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

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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