Condition category
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information



Primary contact

Dr Danny McAuley


Contact details

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

Additional identifiers

EudraCT number 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



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:

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


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)


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



Phase II

Drug names


Primary outcome measures

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

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


Overall trial end date


Reason abandoned


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


Age group




Target number of participants


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


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

Regional Intensive Care Unit
BT12 6BA
United Kingdom

Sponsor information


The Royal Group Hospitals Trust (UK)

Sponsor details

Grosvenor Road
United Kingdom
+44 (0)2890 240503

Sponsor type




Funder type


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


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


Funder name

Added 24/06/2010:

Alternative name(s)

Funding Body Type

Funding Body Subtype


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


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

Results - basic reporting

Publication summary

2011 results in
2013 results in

Publication citations

  1. 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.

  2. 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.

Additional files

Editorial Notes