Acute lung injury
Conditions
Interventions
Trade Name: Simvastatin
Product Name: Simvastatin
Product Code: N/A
Pharmaceutical Form: Tablet
INN or Proposed INN: Simvastatin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentra
Sponsors
National University of Ireland, Galway
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient must be receiving invasive mechanical ventilation 2. Patient must have ALI as defined by acute onset of: a) hypoxic respiratory failure (PaO2/FiO2 = 40 kPa from 2 arterial blood gases >1 hour apart). b) bilateral infiltrates on chest X-ray consistent with pulmonary oedema. c) No clinical evidence of left atrial hypertension or if measured, a pulmonary arterial occlusion pressure (PAOP) less than or equal to 18 mmHg. If a patient has a PAOP > 18 mmHg, then the other criteria must persist for more than 12 hours after the PAOP has declined to 28 days). The findings of vascular redistribution, indistinct vessels, and indistinct cardiac borders are not considered “consistent with pulmonary oedema”. All ALI criteria (a-c above) must occur within the same 24 hour period. The time of onset of ALI is when the last ALI criterion is met. Patients must be enrolled within 48 hours of ALI onset Are the trial subjects under 18? yes Number of subjects for this age range: 25 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 130 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 115
Exclusion criteria
Exclusion criteria: 1. Age 10 times the upper limit of the normal range* 5. Transaminases >8 times the upper limit of the normal range* 6. Patients currently receiving ongoing and sustained treatment with any of the following; itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil or diltiazem. Patients receiving low dose erythromycin as a prokinetic will not be excluded 7. Patients with severe renal impairment (estimated creatinine clearance less than 30ml/minute) not receiving renal replacement therapy 8. Severe liver disease (Child's Pugh score >12; Appendix 1) 9. Current or recent treatment (within 2 weeks) with statins 10. Physician decision that a statin is required for proven indication 11. Contraindication to enteral drug administration, e.g. patients with mechanical bowel obstruction. Patients with high gastric aspirates due to an ileus are not excluded. 12. Domiciliary mechanical ventilation except for CPAP/BIPAP used for sleep-disordered breathing. 13. Known participation in other investigational medicinal product (IMP) trials within 30 days 14. Consent declined 15. Treatment withdrawal imminent within 24 hours 16. Non-english speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available. *If CK, ALT and AST values are not available as part of routine care, a blood sample will be obtained after informed consent but before randomisation. CK, ALT, AST values may be obtained up to 72 hours prior to randomisation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The aim is to test the hypothesis that treatment with enteral simvastatin 80mg once daily for a maximum of 28 days will be of therapeutic value in patients with acute lung injury (ALI). The study has two distinct objectives: Objective 1: To conduct a prospective randomised, double-blind, placebo controlled phase II multi-centre trial of simvastatin for the treatment of ALI.;Secondary Objective: To study the biological effect of simvastatin treatment on: (2a) systemic markers of inflammation; (2b) systemic cell-specific indices of activation and injury to the alveolar epithelium and endothelium; (2c) lung extracellular matrix degradation; (2d) assess whether response to simvastatin is determined by genetic polymorphisms as well as link genotypic information to the phenotypic information recorded as part of this study.;Primary end point(s): The primary outcome measure is Ventilator Free Days to day 28. ;Timepoint(s) of evaluation of this end point: 28 days, defined as the number of days from the time of initiating unassisted breathing to day 28 after randomisation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): There are a number of secondary outcomes for this clinical trial which include clinical outcomes, safety, biological mechanisms and data for the economic evaluation. Clinical Outcomes 1.Change in oxygenation index (OI) from baseline to day 3, 7, 14 and 28 2.Change in sequential organ failure assessment (SOFA) score from baselines to day 3, 7, 14 and 28 3.Non Pulmonary organ failure free days, (defined as the number of days in the first 28 days after randomisation that the patient has none of: cardiovascular support, renal support, liver support or neurological support). 4.All cause mortality 28 days post randomisation 5.Mortality at (first) discharge from critical care 6.Mortality at (first) discharge from hospital 7.Mortality at 12 months post randomisation Safety 1.CK >10 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28) 2.ALT/AST >8 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28) 3.Need for renal replacement therapy in patients with CK elevated >10 fold 4.Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs) as defined in section 7.4.2 Biological mechanisms 1. Neutrophil activation biomarkers which may include but are not limited to measurement of plasma MPO and MMP-8 2. Plasma inflammatory response biomarkers which may include but are not limited to measurement of CRP, cytokines (including but not limited to TNFa, IL-1ß, IL-6, IL-8), proteases and anti-proteases, HO-1, adhesion and activation molecule expression (including but not limited to sICAM-1), coagulation factors (including but not limited to thrombin-anti-thrombin complex, tissue factor, protein C, thrombomodulin and plasminogen activator inhibitor-1), RAGE ligands and vitamin D status 3. Alveolar epithelial and endothelial injury biomarkers which may include but are not limited to measurement of plasma cell specific biomarkers such as RAGE, SP-D, Ang I/ | — |
Countries
Ireland, United Kingdom
Contacts
Public ContactCaroline Whiriskey
NUIG
Outcome results
None listed