E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). Many patients admitted to the Intensive Care Unit (ICU) have a breathing machine, or ventilator, to help them breathe and ensure that enough oxygen gets into their blood. For reasons that are unclear, when people are critically ill their lungs often fail, which is termed acute lung injury. Currently, there are no specific drugs that can be used to treat patients with ALI. Some small studies that have taken place over the past few years have suggested that giving patients with ALI a drug called simvastatin may help the patients to recover more quickly. Simvastatin is usually used to treat patients with high cholesterol. At the moment, nobody is sure whether simvastatin will help patients in the ICU with ALI. This study is being conducted to find out if simvastatin is effective in the treatment |
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E.2.2 | Secondary objectives of the trial |
To study the mechanisms of simvastatin treatment on inflammation and damage to the lungs. In addition we hope to investigate if the response to simvastatin is genetically determined. We also want to assess cost effectiveness. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 < 18 mmHg, and still be within the 48-hour enrolment window Acute onset is defined as follows: the duration of the hypoxia criterion (a) and the chest X-ray criterion (b) must be <28 days at the time of randomisation. Infiltrates considered “consistent with pulmonary oedema” include any patchy or diffuse infiltrates not fully explained by mass, atelectasis, or effusion or opacities known to be chronic (>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 |
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E.4 | Principal exclusion criteria |
1. Age < 16 years 2. More than 48 hours from the onset of ALI 3. Patient is pregnant 4. CK >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, HIV protease inhibitors, nefazodone and cyclosporine, amiodarone, verapamil or diltazem. 7. Patients with severe renal impairment (estimated calculated 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 12. Domiciliary mechanical ventilation except for CPAP/BIPAP used for sleep disordered breathing. 13. Participation in other investigational medicinal product (IMP) trials within 30 days 14. Consent declined 15. Treatment withdrawal imminent within 24 hours * 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 and AST values may be obtained up to 72 hours prior to randomisation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is Ventilator Free Days to day 28. |
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E.5.2 | Secondary end point(s) |
There are a number of secondary outcomes which include: (a) Change in oxygenation index (OI) from baseline to day, 3, 7, 14 and 28; (b) Change in sequential organ failure assessment (SOFA) score from baseline to day 3, 7, 14 and 28; (c)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). (d) All cause mortality 28 days post randomisation; (e) Mortality at (first) discharge from critical care; (f) Mortality at (first) discharge from hospital; (g) Mortality at 12 months post randomisation; (h) Safety; (i) Biological mechanisms; (j) Health-related quality of life; (j) Cost effectiveness. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 23 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will end when 540 patients have been recruited and completed 12 month follow up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |