Simvastatin in acute lung injury

Current primary outcome measures as of 08/03/2011:
The primary outcomes will be ventilator free days.

Previous primary outcome measures:
Ventilator free days (VFDs) to day 28 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.

If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or dies prior to day 28, without initiating unassisted breathing or before 48 consecutive hours of unassisted breathing, VFDs will be 0. Patients transferred to another hospital or other health care facility will be followed to day 28 to assess this endpoint.

For example, if a subject initiates unassisted breathing on day 16 and survives to day 28, he/she will be assigned a value of 12 VFDs. If a similar subject begins unassisted breathing on day 16 but dies on day 25, the VFDs is 9. In keeping with previous trials unassisted breathing is defined as:
1. Extubated with supplemental oxygen or room air
2. Open T-tube breathing
3. Tracheostomy mask breathing
4. CPAP less than or equal to 5 cm H20 without pressure support

Patients receiving pressure support via non-invasive ventilation will be defined as receiving assisted ventilation.

Current secondary outcome measures as of 07/09/2012:
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 TNF-alpha, IL-1 aplha, 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/II and vWF)
4. Systemic endothelial function biomarkers which may include but is not limited to measurement of spot urine albumin:creatinine ratio (ACR)
5. Pulmonary extracellular matrix (ECM) degradation and turnover biomarkers which may include but are not limited to measurement of urinary desmosine indexed to urine creatinine and procollagen peptide III
6. 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
7. Peripheral blood NF-êB activation

Data for Economic Evaluation
1 Health related quality of life (HRQoL)
1.1EQ-5D at discharge 3, 6 and 12 months post randomisation
2. Resource use:
2.1 Length of ICU stay (level 3 care)
2.2 Length of HDU stay (level 2 care)
2.3 Length of hospital stay
2.4 Health service contacts up to 12 months post randomisation

Previous secondary outcome measures from 14/09/2011, until 07/09/2012:
There are a number of secondary outcomes which include:
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
8. Safety:
8.1 CK >10 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28)
8.2 ALT/AST >5 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28)
8.3 Need for renal replacement therapy in patients with CK elevated >10 fold
8.4 Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs) as defined in section 7.4.2
9. Biological mechanisms
10. Health-related quality of life
11. Cost effectiveness

Previous secondary outcome measures from time of registration:
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. All cause mortality 28 days post-randomisation
4. Mortality at (first) discharge from ICU
5. Mortality at (first) discharge from hospital
6. Mortality at 12 months post randomisation

Safety:
1. CK greater than 10 times the upper limit of normal (measured on days 1, 3, 7, 14 and 28)
2. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (measured on days 1, 3, 7, 14 and 28)
3. Need for renal replacement therapy in patients with CK elevated greater than 10-fold
4. Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs)

Biological mechanisms:
1. Neutrophil activation as measured by plasma MPO and MMP-8
2. Plasma inflammatory response as measured plasma CRP, TNF-alpha, IL-1-alpha, IL-6, IL-8 and sICAM-1
3. Alveolar epithelial and endothelial injury as measured by plasma RAGE, SP-D and vWF
4. Systemic endothelial function as measured by spot urine albumin:creatinine ratio (ACR)
5. Lung extracellular matrix (ECM) degradation as measured by urinary desmosine indexed to urine creatinine
6. 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
7. Peripheral blood NF-kappa-B activation

Data for economic evaluation:
1. Health related quality of life (HRQoL) EQ-5D at discharge 3, 6 and 12 months after randomisation
2. Resource use:
2.1. Length of ICU stay (level 3 care)
2.2. Length of HDU stay (level 2 care)
2.3. Length of hospital stay
2.4. Health service contacts up to 12 months after randomisation
2.5. Patient out-of-pocket expenditure and loss of earnings up to 12 months after randomisation
2.6. Carer out-of-pocket expenditure and loss of earnings up to 12 months after randomisation