Keratinocyte growth factor in acute lung injury to reduce pulmonary dysfunction – a randomised placebo-controlled trial (KARE): study protocol

Trials

Daniel F McAuley³  Michael A Matthay¹  Jospeh J Elborn²  Cliona McDowell⁴  Cecilia M O’Kane²  Laurence JM Cross³ 

[1] Departments of Medicine and Anesthesia, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA;Centre for Infection and Immunity, The Queen’s University of Belfast, Health Sciences Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland;Regional Intensive Care Unit, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland;Clinical Research Support Centre, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland

关键词: Respiratory failure;    Pulmonary oedema;    Oxygenation index;    Adult respiratory distress syndrome;    Acute lung injury;    Palifermin;    Keratinocyte growth factor;   

Others  :  1094727
DOI  :  10.1186/1745-6215-14-51

 received in 2012-10-16, accepted in 2013-01-18,  发布年份 2013

【 摘 要 】

Background

Acute lung injury is a common, devastating clinical syndrome associated with substantial mortality and morbidity with currently no proven therapeutic interventional strategy to improve patient outcomes. The objectives of this study are to test the potential therapeutic effects of keratinocyte growth factor for patients with acute lung injury on oxygenation and biological indicators of acute inflammation, lung epithelial and endothelial function, protease:antiprotease balance, and lung extracellular matrix degradation and turnover.

Methods/design

This will be a prospective, randomised, double-blind, allocation-concealed, placebo-controlled, phase 2, multicentre trial. Randomisation will be stratified by presence of severe sepsis requiring vasopressors. Patients in an ICU fulfilling the American–European Consensus Conference Definition of acute lung injury will be randomised in a 1:1 ratio to receive an intravenous bolus of either keratinocyte growth factor (palifermin, 60 μg/kg) or placebo (0.9% sodium chloride solution) daily for a maximum of 6 days. The primary endpoint of this clinical study is to evaluate the efficacy of palifermin to improve the oxygenation index at day 7 or the last available oxygenation index prior to patient discontinuation from the study.

A formal statistical analysis plan has been constructed. Analyses will be carried out on an intention-to-treat basis. A single analysis is planned at the end of the trial. P = 0.05 will be considered statistically significant and all tests will be two-sided. For continuously distributed outcomes, differences between groups will be tested using independent-sample t tests, analysis of variance and analysis of covariance with transformation of variables to normality or nonparametric equivalents. The trial will be reported in line with the Consolidated Standards of Reporting Trials (Consort 2010 guidelines).

Trial registration

http://ISRCTN95690673 webcite

【 授权许可】

   
2013 Cross et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Brun-Buisson C, Minelli M, Bertolini G, Brazzi L, Pimentel J, Lewandowski K, Bion J, Romand JA, Villar J, Thorsteinsson A, Damas P, Armaganidis A, Lemaire F: ALIVE study group: epidemiology and outcome of acute lung injury in european intensive care units. Results from the ALIVE study. Intensive Care Med 2004, 30:51-61.
• [2]Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD: Incidence and outcomes of acute lung injury. N Engl J Med 2005, 353:1685-1693.
• [3]Dowdy DW, Eid MP, Dennison CR, Mendez-Tellez PA, Herridge MS, Guallar E, Pronovost PJ, Needham DM: Quality of life after acute respiratory distress syndrome: a meta-analysis. Intensive Care Med 2006, 32:1115-1124.
• [4]Rossi C, Simini B, Brazzi L, Rossi G, Radrizzani D, Iapichino G, Bertolini G: Gruppo italiano per la valutazione degli interventi in terapia intensiva: variable costs of ICU patients: a multicenter prospective study. Intensive Care Med 2006, 32:545-552.
• [5]Irish Critical Care Trials Group: Acute lung injury and the acute respiratory distress syndrome in Ireland: a prospective audit of epidemiology and management. Crit Care 2008, 12:R30. BioMed Central Full Text
• [6]Cheung AM, Tansey CM, Tomlinson G, Diaz-Granados N, Matté A, Barr A, Mehta S, Mazer CD, Guest CB, Stewart TE, Al-Saidi F, Cooper AB, Cook D, Slutsky AS, Herridge MS: Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 2006, 174:538-544.
• [7]Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 2000, 342:1334-1349.
• [8]Modelska K, Pittet JF, Folkesson HG, Courtney Broaddus V, Matthay MA: Acid-induced lung injury. Protective effect of anti-interleukin-8 pretreatment on alveolar epithelial barrier function in rabbits. Am J Respir Crit Care Med 1999, 160:1450-1456.
• [9]Ware LB, Matthay MA: Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001, 163:1376-1383.
• [10]McAuley DF, Frank JA, Fang X, Matthay MA: Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury. Crit Care Med 2004, 32:1470-1476.
• [11]Perkins GD, McAuley DF, Thickett DR, Gao F: The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 2006, 173:281-287.
• [12]Perkins GD, Gao F, Thickett DR: In vivo and in vitro effects of salbutamol on alveolar epithelial repair in acute lung injury. Thorax 2008, 63:215-220.
• [13]Adhikari N, Burns KE, Meade MO: Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev 2004, 4:CD004477.
• [14]Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, Holets S, Kallet RH, Liu KD, MacIntyre N, Moss M, Schoenfeld D, Steingrub J, Thompson BT, National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Randomized, placebo-controlled clinical trial of an aerosolized β-2-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011, 184:561-568.
• [15]Rice TW, Wheeler AP, Thompson BT, DeBoisblanc BP, Steingrub J, Rock P: NIH NHLBI acute respiratory distress syndrome network of investigators: enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011, 306:1574-1581.
• [16]Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE: BALTI-2 study investigators. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012, 379:229-235.
• [17]Matthay MA, Zimmerman GA, Esmon C, Bhattacharya J, Coller B, Doerschuk CM, Floros J, Gimbrone MA Jr, Hoffman E, Hubmayr RD, Leppert M, Matalon S, Munford R, Parsons P, Slutsky AS, Tracey KJ, Ward P, Gail DB, Harabin AL: Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med 2003, 167:1027-1035.
• [18]Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA: Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USA 1989, 86:802-806.
• [19]Blijlevens N, Sonis S: Palifermin (recombinant keratinocyte growth factor-1): a pleitrophic growth factor with multiple biological activities in preventing chemotherapy and radiotherapy induced mucositis. Ann Oncol 2007, 18:817-826.
• [20]Martin J: British National Fomularly. Volume 62. UK: BMJ Publishing Group. 2012BMJ Group and Pharmacuetical Press; 2012. [British Medical Association and the Royal Pharmaceutical Society of Great Britain]
• [21]Ware LB, Matthay MA: Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002, 282:L924-L940.
• [22]Mason CM, Guery BP, Summer WR, Nelson S: Keratinocyte growth factor attenuates lung leak induced by alpha-naphthylthiourea in rats. Crit Care Med 1996, 24:925-931.
• [23]Sugahara K, Iyama K, Iyama K, Kuroda MJ, Sano K: Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats. J Pathol 1998, 186:90-98.
• [24]Lee JW, Fang X, Gupta N, Serikov V, Matthay MA: Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci USA 2009, 106:16357-16362.
• [25]Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R: The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994, 149:818-824.
• [26]Fort P, Farmer C, Westerman J, Johannigman J, Beninati W, Dolan S, Derdak S: High-frequency oscillatory ventilation for adult respiratory distress syndrome – a pilot study. Crit Care Med 1997, 25:937-947.
• [27]Seeley E, McAuley DF, Eisner M, Miletin M, Matthay MA, Kallet RH: Predictors of mortality in acute lung injury during the era of lung protective ventilation. Thorax 2008, 63:994-998.
• [28]Belfast Health and Social Care Trust. http://www.belfasttrust.hscni.net webcite
• [29]Clinical Research Support Centre. http://www.crsc.hscni.net webcite
• [30]Schulz KF, Altman DG, Moher D: CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials 2010, 11:32. BioMed Central Full Text
• [31]Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, McAuley DF: A randomized clinical trial of hydroxymethylglutaryl-coenzyme a reductase inhibition for acute lung injury (the HARP Study). Am J Respir Crit Care Med 2011, 183:620-626.
• [32]Harvey S, Harrison DA, Singer M, Ashcroft J, Jones CM, Elbourne D, Brampton W, Williams D, Young D, Rowan K: PAC-Man study collaboration: assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet 2005, 366:472-477.