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| [ Print-friendly version ] |
| Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP) |
| ISRCTN | ISRCTN70127774 |
| ClinicalTrials.gov identifier | |
| Public title | Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP) |
| Scientific title | Hydroxymethylglutaryl-CoA reductase inhibition in Acute lung injury to Reduce Pulmonary oedema and inflammation: a phase II, single centre, prospective, double-blind, randomised, placebo-controlled trial |
| Acronym | HARP |
| Serial number at source | EME 08/99/08; RGHT000275 |
| Study hypothesis |
Treatment with hydroxymethylglutaryl-CoA (HMGCoA) reductase inhibitor, simvastatin, is safe and improves important surrogate clinical outcomes in adult patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).
Link to EME project website: http://www.eme.ac.uk/projectfiles/089908info.pdf |
| Lay summary | Not provided at time of registration |
| Ethics approval |
1. MREC approved on the 31st July 2006
2. MHRA approved on the 4th September 2006 |
| Study design | Phase II single centre prospective double-blind randomised placebo-controlled trial |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) |
| Participants - inclusion criteria | Mechanically ventilated adult patients admitted to the intensive care unit at the Royal Victoria Hospital, within 48 hours of the onset ALI or ARDS, will be eligible for inclusion in the study. ALI and ARDS will be defined according to the American European Consensus Conference definition. |
| Participants - exclusion criteria |
Current exclusion criteria as of 17/04/2012
1. Age < 16 years 2. More than 48 hours from the onset of ALI 3. Patient is known to be 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, cyclosporine, amiodarone, verapamil or diltiazem. 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 and AST values may be obtained up to 72 hours prior to randomisation. Previous exclusion criteria 1. Aged under 18 years 2. Pregnancy 3. Creatinine kinase (CK) more than five times upper limit of normal range 4. Transaminases more than three times upper limit of normal range 5. Participation in other intervention trials within previous 30 days 6. Current treatment with statins 7. Contraindication to enteral nutrition 8. Unlikely to survive beyond 48 hours 9. Patients with significant end stage disease as previously defined and assent declined from the next of kin |
| Anticipated start date | 02/08/2006 |
| Anticipated end date | 04/08/2009 |
| Status of trial | Completed |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | 60 |
| Interventions | Patients will be stratified for the presence of severe sepsis as a clinical risk factor for the development of acute lung injury. Stratified block randomisation using a microcomputer to simvastatin 80 mg or placebo enterally (1:1) will be performed. |
| Primary outcome measure(s) | Reduction in extravascular lung water (EVLW) in the simvastatin treated group at day 7 |
| Secondary outcome measure(s) |
Current secondary outcome measure (s) as of 17/04/2012
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 days 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 8. CK >10 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28) 9. ALT/AST >8 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28) 10. Need for renal replacement therapy in patients with CK elevated >10 fold 11. Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs). 12 Biological mechanisms 13 Health-related quality of life 14. Cost effectiveness Previous secondary outcome measure(s) 1. Physiological severity of lung injury as measured by PaO2:FiO2 ratio at day 7, respiratory compliance at day 7 2. Effects on the pulmonary circulation as measured by change in pulmonary dead space at day 7 3. Extra-pulmonary organ failure as measured by sequential organ failure assessment (SOFA) score at day 7 |
| Sources of funding |
1. Research and Development Office (UK) - Doctoral Fellowship scheme from Central Services Agency, Northern Ireland
2. REVIVE (UK) - Charity for the Regional Intensive Care Unit at the Royal Group Hospitals Trust Added 24/06/2010: 3. Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: 08/99/08) |
| Trial website | |
| Publications | 1. 2011 results in http://www.ncbi.nlm.nih.gov/pubmed/20870757 |
| Contact name | Dr Danny McAuley |
| Address |
Regional Intensive Care Unit
Royal Victoria Hospital Grosvenor Road |
| City/town | Belfast |
| Zip/Postcode | BT12 6BA |
| Country | United Kingdom |
| d.f.mcauley@qub.ac.uk | |
| Sponsor | The Royal Group Hospitals Trust (UK) |
| Address | Grosvenor Road |
| City/town | Belfast |
| Zip/Postcode | BT126BA |
| Country | United Kingdom |
| Tel | +44 (0)2890 240503 |
| I.Young@qub.ac.uk | |
| Date applied | 21/03/2006 |
| Last edited | 17/04/2012 |
| Date ISRCTN assigned | 24/04/2006 |
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| © 2012 ISRCTN unless otherwise stated. | |
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