injury during their hospital stay. The development of Acute Kidney Injury leads to longer recovery times, may require lifelong dialysis, and is associated with increased risk of death. The purpose of this clinical trial is to determine if a simple and cheap amino acid infusion can reduce the onset of Acute Kidney Injury resulting from cardiac surgery. 2.CO-PRINCIPAL INVESTIGATORS Provide information about each co-principal investigator in the format requested for Principal Investigator (above), including time to be spent on the project. Dr. John Brereton, Cardiovascular Surgery, RNSH (2 days per month) Professor Carol Pollock, Nephrology, RNSH (1 day per month) Elizabeth A. Sweetman, Northern Clinical School Intensive Care Research Unit, RNSH (7 days per month) For complete details please see page 6 for Dr. Brereton and page 8 for Prof Pollock and page 11 for Ms Sweetman.

Page 6 of 24


PRINCIPAL INVESTIGATOR / CO-PRINCIPAL INVESTIGATOR Complete a separate form for the Principal and each Co-Principal Investigator (see also (2) following) Name: Dr John Brereton Title First Name Last Name

Position: VMO, Departmant of Cardiothoracic Surgery

Current Appointment : VMO, Permanent

Indicate if permanent/temporary; full-time/part-time. If temporary, give details

Discipline: Cardiothoracic Surgery Department/Section: Surgery Postal Address: Royal North Shore Hospital, Dept of Cardiac Surgery, Pacific Hwy, St. Leonards, NSW Phone: 9439-9699 Fax: 9436-3613

Mobile: E-mail Address: "R. Brereton" <[email protected]>

Time to be spent on this project : Indicate the amount of time to be spent on this project in average days/month 2 days per month. Previous RNSH or NSHRF Grants : List the project numbers, names & publications arising or all previous NSH research grants held since 2006. nil Other Research Grants (currently & previously held since 2006). Provide project title, funding body & level of funding for each year the project was funded nil Expected Commitments for 2012 - List the project details and time required on each Systematic review of ‘no-touch aorta’ cardiac bypass surgery – 1 day per month.

Page 7 of 24

TRACK RECORD For each principal investigator a brief CV (maximum ½ page) should be attached for track record evaluation. Track records will be assessed relative to opportunity. Brief Track Record: Dr John Brereton Dr Brereton graduated from medical school in 1983 and completed his General Surgical training at John Hunter Hospital in 1992 then completed Cardiothoracic Surgical training at Royal North Shore Hospital and Prince Henry Hospital in 1996. He has been a cardiothoracic surgeon with the Royal North Shore Hospital since 1997 and was the Head of the Cardiothoracic Surgery Department between 2004 and 2008. He received the Robert Craig Memorial Prize in Surgery at Sydney University in 1983. In 2001 he conceived procedures combining off-pump coronary surgery, total arterial revascularisation and multiple non-aortic inflows, simultaneously with surgeons elsewhere in the world. This was with the intent of adding to the known survival benefit of the left mammary to left anterior descending graft by increasing both early and long-term survival in patients treated surgically for coronary disease. By 2004 a likely reduction in the operative risk of stroke was apparent and the term “anaortic” defined to denote an operation with the important distinction of absence of aortic handling and absence of cardiopulmonary bypass. By 2007 it was clear that the risk of stroke in patients undergoing the anaortic procedure at Royal North Shore Hospital was significantly and substantially lower than in those undergoing the standard procedure or the off-pump procedure. In 2008 and 2009 an exhaustive systematic review was conducted confirming support for these findings from other units throughout the world. As well as publication of these results in national and international cardiothoracic journals, he has been an invited speaker at the Annual Scientific Meetings of the Australian Society of Cardiothoracic Surgeons, the Royal Australasian College of Surgeons, the Cardiac Society of Australia and New Zealand, and the Australian and New Zealand College of Anaesthetists. He has co-authored 6 research papers on this subject alone since 2008 and is seeking funding for his Department’s first clinical trial.

Page 8 of 24


CO-PRINCIPAL INVESTIGATOR 2 Name: Prof Carol Pollock Title First Name Last Name

Position: Renal Physician

Current Appointment : Permanent Indicate if permanent/temporary; full-time/part-time. If temporary, give details

Discipline: Medicine Department/Section: Nephrology Postal Address: Royal North Shore Hospital, Dept of Nephrology, Pacific Hwy, St Leonards, NSW 2065 Phone: 9926 7126 Fax: 9436 3719 Mobile: E-mail Address: [email protected] Time to be spent on this project : Indicate the amount of time to be spent on this project in average days/month 1 day per month. Previous RNSH or NSHRF Grants : List the project numbers, names & publications arising or all previous NSH research grants held since 2006. nil Other Research Grants (currently & previously held since 2006). Provide project title, funding body & level of funding for each year the project was funded 2011 – 2012 National Health and Medical Research Council Project Grant Investigators: W Cheung, L Campbell, W Middleton, CA Pollock, GR Flucher, W Watt, P McElduff, Subject: Diabetes Case Detection Through Emergency Department Admissions Funding: $160, 016 2011-2013 National Health and Medical Research Council Project Grant Investigators: CA Pollock J Forbes and U Panchapakesan Subject: Sodium dependent glucose transport and diabetic nephropathy. Funding: $489,000 2010-2013 National Health and Medical Research Council Project Grant Investigators: Doig GS, Bellomo R, Davies AR, Simpson F, (CA Pollock as AI) Subject: Nephro-protective effects of L-amino acids in critically ill patients: A multi-centre RCT. Funding: $829,300. 2010 : Hillcrest Foundation Investigator: CA Pollock Subject: A novel therapeutic target to prevent fibrosis in the diabetic kidney: KCa3.1 Funding: $50,000 2010 Boehringer Ingleheim Investigators: C Pollock and A Mather Subject: Renal Protection with SGLT2 inhibition Funding: $118,000 2010-2012 National Health and Medical Research Council Partnership Grant Investigators: M Haines and co-investigators (including C Pollock as AI) Subject: Determinants of effective clinical networks Funding: $1,000,000

Page 9 of 24

2010-2012 National Health and Medical Research Council Project Grant Investigators: S Chadban, CA Pollock, Wu H, U Panchapakesan Subject: The role of Toll-like receptors in diabetic nephropathy Funding: $800,000 2009-10: Hillcrest Foundation Investigator: CA Pollock Subject: A novel therapeutic target to prevent fibrosis in the diabetic kidney: KCa3.1 Funding: $50,000 2008-9: Hillcrest Foundation Investigator: CA Pollock Subject: Krüppel-like factors KLF4 and KLF6 and their regulation on macrophage migration inhibitory

factor (MIF) in modifying inflammation and repair process in diabetic nephropathy Funding: $50,000 2008-2010 National Health and Medical Research Council Project Grant Investigators: CA Pollock, X Chen, W Qi Subject: TGFbeta isoforms differentially regulate fibrosis and inflammation in diabetic nephropathy via

KLF transcription factors Funding: $518,750 2007-8: Hillcrest Foundation Investigator: CA Pollock Subject: Kruppel like transcription factors and oxidative stress in epithelial to mesenchymal

transformation Funding: $50,000 2007-9: National Health and Medical Research Council Project Grant Investigators: CA Pollock S Saad Subject: The role of peroxisome proliferator activated receptor gamma in sodium transport in human

proximal tubule cells Funding: $544,500 2007-9: National Health and Medical Research Council Project Grant Investigators: CA Pollock D Harris, B Cooper Subject: Initiating Dialysis Early and Late Trial Funding: $662,053 2006-7: Hillcrest Foundation Investigator: CA Pollock Subject: Kruppel like transcription factors and oxidative stress in epithelial to mesenchymal

transformation Funding: $50,000 Expected Commitments for 2012 - List the project details and time required on each NHMRC Diabetes case detection project grant: 1 day per month NHMRC Sodium dependent glucose transport project grant: 3 days per month NHMRC Determinants of effective clinical networks partnership grant: 1 day per month NHMRC Toll-like receptors in diabetic nephropathy project grant: 2 days per month

Page 10 of 24

TRACK RECORD For each principal investigator a brief CV (maximum ½ page) should be attached for track record evaluation. Track records will be assessed relative to opportunity. Brief Track Record: Professor Carol Pollock Professor Pollock commenced her basic research interests in progressive renal disease during her PhD studies in 1988. To date she has supervised to completion 11 PhD students one Masters and one BSc(Med) student. She is currently supervising 5 PhD students in the areas of progressive renal disease and vascular complications of diabetes mellitus. Hence she plays a key role in mentoring junior scientific staff. In the last 2 yrs Prof Pollock has delivered 7 invited addresses to National Societies (Renal, Cardiac and Endocrinology meetings) and 6 invited addresses to International meetings. She has current editorial responsibilities for The Clin J Am Soc Nephrol, having previously been a subject Editor for Nephron and Nephrology. She is on the publications committee of the International Society of Nephrology with oversight of Kidney International, Nature Clinical Practice Nephrology and the Gateway website and is the Editor of ISN News. In 2007 she was a member of the NHMRC Discipline Panel in Cardiac Renal and Exercise Physiology, having served on multiple discipline panels and RGICs as a member and deputy chairperson since the early 1990’s. She was an NHMRC assigner in 2008. She reviews for multiple grant giving bodies nationally and internationally. Prof Pollock has authored over 165 publications to date, the majority as first or senior author. She is currently Chairman of the Northern Sydney Local Health District Board, immediate past Chairperson and now member of the Board of the Clinical Excellence Commission and of the Agency for Clinical Innovation (both Statutory Bodies of NSW Health, immediate past Chairman of Area Health Advisory Council for the Northern Sydney Central Coast Area Health Service (NSCCAHS), Research Chairman of the NSCCAHS, Associate Director of the Kolling Institute and Chairman of the Clinical Variation in Practice subcommittee of the Health Efficiency taskforce (an interagency committee comprised of NSW Treasury, Office of the Premier and Cabinet and Dept of Health) . She currently serves on the Ministerial Health Advisory Committee, the NSW Health Leadership Committee and Steering Committees for the NSW Health Atlas and the Independent Pricing Authority and Regulatory Tribunal (IPART) review in NSW hospital care. She currently serves on the executive of the NSW Cardiovascular Research Network, an initiative of the NSW Office of Science and Medical Research and the Heart Foundation. She is a founding director and Chairman of BioMed North, a company supporting the development of intellectual property out of Area Health Services, and sits on the Board of several philanthropic organisations supporting medical research.

Page 11 of 24

INVESTIGATOR DETAILS CO-PRINCIPAL INVESTIGATOR 3 Name: Ms Elizabeth Sweetman Title First Name Last Name

Position: Senior Research Fellow, Northern Clinical School Intensive Care Research Unit

Current Appointment : Permanent.

Discipline: Intensive Care Department/Section: Medicine Postal Address: Royal North Shore Hospital Intensive Care Unit, Pacific Hwy, St Leonards, NSW Phone: 9926 8656 Fax: 9439 8418 Mobile: E-mail Address: [email protected] Time to be spent on this project : Indicate the amount of time to be spent on this project in average days/month 7 days per month Previous RNSH or NSHRF Grants : List the project numbers, names & publications arising or all previous NSH research grants held since 2006. nil Other Research Grants (currently & previously held since 2006). Provide project title, funding body & level of funding for each year the project was funded 2011-2012 Sydney Medical School Cardiothoracic Surgery Research Grant Scheme Investigators: Doig GS and Sweetman EA. Subject: A systematic review and meta-analysis of outcomes attributable to off-pump coronary artery

bypass surgery without aortic manipulation compared to on-pump coronary artery bypass surgery.

Funding: $24,000 2010-2013 National Health & Medical Research Council Project Grant Investigators: Doig GS, Bellomo R, Davies AR, Simpson F, Reade M, Pollock C, Chesher D, Harrigan P,

Devarajan, P, Botha J and Sweetman EA. Subject: Nephro-protective effects of L-amino acids in critically ill patients: A multi-centre randomised

controlled trial. Funding: $829,300 2010-2012 Baxter Health Care Pty Ltd, Investigators: Doig GS, Simpson F, Sweetman EA and Bellomo R. Subject: The effects of amino acid supplementation in critically ill patients at high risk of clinically

significant renal dysfunction: Product support for a multi-centre randomised controlled trial. Funding: $142,920 2009-2010. Sydney Medical School Cardiothoracic Surgery Research Grant Scheme, Investigators: Doig GS and Sweetman EA. Subject: A systematic review and meta-analysis of outcomes attributable to off-pump coronary artery

bypass surgery without aortic manipulation. Funding: $20,000 2009-2010 Baxter Health Care Pty Ltd, Investigators: Doig GS, Simpson F, Sweetman EA and Bellomo R. Subject: Background work in preparation for a multi-centre randomised controlled trial: The effects of

amino acid supplementation in critically ill patients at high risk of clinically significant renal dysfunction.

Funding: $20,000

Page 12 of 24

Expected Commitments for 2012 - List the project details and time required on each Nephro-Protective Trial (NHMRC Project Grant) = 7 days per month (30% of time).

TRACK RECORD

For each principal investigator a brief CV (maximum ½ page) should be attached for track record evaluation. Track records will be assessed relative to opportunity. Brief Track Record: Elizabeth A. Sweetman Elizabeth A. Sweetman is a Senior Research Fellow with the Northern Clinical School Intensive Care Research Unit, University of Sydney and Royal North Shore Hospital. Elizabeth is currently in the second year of her PhD entitled “Towards improving the conduct of large-scale clinical research projects: Appropriateness of organisational structures”.

Since commencing her PhD in 2009, Elizabeth has co-authored 7 papers and has recently had her first paper accepted as lead author. Elizabeth has also presented these projects at National and International conferences in the form of posters (4) and oral presentations (1). She will present her most recent poster at the upcoming European Society of Intensive Care Medicine meeting in Berlin, October 2011. Elizabeth was awarded the Beryl and Jack Jacobs International Travel Award from the RNSH to support this research presentation.

In addition to her outstanding research output for a second year PhD student, Elizabeth is a Chief Investigator on two grants from the Sydney Medical School Cardiothoracic Surgery Research Grant Scheme and an Associate Investigator on an NHMRC Level I Project Grant which funds a multi-centre clinical trial evaluating the role of amino acids in the prevention of Acute Kidney Injury in critically ill patients. She is also a Chief Investigator on two Industry funded grants. As a result of the recognition she has received for her contributions to critical care research, Elizabeth was recently awarded a highly prestigious Visiting Fellowship to the UK’s Intensive Care National Audit and Research Centre. Elizabeth was the ICNARC Visiting Fellow from 31st May till 16th June, 2011. In addition to her own research focus, Elizabeth is member of the Management Commitment of three ongoing major multi-centre clinical trials: the NHMRC funded Early PN Trial, the NHMRC funded Nephro-Protect Trial and the NHMRC funded Refeeding Syndrome Trial. Elizabeth has a strong research interest in the conduct of clinical trials, educational delivery at the commencement of a trial and protocol violations over the course of a clinical trial. Her past research output and involvement in successful major clinical trials demonstrates she has the background, skills and knowledge to successfully design, manage and complete a project of the scope described in this grant submission.

Page 13 of 24

3.ASSOCIATE INVESTIGATORS Provide brief details for each associate investigator, including time to be spent on the project Fiona Simpson, Senior Research Fellow, Northern Clinical School Intensive Care Research Unit, RNSH (2 days per month) Philippa T. Heighes, Research Fellow, Northern Clinical School Intensive Care Research Unit, RNSH (2 days per month) Doug Chesher, Head, Pathology North (0.5 day per month) 4. PROJECT DETAILS a) Name of operational unit(s)/service(s) where this work will primarily be conducted This work will be conducted in the Department of Cardiothoracic Surgery and the Department of Intensive Care (Cardiothoracic Intensive Care Unit). b) What are the specific objectives of the research project to be achieved within the period of the grant? 1. Hire staff, refine protocol and obtain final HREC approval by June 2012. 2. Site education leading to first patient recruited before Sept 2012. 3. Recruit last patient Dec 2013. 4. Submit final manuscripts for publication June 2014. c) Is the research detailed in this application related to a research project previously funded by a NSH or

NSHRF research grant? No. d) Is the research outlined in the application related to a larger or ongoing project? Indicate “yes” or “No”. If Yes, provide details including the name of the principal researcher, the unit which is primarily funding the project, the source of the project’s funds and the nature of the contribution that this project is likely to make to the larger project. Yes. The principal investigator (A/Prof Gordon Doig) received $829,000 from the NHMRC to investigate the effects of an amino acid infusion on the prevention of kidney injury during critical illness. This larger trial (474 patients) is currently recruiting at 16 hospitals throughout ANZ and will complete recruitment in 2015. The larger trial has generated important dosing and safety information that has been used to inform the design of this current project however the larger trial will not recruit cardiac surgery patients. The current project, to be funded by the NSHRF, will generate important information regarding the effectiveness of this intervention in cardiac surgery patients. e) Has any other research support been sought for this project? No. Other support has not been sought for this project. f) Project start date 1 January 2012. We will have the study completely designed and obtain final HREC and Guardianship Tribunal approval within the first 6 months of 2012. g) Project completion date (where applicable) Recruitment will complete by end of 2013 with final manuscripts to be submitted before June 2014. h) Departmental/Unit/Facility and organisational support for the project The Northern Clinical School’s Intensive Care Research Unit will provide the necessary methodological expertise and infrastructure to conduct, analyze and interpret this clinical trial. Pathology North has committed to run the Cystatin C assays. The Department of Cardiovascular Surgery will support the trial in all other aspects of conduct.

Page 14 of 24

5. RESEARCH PROPOSAL Background More than 7,000 patients undergo cardiac bypass surgery throughout Australia each year with up to 30% of these patients developing new onset Acute Kidney Injury (AKI) after their surgery. Mild AKI after bypass surgery is associated with the need for a longer hospital stay however in twenty percent of patients who develop AKI, it is severe enough to require renal replacement therapy (RRT).1 Severe AKI requiring RRT is associated with a significantly higher risk of death and may increase costs of care by up to 60% compared to matched cardiac surgery patients who do not require RRT.2

AKI after cardiac surgery presents a significant health burden to individual patients and exacts a considerable toll on societal resources. Interventions targeting patients at risk of AKI may significantly reduce the burden of illness and could significantly reduce costs to the Australian health care system. Effects of L-amino acids on renal haemodynamics It is widely accepted that dietary protein intake has a major influence on renal hemodynamics, both acutely and chronically. In the healthy adult, renal blood flow and glomerular filtration rate (GFR) increase by 25 to 60% for several hours after the consumption of a high protein meal or IV infusion of amino acids.3 Animal models of kidney injury demonstrate this hyperfiltration response protects the kidney from ischaemic insults 4 and in vitro and in vivo murine models show that, in the setting of acute tubular necrosis, tubular cells regenerate more rapidly when the kidney is provided with an exogenous source of amino acids.5 Our own work, published in JAMA,6 suggests these protective effects of amino acids may be preserved after cardiac surgery. Our preliminary data: Australian and New Zealand (ANZ) Nutrition Guidelines Trial The ANZ Nutrition Guidelines Trial has recently been published in JAMA.6 It was a 1,118 patient clinical trial that allocated 27 ICUs from throughout Australia and New Zealand to implement an evidence-based guideline for nutritional support or remain as controls. Successful implementation of the nutrition guideline resulted in significantly more patients being fed with nutritional goals achieved significantly more often. These improvements in nutritional support translated into a significantly shorter overall duration of AKI among intervention patients (1.54 vs. 2.12 renal dysfunction days per 10 patient•days, p=0.038).

Furthermore, we observed a dose-response relationship between protein intake and AKI (Figure 1): In all patients, higher protein intake was associated with less AKI. The consistency of this treatment effect was investigated by conducting two additional subgroup analyses: one into patients at high risk of developing AKI at entry into the ANZ Nutrition Guidelines Trial 7 and the second into patients who were enrolled into the trial after cardiac surgery. Two-hundred and fifty-two patients were at high risk of AKI at study entry. Compared to controls, intervention patients at high risk of AKI had significantly higher protein intake (48.3 vs. 37.2 g/day, p=0.047) and were fed on significantly more days of their ICU stay (8.0 vs. 6.5 fed days per 10 day ICU stay, p=0.008). This translated to a significant reduction in need for RRT (33% vs. 46%, p=0.028) and a significantly shorter duration of AKI (3.8 vs. 5.6 days per 10 patient•days, p=0.009). Only 27 cardiac surgery patients were enrolled into the ANZ Nutrition Guidelines Trial (15 controls and 12 guideline

patients). In this small subgroup analysis, cardiac surgery patients appeared less likely to develop AKI (41% vs. 73%, p=0.08) and they recovered from AKI faster (2.4 vs. 4.6 days to recovery, p=0.13) if they were randomised to the nutrition guideline intervention arm of the trial. The hyperfiltration response to protein intake is known to be preserved after cardiac surgery.8 Clinical trials investigating the thermogenic effects of amino acids demonstrate length of stay can be reduced if patients receive an amino acid infusion commenced during cardiac surgery.9 Data presented from our ANZ Nutrition Guidelines Trial suggest amino acids may also reduce the risk of developing new onset AKI after cardiac surgery. A well controlled pilot trial is required to investigate these potentially important benefits.

df

Figure 1. Protein intake and kidney injury in 1,118 critically ill patients

Page 15 of 24

b) Research plan/method (maximum 2 pages) Aim

The effects of a continuous supplementary infusion of a standard mixture of L-amino acids will be compared to standard care with regards to the onset and severity of clinically significant renal dysfunction, need for acute renal replacement therapy (RRT), renal recovery rates, need for ongoing dialysis, and health status (quality of life, physical function and overall survival) at follow-up 90 days after randomisation.

This pilot randomised controlled trial (RCT) will also provide an opportunity to investigate novel risk factors for AKI that may be able to predict response to treatment. Primary outcomes: Measures of renal function The primary outcome for this clinical trial will be days of clinically significant renal dysfunction, defined using the validated global organ dysfunction scale known as the Brussels Table.10 Efficacy will also be assessed by grading the severity of AKI using the RIFLE criteria and expressing the outcome as duration of renal dysfunction above each grade (Ex. days of Risk, days of Injury, days of Failure, etc). Days of RRT and dose of RRT will also be analysed.

In addition to the above measures, renal function and renal recovery will be characterised with baseline and serial measurements of cystatin C. Compared with reference methods, cystatin C has been shown to be more reliable than serum creatinine at assessing GFR in stable chronically ill populations and more sensitive than serum creatinine in critically ill patients. Cystatin C is not a routine biochemical assay conducted at RNSH however Pathology North has agreed to conduct cystatin C assays for this project.

To determine sampling frequency and sampling intervals for cystatin C, we inspected the onset and duration of AKI in patients enrolled into the ANZ Nutrition Guidelines Trial. To obtain optimal coverage of the AKI risk period at the lowest cystatin C assay cost, we intend to collect serum samples at study baseline, Study Day 1 and every second day for the first week followed by every third day up to Study Day 16. Our expected length of stay distribution for the target population of 72 patients indicates this sampling strategy may require 72 x 8 = 576 assays. Secondary outcomes: Measures of morbidity Secondary clinical outcomes will include: duration of ICU and hospital stay; duration of ventilation; need for antibiotics; other organ system dysfunctions; organ system support and; measures of lean body mass. Physical Function and Quality of Life at Day 90 will be characterised using the Zubrod / Eastern Cooperative Oncology Group (ECOG) / WHO Performance Status Scale and the public domain version of the SF-36 questionnaire. Vital status and need for ongoing dialysis will be recorded at day 90. Estimates of resource consumption and outcome benefits generated by this trial will be combined with published costs of treatments to generate an economic simulation to investigate the cost-effectiveness of the study intervention. Sample size and power Data from the ANZ Nutrition Guidelines Trial shows cardiac surgery patients experienced a reduction in the number of days of clinically significant renal dysfunction if they received improved nutritional support (2.4 vs. 4.6 days of renal dysfunction per 10 patient•days, p=0.13). With a standard deviation of 3.31, using standard formulas at 80% power with a two-sided significance threshold of 0.05, a trial of 72 patients (36 in each group) is required to detect a difference between groups of 2.2 days less renal failure (4.6 days – 2.4 days = 2.2 days between groups). Patient eligibility Patients will be screened for eligibility prior to scheduling of cardiac surgery. Patients with pre-existing Chronic Kidney Disease Stage 3 or higher (eGFR < 60 ml/min/1.73m2) who are scheduled to undergo on-pump valve replacement or on-pump coronary artery bypass graft surgery expected to require longer than one hour on-pump will be considered eligible. Detailed eligibility criteria will be developed to exclude patients likely to be harmed and those who are unlikely to benefit. Consent A priori informed consent will be obtained directly from the patient during office visits prior to scheduling of surgery. Recruitment feasibility

The RNSH Department of Cardiothoracic Surgery sees in excess of 200 potentially eligible cases each year. Assuming consent success as low as 40%, we anticipate recruitment of 72 patients in 1 year.

Page 16 of 24

Randomisation Allocation concealment will be maintained through the use of a central randomisation web site that is secure, encrypted and password protected. The web site is hosted by the Northern Clinical School Intensive Care Research Unit in a secure University of Sydney machine room (http://icu-10.med.usyd.edu.au/Research). Within study centre, randomisation will be stratified based on CKD stage. Blocks of variable size and a random seed will be used to ensure allocation concealment cannot be violated by deciphering the sequence near the end of each block. To further protect from deciphering, block size and strata thresholds will not be revealed to site investigators. Study treatments Study intervention:

If randomised to the intervention arm, the patient will receive a continuous infusion of a standard mixture of L-amino acids (Synthamin 17 EF, without electrolytes) delivered at a rate of 42 mls/h to achieve a daily protein intake of at least 100 g/day. The initial infusion will begin one hour before cessation of bypass and will continue until the patient is discharged from the ICU or no longer has a working central line.

If the patient begins to receive any form of nutritional support, the infusion rate of the study L-amino acid intervention will be reduced such that the total protein intake from all sources (nutrition and study intervention) is 2.0g/kg/day. The attending clinician will select the route, starting rate, metabolic targets, and protein goals based on current practice in their ICU.

The use of Synthamin 17EF will be entirely consistent with its TGA licensing indications. Standard care:

Standard care in patients randomised to the control arm will consist of normal post-operative management for all aspects of care, including fluid replacement, nutrition etc. If the patient requires any form of nutritional support the attending clinician will select the route, starting rate, metabolic targets, and protein goals based on current practice in their ICU. Cessation of either study treatment

If at any time during the trial the treating clinician deems that it is in the patient’s best interest due to safety issues then, at the discretion of the treating physician, the study treatment (intervention or standard care) can be withdrawn.

All patients withdrawn from the allocated treatment arm will be followed up according to the study protocol and analysed according to the intention to treat principle. Ancillary treatments

All other aspects of patient management are unaffected by study procedures and the treating clinician will be free to provide whatever care is deemed appropriate and necessary. Analysis of results

The primary findings of this project will be based on analyses conducted under the principle of intention to treat (ITT). All patients enrolled and randomised into the trial will be accounted for and analysed.

The primary outcome, days of clinically significant renal dysfunction, will be analysed using a Poisson model, adjusted with an offset term (ICU length of stay) to account for time at risk.

Baseline variables with a p-value less than 0.15 will be considered to be in imbalance. If imbalance is detected, the primary outcome will be re-assessed using multivariate regression analysis accounting for this imbalance. An exploratory analysis will be undertaken to determine if any demographic or physiological measures recorded at entry into the trial can predict the onset of AKI and response to treatment. Safety and Data Monitoring Committee An independent Safety and Data Monitoring Committee (SDMC), comprising experts in clinical trials, biostatistics, nephrology and intensive care, will be established. The committee will independently review all major serious adverse events blinded to study treatment. Using the Haybittle-Peto approach the SDMC will be charged with informing the study management committee if there emerges a difference in serious adverse events between study groups that exceeds three standard deviations in magnitude. If such a difference occurs, the SDMC will be empowered to conduct a blinded interim analysis on the primary outcome to ensure patient safety. If a difference in the primary outcome exceeds three standard deviations, the SDMC is empowered to stop the trial.

Page 17 of 24

c) References to published work relevant to this application (up to 10) 1. Mitter N, Shah A, Yuh D, et al. Renal injury is associated with operative mortality after cardiac surgery for women and men. J Thorac Cardiovasc Surg 2010;140:1367-7 2. Dasta JF, Kane-Gill SL, Durtschi AJ, et al. Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant 2008;23:1970-4. 3. Woods LL. Mechanisms of renal hemodynamic regulation in response to protein feeding. Kidney International 1993;44(4):659-75. 4. Roberts PR, Black KW, Zaloga GP. Enteral feeding improves outcome and protects against glycerol-induced acute renal failure in the rat. Am J Respir Crit Care Med 1997;156:1265-9. 5. Toback FG, Dodd RC, Maier ER, Havener LJ. Amino acid administration enhances renal protein metabolism after acute tubular necrosis. Nephron 1983;33(4):238-43. 6. Doig GS, Simpson F, Finfer S, et al. Effect of evidence-based feeding guidelines on mortality of critically ill adults: A cluster randomized trial. JAMA 2008;300:2731-41. 7. Doig GS, Simpson F, Sweetman EA and Bellomo R. Improved nutritional support is associated with reduced renal dysfunction in critical illness: A post-hoc exploratory subgroup analysis. Am J Respir Crit Care Med 179;2009:A1567 8. Jeppsson A, Ekroth R, Friberg P, et al. Renal Effects of Amino Acid Infusion in Cardiac Surgery. J Cardiothoracic and Vasc Anes 2000;14(1):51-56. 9. Umenai T, Nakajima Y, Sessler DI, et al. Perioperative amino acid infusion improves recovery and shortens the duration of hospitalization after off-pump coronary artery bypass grafting. Anes Analg 2006;103:1386-93. 10. Bernard GR, Doig GS, Hudson LD, et al. Quantification of organ failure for clinical trials and clinical practice. Am J Resp Crit Care Med 1995;151:A323.

Page 18 of 24

d) Potential impact of the proposal (maximum ½ page) Up to 30% of all patients develop some form of AKI after cardiac surgery. Costs of care and length of stay are accepted to be double those of matched controls, while risk of death may be five-fold higher.3 Thirteen percent of patients who develop new onset AKI while in hospital require RRT for longer than a year. The development of new onset AKI post-cardiac surgery is a significant problem for our patients and our health system. Estimates of treatment effectiveness available from the ANZ Nutrition Guidelines trial suggest new onset AKI may be halved by our study intervention. Given the incidence of AKI, costs of treatment and impact of long term RRT on quality of life, any reduction in incidence, severity or need for long term RRT would be meaningful to patients and our health system. The results of this pilot project will be used to determine whether a larger confirmatory trial is required. Funding for a confirmatory trial will be sought from a major funding body, such as the NHMRC.

Page 19 of 24

6. ETHICAL CONSIDERATIONS Indicate if this proposal will require clearances from ethics or safety committees Clearance will be obtained from the RNSH HREC prior to conducting this study. The NSW Guardianship Tribunal will be consulted for approval to use of proxy/person responsible consent. Clearance from other safety committees should not be required. A priori informed consent will be acquired using an English language consent document only. Participation, rights, risks and benefits will be clearly explained to either the patient and/or their person responsible by the site investigator, co-investigator or designee prior to enrolling a patient into the trial. When a person whose primary language is other than English is approached, and if they appear to have any difficulty understanding English, the site investigator or research nurse making the decision to enrol a patient in the study will contact the hospital's Health Care Interpreter Service in order to arrange for an interpreter to be present whilst the study is explained and consent obtained or to offer a translation by telephone. If this cannot be arranged the patient will not be entered into the trial. People in Dependent Relationships: We recognise that the site investigator or research nurse may sometimes also be responsible for aspects of a potential participant's routine health care. In these situations, great care will be taken to ensure the potential participant does not feel coerced to provide consent. Potential participants will be reassured that any decision to accept or decline participation will not influence the quality of the care they will receive. In some cases, it may be appropriate for consent to be sought by an independent person. Anyone appearing to be particularly vulnerable to undue influence in this situation will be provided with sufficient time to make their own decisions or they may be referred to a patient advocate, with whom they may discuss their decisions. In all cases, to ensure free and informed consent following discussion of the study, we will ask the patient and/or person responsible if they have any further questions, and whether they would like to speak to the site investigator or co-investigator. The patient or person responsible will be given appropriate time to read the study information document and allowed to ask questions of the site investigator or consult members of their family. People Dependent on Medical Care: The development of acute kidney injury after cardiac surgery may increase the risk of death and result in the need for long term dialysis. Involvement in this study may significantly improve patient quality of life after a catastrophic critical illness. There are no documented risks arising from the appropriate application of this intervention. Aboriginal and Torres Strait Islander peoples: It is possible that Aboriginal and Torres Strait Islander peoples may be cared for at participating sites and may qualify for enrollment into the trial. We are unaware of any aspects of this trial that conflict with the unique cultural distinctiveness of Aboriginal and Torres Strait Islanders who may present for care in participating ICUs.

Page 20 of 24

BUDGET

Detail the budget items requested under this application, with a brief explanation of why they are requested and relative priorities for each item : A: essential (project could not proceed without this item) B: high priority (project would be difficult to undertake without this item) C. lower priority (project would be enhanced by this item, but could proceed without undue difficulty) A: Cystatin C assay (Costed and conducted by Pathology North) 8 samples x 72 patients x $18 per assay. = $10,368 A: Synthamin 17EF (Purchased from Baxter Healthcare) 72 pts x 10 day stay (avg) x 2 bottles per day x $15 per bottle = $21,600 A: Data Management (12 mths data entry during recruitment plus 6 mths data cleaning after last patient enrolled) $18K per year over 1.5 years = $36,000 A: Research Coordinator (Under direction from the Chief Investigators, this person will be responsible for all aspects of daily study conduct, including consent, managing the study intervention, bedside data collection etc.) 14 h per patient @ $46 x 72 pts = $46,800 A: Data base development (Custom database for data entry with error checking algorithms to reduce transcription errors.) $3,000 A: Study web site (Set-up and maintenance of randomisation and patient management web site) $6,000 B: Start-up training (Two day site initiation meeting for all new research staff and site investigators.) $5,000 B: Misc office costs (Printing and binding of study material, protocol, data dictionary, posters etc.) $6,000 C: Dissemination of results (Publication costs plus costs of presentation at one National and one International meeting) $7,000 FUNDING REQUESTED IN FINANCIAL YEARS (FY) IN THE FOLLOWING CATEGORIES:

FY 11/12 (Jan 12 – Jun 12)

FY 12/13

F/Y 13/14 Total

Salaries $18,000 $36,000 $28,800 $82,800

On Costs Included in salary costs

Equipment $3,000 $2,000 $2,000 $7,000

Consumables $17,368 $8,000 $9,000 $34,368

Other Costs $9,000 $2,000 $9,000 $20,000

TOTAL GRANT $47,368 $48,000 $48,800 $144,168

Page 21 of 24

NOMINATION OF ASSESSORS

You may nominate 3 assessors, at least one of whom is outside Royal North Shore Hospital, whom you consider appropriate to provide an assessment of the research proposal. If possible, nominate assessors from within Australia. If assessors’ reports have been received from NHMRC or other funding bodies, these may be attached together with your responses to the assessors’ questions/comments. (see also 4e) The NSHRF Research Advisory Committee will use your nominees or NHMRC assessment if possible. Nominated assessors should not have a conflict of interest with the application. Please ensure that the assessors nominated are available to review your application in October 2011. PREFERRED ASSESSOR (1) Name: Prof Rinaldo Bellomo Title First Name Last Name Position/Institution: Senior Staff Specialist in Intensive Care and Professor of Medicine / Austin Health Postal Address: Austin and Repatriation Medical Centre, Intensive Care Unit, Studley Road, Heidelberg, VIC 3084 Phone: 03 9496 5992 Fax: 03 9496 3932 Mobile n/a E-mail Address: [email protected] Reason : Professor Bellomo is dual trained in Nephrology and Intensive Care. He is considered to be one of the three top researchers in the field of critical care nephrology in the world. He is imminently qualified to comment on the physiological underpinnings, background work and design of this clinical trial. PREFERRED ASSESSOR (2) Name: Dr Bruce Cooper Title First Name Last Name Position/Institution: Staff Specialist, Nephrology Postal Address: Royal North Shore Hospital, Department of Nephrology, Pacific Hwy, St Leonards, NSW, 2065 Phone: 9926 7044 Fax: 9926 5484 Mobile 0412478181 E-mail Address: [email protected] Reason : Provide a brief explanation of the relevance of the particular expertise of this assessor for the proposal (100 words max) Dr Cooper completed his PhD in dialysis related research and subsequently a Masters of Epidemiology. Hence he has the clinical and statistical background to appropriately assess the grant. PREFERRED ASSESSOR (3) Name: Dr Manu Mathur Title First Name Last Name Position/Institution: Head of Dept Cardiothoracic Surgery RNSH Dept Cardiothoracic Surgery Royal North Shore Hospital Phone: 99268895 Fax: 94363613 Mobile 0422306162 E-mail Address: [email protected] Reason : Provide a brief explanation of the relevance of the particular expertise of this assessor for the proposal (100 words max) Senior Cardiothoracic Surgeon with established track record of research, authorship and presentation.

Page 22 of 24

NOMINATION OF NON-ASSESSOR You may nominate the name of 1 assessor whom you do not wish to review your proposal, but must provide a reason for requesting any veto. Name: Title First Name Last Name Position/Institution: Reason: Advise why you believe the person is not suitable to assess your application (maximum 200 words)

Page 23 of 24

SIGNATURES

1. Signatures of Principal Investigators I certify that all details given in this application are correct and I agree to carry out the project in strict accordance with methods outlined in this project application Signature: Date Signature Signature Signature 2. Certification by Head of Department

I certify that the project is appropriate to the general facilities available in my department/facility and that I am prepared to have the project carried out as written in the methods of this grant application

NAME: TITLE:

DEPARTMENT: Cardiovascular Surgery HOSPITAL: Signature: Date

2. Certification by Head of Department

I certify that the project is appropriate to the general facilities available in my department/facility and that I am prepared to have the project carried out as written in the methods of this grant application

NAME: TITLE:

DEPARTMENT: Intensive Care HOSPITAL: Signature: Date 2. Certification by Head of Administering Organisation (or nominee)

I certify that this request satisfies all the requirements of this Organisation.

NAME: TITLE:

DEPARTMENT: INSTITUTION: Signature: Date

Page 24 of 24

CHECKLIST

Please confirm that all sections have been completed before submitting this Application PROJECT SUMMARY

INVESTIGATOR DETAILS (separate form for each)

PROJECT DETAILS

BUDGET

NOMINATION OF ASSESSOR/s

NOMINATION OF NON-ASSESSOR

SIGNATURES : PRINCIPAL INVESTIGATORS

HEAD OF DEPARTMENT

HEAD OF ADMINISTERING ORGANISATION

The signed original & 10 copies of the application to be provided to : The Grants Officer

Research Office Royal North Shore Hospital Building 51 Reserve Road St Leonards 2065

A copy of the application should also be emailed to : [email protected]

APPLICATIONS CLOSE 4.00pm FRIDAY 23 SEPTEMBER 2011

Documents

Online-Only Supplement: Intravenous amino acid therapy for ... · printed OR written on to a blank form to create a permanent record of calculations. It is the site investigator's