Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunctio

Lead Research Organisation: Queen's University of Belfast

Abstract

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Technical Summary

Scientific Abstract|The first section details the plan for undertaking a phase 2 randomised trial to test the effectiveness and safety of simvastatin in ALI/ARDS (Objective 1). The second section describes the studies of biological markers of inflammation and lung injury to provide insight into the mechanism of action of simvastatin in ALI/ARDS (Objective 2).|Objective 1:|Design: This will be a prospective, randomised, double-blind, placebo-controlled phase 2 multi-centre, clinical study of simvastatin in patients with ALI/ARDS.|Setting: Fourteen adult general ICUs.|Target population: Mechanically ventilated, intubated adult patients with ALI/ARDS defined according to the American-European Consensus Conference definition. Exclusion criteria will include: age <16 years old; more than 48 hours from the onset ALI; pregnancy; creatine kinase (CK) >10 x upper limit of the normal range; transaminases >5 x upper limit normal; CYP3A4 inhibitors as listed in the detailed project description; severe renal impairment (calculated creatinine clearance less than 30ml/minute) not receiving renal replacement therapy, severe liver disease (Childs Pugh score > 11); domiciliary mechanical ventilation; current or recent treatment (within 2 weeks) with statins; participation in other trials within 30 days; contraindication to enteral drug administration; and consent declined.|Interventions: Patients will be randomised to receive once daily simvastatin 80mg or identical placebo tablet administered enterally via a feeding tube or orally for up to 28 days.|Outcomes and duration of follow-up: The primary clinical efficacy outcome will be ventilator free days (VFDs). VFDs are the number of days after initiating unassisted breathing to day 28 after randomisation, assuming a subject survives for at least 48 hours after initiating unassisted breathing. VFDs represent a validated outcome measure which quantifies the number of days alive and free from mechanical ventilation. It remains the most useful and validated clinical outcome measure in phase 2 clinical trials in ALI/ARDS.|The following secondary outcomes will also be assessed: 1) pulmonary dysfunction; as measured by oxygenation index (OI), which measures both impaired oxygenation and the amount of mechanical ventilation delivered; 2) non-pulmonary organ failure as measured by the SOFA score; 3) 28 day mortality; 4) safety and tolerability as assessed by the frequency of serious adverse events and suspected unexpected serious adverse reactions (SUSARs); 5) Health-related quality of life (QoL) as assessed using the self-administered EuroQol-5D (EQ-5D) postal questionnaire; and 6) cost effectiveness.|Patient data will be recorded in the case record form daily by the research nurse until day 28. Follow-up at 3, 6 and 12 months will use a postal questionnaire containing the EQ-5D and resource use questions for the health economic analysis.|Objective 2:|We will test the hypothesis that simvastatin decreases neutrophil activation, pro-inflammatory cytokines and adhesion molecule expression, and will explore whether this occurs by reduced NFkB activation. Furthermore, we will investigate whether simvastatin reduces plasma levels of cell-specific indices of activation and injury to the alveolar epithelium and the endothelium. We shall also assess simvastatins effect on lung extracellular matrix destruction.|Blood and urine will be taken on days 0, 3, 7, 14 and 28.|Sample size: The mean (standard deviation; SD) VFDs in 432 patients with ALI/ARDS was 12.7 (10.6) days. On the basis of published data, a conservative treatment effect of 20% has been estimated for this study. A 20% treatment effect represents a 2.6 day increase in VFDs. A 2.6 day increase in VFDs either as a result of improved mortality and/or decreased duration of ventilation would be of major importance. A sample size of 524 subjects (262 in each group) will have 80% power at a two-tailed significance level of 0.05 to detect a 20% difference

Publications

10 25 50
 
Guideline Title Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome
Description Citation in clinical guideline
Geographic Reach Europe 
Policy Influence Type Citation in clinical guidelines
 
Description Citation in clinical review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description Citation in systematic review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Citation in systematic review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Citation in systematic review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Development and clinical evaluation of a POC theranostic assay to inform therapy choice in Acute Respiratory Distress Syndrome
Amount £1,166,818 (GBP)
Funding ID 18045 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 01/2019 
End 12/2020
 
Description EME programme (Endotypes)
Amount £239,772 (GBP)
Funding ID EME 16/33/01 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Public
Country United Kingdom
Start 08/2017 
End 01/2019
 
Description EME programme (STRESS-L)
Amount £1,570,833 (GBP)
Funding ID EME 14/150/85 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Public
Country United Kingdom
Start 02/2017 
End 04/2021
 
Description Health Research Awards
Amount £240,000 (GBP)
Organisation Health Research Board (HRB) 
Sector Public
Country Ireland
Start 06/2011 
End 09/2015
 
Description MRC EMINENT scheme
Amount £800,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2016 
End 11/2018
 
Description MRC Proximity to Discovery
Amount £15,600 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2016 
End 02/2017
 
Description NIHR clinician scientist award (Shyamsundar)
Amount £913,841 (GBP)
Funding ID CVD/5137/15 
Organisation National Institute for Health Research 
Department NIHR Fellowship Programme
Sector Public
Country United Kingdom
Start 05/2015 
End 04/2020
 
Description Opportunity led scheme
Amount £115,953 (GBP)
Organisation Department of Health Social Services and Public Safety (DHSSPS) 
Sector Public
Country United Kingdom
Start 09/2014 
End 08/2015
 
Description RfPB
Amount £226,000 (GBP)
Funding ID PB-PG-0211-24123 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2013 
End 11/2016
 
Description SIGNET Statins for Improving orGan outcomE in Transplantation
Amount £1,333,915 (GBP)
Funding ID NIHR131124 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2020 
End 06/2026
 
Title HARP-2 samples 
Description Samples collected from HARP-2 to be used in project to inform endotypes in ARDS 
Type Of Material Biological samples 
Year Produced 2016 
Provided To Others? Yes  
Impact Funding from MRC EMINENT scheme to inform endotypes in ARDS 
 
Title HARP-2 database 
Description Data from an RCT of 540 patients with ARDS comparing simvastatin 80 mg or placebo once daily for up to 28 days. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials (2016). Nagendran M McAuley DF Kruger P Papazian L Truwit J Thompson BT Clarke M Gordon AC. Intensive Care Medicine. Additional funding from NIHR EME programme "Defining ARDS and sepsis sub-phenotypes: a re-analysis of two trials to inform a stratified medicine approach with future trials" (EME 16/33/01) 
 
Description Collaboration CC at USCF 
Organisation University of California, San Francisco
Department School of Medicine (UCSF)
Country United States 
Sector Academic/University 
PI Contribution Secondary analysis of the HARP-2 trial to define endotypes in ARDS Grant application to investigate e-cigarette smoking in inducing pulmonary inflammation using the human LPS model
Collaborator Contribution Secondary analysis of the HARP-2 trial to define endotypes in ARDS Grant application to investigate e-cigarette smoking in inducing pulmonary inflammation using the human LPS model
Impact Publication Grant application
Start Year 2016
 
Description REMAP-CAP simvastatin domain 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Lead for simvastatin domain in REMAP-CAP trial
Collaborator Contribution UK lead for REMAP-CAP trial
Impact 1. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 (2021). The writing committee for the REMAP-CAP investigators. NEJM (in press). 2. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19. The REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial (2020). The writing committee for the REMAP-CAP investigators. JAMA (in press).
Start Year 2020
 
Description Randox 
Organisation Randox Laboratories
Country Global 
Sector Private 
PI Contribution Undertaking a clinical validation trial and informing the development of a sepsis diagnostic assay Undertaking a trial to inform the development of a point of care (POC) assay to identify endotypes in Acute Respiratory Distress Syndrome
Collaborator Contribution Development of a sepsis diagnostic assay Development of a POC assay to identify endotypes in Acute Respiratory Distress Syndrome
Impact No outputs yet
Start Year 2012
 
Title HARP-2 
Description Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2014
Development Status Closed
Clinical Trial? Yes
Impact Completed phase 2/3 trial in patients with ALI. 
URL http://www.isrctn.com/ISRCTN88244364
 
Title MoDUS 
Description This study is a randomised, double-blind, placebo controlled trial to investigate if simvastatin reduces delirium in the critically ill. 142 patients will randomly allocated to be given either simvastatin or a placebo. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Ongoing phase 2 trial in patients with delirium. 
URL http://www.isrctn.com/ISRCTN89079989
 
Description 'Local Talent, Global Impact' Medical Research public talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Approximately 300 local people attended this evening meeting where 4 medical researchers presented to the public about the research taking place at Queen's and its impact on patient outcomes. My presentation was on 'Finding New Treatments for Failing Lungs'

Recognition of the importance of acute lug injury.
Year(s) Of Engagement Activity 2013
URL http://www.qub.ac.uk/home/ResearchandEnterprise/BusinessNetworks/OtherLectures/2012Lectures/MedicalR...
 
Description Clinical Trial Targets Acute Respiratory Distress Syndrome with Cholesterol Drug 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Media interest in novel treatments for ARDS
Year(s) Of Engagement Activity 2012