Contact information
Type
Scientific
Primary contact
Dr Danny McAuley
ORCID ID
Contact details
Regional Intensive Care Unit
Royal Victoria Hospital
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
d.f.mcauley@qub.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
EME 08/99/08; RGHT000275
Study information
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
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
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
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
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 names
Simvastatin
Primary outcome measure
Reduction in extravascular lung water (EVLW) in the simvastatin treated group at day 7
Secondary outcome measures
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
Overall trial start date
02/08/2006
Overall trial end date
04/08/2009
Reason abandoned (if study stopped)
Eligibility
Participant 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.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
60
Participant 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
Recruitment start date
02/08/2006
Recruitment end date
04/08/2009
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Regional Intensive Care Unit
Belfast
BT12 6BA
United Kingdom
Sponsor information
Organisation
The Royal Group Hospitals Trust (UK)
Sponsor details
Grosvenor Road
Belfast
BT126BA
United Kingdom
+44 (0)2890 240503
I.Young@qub.ac.uk
Sponsor type
Government
Website
Funders
Funder type
Government
Funder name
Research and Development Office (UK) - Doctoral Fellowship scheme from Central Services Agency, Northern Ireland
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
REVIVE (UK) - Charity for the Regional Intensive Care Unit at the Royal Group Hospitals Trust
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Added 24/06/2010:
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: 08/99/08)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2011 results in http://www.ncbi.nlm.nih.gov/pubmed/20870757
2013 results in http://www.ncbi.nlm.nih.gov/pubmed/23870614
Publication citations
-
Results
Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, McAuley DF, A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study)., Am. J. Respir. Crit. Care Med., 2011, 183, 5, 620-626, doi: 10.1164/rccm.201003-0423OC.
-
Results
McAuley DF, O'Kane CM, Craig TR, Shyamsundar M, Herwald H, Dib K, Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury., BMC Pulm Med, 2013, 13, 47, doi: 10.1186/1471-2466-13-47.