Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP)

ISRCTN	ISRCTN70127774
DOI	https://doi.org/10.1186/ISRCTN70127774
Protocol serial number	EME 08/99/08; RGHT000275
Sponsor	The Royal Group Hospitals Trust (UK)
Funders	Research and Development Office (UK) - Doctoral Fellowship scheme from Central Services Agency, Northern Ireland, REVIVE (UK) - Charity for the Regional Intensive Care Unit at the Royal Group Hospitals Trust, Added 24/06/2010:, Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: 08/99/08)

Submission date: 21/03/2006
Registration date: 24/04/2006
Last edited: 03/02/2014

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Respiratory

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Danny McAuley
Scientific

Regional Intensive Care Unit
Royal Victoria Hospital
Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Email	d.f.mcauley@qub.ac.uk

Study information

Primary study design	Interventional
Study design	Phase II single centre prospective double-blind randomised placebo-controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
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
Study acronym	HARP
Study objectives	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
Ethics approval(s)	1. MREC approved on the 31st July 2006 2. MHRA approved on the 4th September 2006
Health condition(s) or problem(s) studied	Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
Intervention	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.
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Simvastatin
Primary outcome measure(s)	Reduction in extravascular lung water (EVLW) in the simvastatin treated group at day 7
Key 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
Completion date	04/08/2009

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	All
Target sample size at registration	60
Key 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.
Key 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
Date of first enrolment	02/08/2006
Date of final enrolment	04/08/2009

Locations

Countries of recruitment

United Kingdom
Northern Ireland

Study participating centre

Regional Intensive Care Unit

Belfast
BT12 6BA
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/03/2011		Yes	No
Results article	results	19/07/2013		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes