Informed consent will be obtained prior to conducting any trial specific procedures.
Critically ill sedated patients do not have the capacity to give consent; therefore, consistent with requirements of the EU clinical trial directive, we will obtain written informed consent/assent from a representative in keeping with regulatory requirements before randomization. All surviving patients will be informed about the trial at the earliest opportunity after regaining competence and consent to continue in the trial will be sought. The consent from the representative will remain valid until a decision on consent to continue is obtained from the patient.
Randomization and study drug supply
Patient drug packs will be prepared by Victoria Pharmaceuticals (Belfast, UK). Simvastatin 40 mg or identical placebo tablets will be packaged in a white opaque plastic container which will be sealed with a tamper-evident seal and labelled in compliance with applicable regulatory requirements. Each container will contain 70 tablets of the study drug for the treatment of one patient for 28 days (plus 7 days overage). All trial drugs will be packaged identically and identified only by the unique trial identifier.
Patients will be randomized in a 1:1 ratio using an automated centralized 24-hour telephone or web-based randomization service (Centre for Healthcare Randomised Trials, University of Aberdeen, UK). Randomization will be stratified by site and by vasopressor requirement (defined as any inotropic requirement except dopamine <6 mcg/kg/minute). The randomization service will allocate a unique trial identifier to each patient in accordance with the computer-generated study randomization schedule. The randomization service will confirm randomization details by email to the CTU and the study site. A confirmation email will be sent to the hospital pharmacy. The clinician will complete a trial prescription form detailing the unique trial identifier assigned to the patient. The hospital pharmacy will dispense the drug pack labelled with the corresponding unique trial identifier for the patient.
Study drug administration
Patients will be randomized to receive once daily simvastatin 80 mg (as two 40 mg tablets) or two identical placebo tablets administered enterally via a feeding tube or orally for up to 28 days. The first dose of the study drug will be administered as soon as possible, ideally within four hours of randomization and subsequent doses will be given each morning starting on the following calendar day. If for any reason a dose is not administered at the intended time, it will be administered subsequently but not more than 12 hours after the intended time of administration.
Post randomization withdrawals and exclusions
Patients may withdraw or be withdrawn by their representative from the trial or the trial treatment at any time without prejudice. Data recorded up to the point of withdrawal will be included in the trial analysis, unless consent to use their data has also been withdrawn. If a subject withdraws, they will be followed-up wherever possible and data collected as per protocol until the end of the trial. The only exception to this is where the subject also explicitly withdraws consent for follow-up.
Study drug termination criteria
The study drug will be discontinued if any one of the following are met, prior to the maximum treatment period (28 days from randomization):
CK >10 times the upper limit of normal (ULN)
Development of a clinical condition requiring immediate treatment with a statin
Discharge from critical care environment
Discontinuation of active medical treatment
Patient or representative request for withdrawal of patient from the study
Decision by the attending clinician that the study drug should be discontinued on safety grounds
Study drug compliance
Any omission of the study drug will be recorded in the Case Report Form (CRF) to monitor treatment compliance.
Clinical management of patients in the trial
Patients involved in the trial will be managed according to best practice established locally on each unit. Clinicians will be encouraged to use a low tidal volume strategy of ventilation based on ideal body weight, a conservative fluid management protocol and a standardized weaning strategy. Rescue therapies such as high frequency oscillatory ventilation, nitric oxide and extracorporeal membrane oxygenation can be used according to local policy.
The exclusion criteria prevent patients with ALI who have a co-existing condition that requires treatment with a statin as part of standard clinical care being recruited. In patients where there is a clinical indication for acute and immediate treatment with a statin after randomization, for example, acute myocardial infarction, the study drug will be discontinued and a statin commenced. The patient will not be unblinded and data collection will continue. This will be recorded on the CRF. Otherwise, patients will not be commenced on a statin for the duration of the clinical trial.
Study procedures for unblinding
As a placebo controlled, double-blind trial, patients, clinicians and research staff will be blinded to which arm of the study a patient is allocated. All trial drugs will be packaged identically and identified only by a unique trial identifier. The protocol allows for emergency unblinding in the event of significant concerns about patient safety. This option will be used if the patient’s future treatment requires knowledge of the treatment assignment. If a local investigator decides that there is justification to unblind a patient, they should make every attempt to contact the CTU, who will arrange for them to discuss unblinding with a clinical member of the trial team. Emergency unblinding will be performed by telephone contact with the randomization service. All events will be logged.
All data for an individual patient will be recorded in the study CRF. The majority of data will be obtained from the patient’s hospital record. Data will be collected by the site research team until hospital discharge. In the event that a patient is transferred to another hospital, the site research team will liaise with the receiving hospital to ensure complete data collection. The EQ-5D will be administered face-to-face at discharge. The EQ-5D and resource use questionnaires will then be administered by post or by telephone after the patient has been discharged from hospital. On discharge the participating site will provide the trial manager at the CTU with the name, address and contact details for the patient. Postal health-related quality of life and resource utilization questionnaires will be sent out and collected by the CTU. If questionnaires are not returned telephone contact will be made to the trial patient to check that the questionnaire has been received and the patient is happy to complete it, followed by a second copy of the questionnaire. If the second questionnaire is not returned the patient will be contacted by telephone and the outcome data collected over the telephone. Trial patients will be asked to let the CTU know if they move house at any time after hospital discharge.
Patient identification on the CRF and questionnaires will be through their unique trial identifier allocated at the time of randomization and patient initials.
Monitoring and reporting adverse events
HARP-2 is recruiting a population that is already in a life-threatening situation; it is expected that many of the participants will experience adverse events (AEs). Events that are expected in this population (that is, events that are in keeping with the patient’s underlying medical condition) should not be reported as AEs. If any AEs are related to the study drug (that is, are adverse reactions) they must be reported on the AE form within the CRF.
SAEs thought to be related to the study drug or SUSARs (that is, their nature or severity is not consistent with the summary of product characteristics for simvastatin) will be reported to the CTU within 24 hours of becoming aware of their occurrence. The CTU will inform the sponsor and regulatory authorities within the required timelines as per the regulatory requirements.
End of trial
The trial will end when 540 patients have been recruited. The trial will be stopped prematurely if: mandated by the Research Ethics Committee, the Medicines and Healthcare products Regulatory Agency (MHRA), the Irish Medicines Board (IMB), the Sponsor (for example, following recommendations from the Data Monitoring and Ethics Committee (DMEC) or funding for the trial ceases.
Statistical analysis plan
Standard approaches will be used to detect patterns in missing data. 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. A statistical interaction test will be used to assess differences in treatment effects between the subgroups. For binary outcome measures risk ratios and associated 95% CI will be calculated. Binary variables assessed daily will be analyzed using logistic regression analysis corrected for days at risk. Time-to-event outcomes will be analyzed by survival methods and reported as hazard ratios with 95% CI. An interim analysis of efficacy is not planned.
Four subgroup analyses are planned to analyze whether treatment effect is modified by age, vasopressor requirement (defined as any inotropic requirement except dopamine <6mcg/kg/minute); etiology of ALI (due to sepsis versus non-sepsis) and CRP level at baseline. Subgroup analyses will use a statistical test for interaction and will be reported using 99% CI. The trial statistician has written a detailed statistical analysis plan (SAP).
Health economic evaluation
A within-trial cost effectiveness analysis (CEA) will be undertaken to compare the costs and outcomes of patients in each arm of the trial at 12 months follow-up (post-randomization). A health service perspective will be adopted for this analysis as recommended by the National Institute for Health and Clinical Excellence (NICE)  with additional information being collected relating to social care costs. The outcome for the analysis will be the Quality Adjusted Life Year (QALY) and utilities will be measured using the EQ-5D at discharge, 3, 6 and 12 months. Resource utilization will be collected at 6 and 12 months only. Administration of the EQ-5D (at four separate time points) has been undertaken to ensure that any utility differences between arms will be fully captured.
Consistent with the perspective chosen for the analysis, resource utilization will be quantified (at all sites to allow evaluation of cost-effectiveness in both jurisdictions); however, the focus of the proposed evaluation will be to determine cost-effectiveness within a UK context. Hence unit costs will be applied from national sources such as the National Health Service (NHS) reference costs, British National Formulary (BNF) and the Personal Social Services Research Unit (PSSRU) Unit Costs of Health and Social Care . Where national costs are not available, unit costs will be identified in consultation with finance departments of hospitals/Trusts. Patient-specific resource utilization (of primary, community and social care services) will be extracted from the trial CRF and via self-completed patient questionnaires. It will not be necessary to discount costs and outcomes (for the within-trial analysis) given the duration of follow-up. Parameter uncertainty will be addressed using sensitivity analysis. Outputs from the analysis will include the incremental cost effectiveness ratio (ICER), a scatter plot on the cost effectiveness plane, cost effectiveness acceptability curve (CEAC) and incremental net benefit (INB) assuming a societal willingness-to-pay of £20,000/QALY or the Republic of Ireland (ROI) equivalent.
The Chief Investigators will have overall responsibility for the conduct of the study. The Trial Management Group will have responsibility for the day to day operational management of the trial. Trial oversight will be provided by a Trial Steering Committee (TSC) comprising investigators, clinicians and trialists. The TSC will operate within the relevant CTU Standard Operating Procedure (SOP). An independent Data Monitoring and Ethics Committee (DMEC) will monitor the safety of participants enrolled in the trial through regular review of adverse event reports. The reports provided to the DMEC will include information on the AEs reported, deaths from all causes at 28 days and recruitment, along with any other data that the committee may request. The DMEC will advise the TSC if, in their view, the randomized comparisons have provided both (i) 'proof beyond reasonable doubt' that for all, or some, the treatment is clearly indicated or clearly contra-indicated and (ii) evidence that might reasonably be expected to materially influence future patient management. Following a report from the DMEC, the TSC will decide what actions, if any, are required. Unless the DMEC requests cessation of the trial the TSC and the collaborators will not be informed of the reports provided to the DMEC.