Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunctio
Lead Research Organisation:
Queen's University Belfast
Department Name: UNLISTED
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
Page VJ
(2014)
Statin use and risk of delirium in the critically ill.
in American journal of respiratory and critical care medicine
Reddy K
(2021)
Acute Respiratory Distress Syndrome Subphenotypes beyond the Syndrome: A Step toward Treatable Traits?
in American journal of respiratory and critical care medicine
O'Kane CM
(2013)
Statins and sepsis: potential benefit but more unanswered questions.
in American journal of respiratory and critical care medicine
Blackwood B
(2014)
How Outcomes Are Defined in Clinical Trials of Mechanically Ventilated Adults and Children
in American Journal of Respiratory and Critical Care Medicine
Shyamsundar M
(2014)
Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial.
in Annals of surgery
Shyamsundar M
(2015)
Reply to Letter: "Effect of Simvastatin on Physiological and Biological Outcomes in Patients Undergoing Esophagectomy: A Randomized Placebo-controlled Trial".
in Annals of surgery
Shankar-Hari M
(2012)
Statin therapy in critical illness: an international survey of intensive care physicians' opinions, attitudes and practice.
in BMC clinical pharmacology
Boyle AJ
(2013)
Pharmacological treatments in ARDS; a state-of-the-art update.
in BMC medicine
McAuley DF
(2013)
Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury.
in BMC pulmonary medicine
Morel J
(2017)
Simvastatin pre-treatment improves survival and mitochondrial function in a 3-day fluid-resuscitated rat model of sepsis.
in Clinical science (London, England : 1979)
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 | £202,683 (GBP) |
Organisation | Randox |
Sector | Private |
Country | United Kingdom |
Start | 01/2022 |
End | 01/2023 |
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 | 07/2017 |
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 | HElping Alleviate the Longer-term consequences of COVID-19 (HEAL-COVID): a national platform trial |
Amount | $3,583,669 (USD) |
Funding ID | NIHR133788 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 02/2021 |
End | 01/2024 |
Description | Health Research Awards |
Amount | £240,000 (GBP) |
Organisation | Health Research Board (HRB) |
Sector | Public |
Country | Ireland |
Start | 05/2011 |
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 | 04/2015 |
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 | 08/2014 |
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 | Statins in Organ Donor ManagementAn evaluation of the benefits of a single dose of Simvastatin given to potential organ donors declared dead by neurological criteria on outcomes in organ recipientsSIGNET 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 | 09/2020 |
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 |