Title: HARP II
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

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 (Child's 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 simvastatin's 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 in VFDs. If a dropout rate of 3% is estimated this study will require a total of 540 patients (270 in each group). Statistical analysis: A statistical analysis plan will be submitted to the DMEC for approval. Analyses will be on an intention-to-treat basis. As VFDs are unlikely to be normally distributed, the groups will be analyzed by comparing the medians and 95% confidence intervals (CI). The comparison of other continuous outcomes will be by analysis of variance, including covariates where appropriate. Statistical diagnostic methods will be used to check for violations of the assumptions, and transformations will be performed where required. For binary outcome measures risk ratios and associated 95% CI will be calculated. Binary variables assessed daily will be analysed using logistic regression analysis corrected for days at risk. Time-to-event outcomes will be analysed by survival methods and reported as hazard ratios with 95% CI. The analysis plan for the statistical evaluation of the biomarkers is given in the protocol. Project timetable and milestones: The trial will be carried out over 4 years. Prior to funding for this study commencing, all the regulatory approvals will be in place which will avoid any delay to recruitment. There will be a 3 month run-in period to allow set-up and training. Patient recruitment has conservatively been estimated at 1.3 patients/centre/month over 31 months. There will be 12 months of follow up to collect health-related QoL outcomes. Data cleaning and validation, analysis of the primary and other physiological outcomes, laboratory assays and analyses, and publication of these results will also be undertaken during this 12 month period. A final 2-month period is required for analysis and publication of the follow-up results. Expertise: The applicants include experienced clinical researchers (DM, JL, CO), experienced ICU clinicians (DM, JL), experts in clinical trial management and statistics (MP), experienced researchers in translational science (CT, CO) and a health economist (GC). This current study has the full support of the established network of 14 research-active ICUs which make up the Irish Critical Care Trials Group (ICCTG). This clinical trial will be managed with the support of the Clinical Research Support Centre (CRSC), which is a UKCRC-registered CTU. The study was developed following discussions with representatives of the Critical Care Patient Liaison Group.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY;INFECTION