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

ISRCTN ISRCTN70127774
DOI https://doi.org/10.1186/ISRCTN70127774
Secondary identifying numbers EME 08/99/08; RGHT000275
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

d.f.mcauley@qub.ac.uk

Study information

Study designPhase II single centre prospective double-blind randomised placebo-controlled trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details below to request a patient information sheet
Scientific titleHydroxymethylglutaryl-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 acronymHARP
Study objectivesTreatment 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) studiedAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
InterventionPatients 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 typeDrug
Pharmaceutical study type(s)
PhasePhase II
Drug / device / biological / vaccine name(s)Simvastatin
Primary outcome measureReduction in extravascular lung water (EVLW) in the simvastatin treated group at day 7
Secondary outcome measuresCurrent 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 study start date02/08/2006
Completion date04/08/2009

Eligibility

Participant type(s)Patient
Age groupAdult
SexBoth
Target number of participants60
Key inclusion criteriaMechanically 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 criteriaCurrent 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 enrolment02/08/2006
Date of final enrolment04/08/2009

Locations

Countries of recruitment

  • Northern Ireland
  • United Kingdom

Study participating centre

Regional Intensive Care Unit
Belfast
BT12 6BA
United Kingdom

Sponsor information

The Royal Group Hospitals Trust (UK)
Hospital/treatment centre

Grosvenor Road
Belfast
BT126BA
Northern Ireland
United Kingdom

+44 (0)2890 240503
I.Young@qub.ac.uk
ROR logo https://ror.org/02tdmfk69

Funders

Funder type

Government

Research and Development Office (UK) - Doctoral Fellowship scheme from Central Services Agency, Northern Ireland

No information available

REVIVE (UK) - Charity for the Regional Intensive Care Unit at the Royal Group Hospitals Trust

No information available

Added 24/06/2010:

No information available

Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: 08/99/08)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot 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
BMC - Part of Springer Nature Springer Nature