Condition category
Respiratory
Date applied
21/05/2010
Date assigned
26/11/2010
Last edited
10/11/2014
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Ms Christine McNally

ORCID ID

Contact details

Clinical Research Support Centre
1st Floor
Elliott Dynes Building
Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
+44 (0)2890 63 5794
harp2@crsc.n-i.nhs.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

9122; 10072DMcA-CS

Study information

Scientific title

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP 2)

Acronym

HARP 2

Study hypothesis

Current Hypothesis as of 08/03/2011:
The aim is to test the hypothesis that treatment with enteral simvastatin 80mg once daily for a maximum of 28 days will be of therapeutic value in patients with acute lung injury (ALI). The study has two objectives:
Objective 1: To conduct a prospective randomised, double-blind, placebo-controlled phase II multi-centre trial of simvastatin for the treatment of ALI.
Objective 2: To study the biological effect of simvastatin treatment on:
(2a) systemic markers of inflammation; (2b) systemic cell-specific indices of activation and injury to the alveolar epithelium and endothelium; (2c) lung extracellular matrix degradation; (2d) assess whether response to simvastatin is determined by genetic polymorphisms.
Patient Population: Patients with ALI
Trial Setting: Adult intensive care units (ICU)
Trial Intervention: Simvastatin 80mg or identical placebo once daily administered enterally for up to 28 days Sample Size: A sample size of 524 subjects (262 in each group) will have 80% power at a two-tailed significance level of 0.05 to detect a 20% difference in ventilator-free days (VFDs). With an estimated dropout rate of 3%, this study will require a total of 540 patients (270 in each group)
Primary Outcome: The primary outcome will be VFDs
Secondary Outcomes: There are a number of secondary outcomes which include: (a) Change in oxygenation index (OI) from baseline to day, 3, 7, 14 and 28; (b) Change in sequential organ failure assessment (SOFA) score from baseline to day 3, 7, 14 and 28; (c) Non pulmonary organ failure free days (d) All cause mortality 28 days post randomisation; (e) Mortality at (first) discharge from Critical Care; (f) Mortality at (first) discharge from hospital; (g) Mortality at 12 months post randomisation; (h) Safety; (i) Biological mechanisms; (j) Health-related quality of life; (k) Cost effectiveness.

Previous hypothesis:
The aim of this study is to test the hypothesis that treatment with enteral simvastatin 80 mg once daily for a maximum of 28 days will be of therapeutic value in patients with acute lung injury (ALI).

Many different circumstances, for example severe infection or as a result of injury in a road traffic accident, may result in a person becoming critically ill. For reasons that are unclear, when people are critically ill their lungs often fail; this is termed acute lung injury (ALI). Normally the lungs are filled with air, however when lung injury occurs, the lungs fill with water. As a result, a person's breathing becomes difficult and a ventilator is needed to take over their breathing. This condition is common, can affect any age group and is often fatal. Furthermore, even after recovery from lung injury, patients frequently go on to experience a poorer quality of life, for example many are unable to return to work or look after themselves, needing considerable help from family or other carers. There is currently no effective treatment for lung injury.

The data from a proof of concept study we carried out, has suggested that simvastatin may assist patients with ALI to recover more quickly, and has informed the design and methodology of this current study.

It is planned to recruit 540 patients to this study. The study is what is called a 'randomised, placebo controlled trial'. This type of trial is widely accepted to be the best way to find out if a treatment really works or not. In this study, there will be two groups of people; one group will be given simvastatin and the other group a dummy drug (placebo). The group (and thus the specific treatment) that a person is allocated to, is decided 'at random' using a computer programme. This ensures that the two groups of patients are the same in all ways except for that treatment. This means that any difference in the experience of patients in either of the groups should be due to the difference in treatment and not to any other difference that could influence the outcome of the treatment.

Blood and urine samples will be taken at baseline, prior to the drug being taken, and on days 3, 7, 14 and 28, to allow us to determine the ways in which ALI develops and how simvastatin might work to alleviate the condition. We will determine how long patients need assistance with their breathing on a ventilator and how fast they recover.

Patients will be followed up at 3, 6 and 12 months with a 15 minute quality of life questionnaire to measure any residual effects of their illness on their lives.

As of 08/03/2011the trial record has been updated. The updates can be found under the relevant field with the date of update.
The previous scientific title was: 'Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction: a randomised randomised, double-blind, placebo-controlled, phase II multi-centre clinical study'

Please note that as of 07/09/2012, the anticipated end date of this trial was changed from 01/06/2014 to 01/09/2015.

Ethics approval

ORECNI on 08/09/2010 (ref: 10/NIR02/36)

Study design

Randomised double-blind placebo-controlled phase II multicentre clinical study

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

Intervention

Simvastatin 80 mg once daily versus placebo, administered enterally via a feeding tube or orally, for up to 28 days.

Intervention type

Drug

Phase

Phase II

Drug names

Simvastatin

Primary outcome measures

Current primary outcome measures as of 08/03/2011:
The primary outcomes will be ventilator free days.

Previous primary outcome measures:
Ventilator free days (VFDs) to day 28 defined as the number of days from the time of initiating unassisted breathing, to day 28 after randomisation, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28.

If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or dies prior to day 28, without initiating unassisted breathing or before 48 consecutive hours of unassisted breathing, VFDs will be 0. Patients transferred to another hospital or other health care facility will be followed to day 28 to assess this endpoint.

For example, if a subject initiates unassisted breathing on day 16 and survives to day 28, he/she will be assigned a value of 12 VFDs. If a similar subject begins unassisted breathing on day 16 but dies on day 25, the VFDs is 9. In keeping with previous trials unassisted breathing is defined as:
1. Extubated with supplemental oxygen or room air
2. Open T-tube breathing
3. Tracheostomy mask breathing
4. CPAP less than or equal to 5 cm H20 without pressure support

Patients receiving pressure support via non-invasive ventilation will be defined as receiving assisted ventilation.

Secondary outcome measures

Current secondary outcome measures as of 07/09/2012:
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 day 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
1. CK >10 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28)
2. ALT/AST >8 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28)
3. Need for renal replacement therapy in patients with CK elevated >10 fold
4. Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs) as defined in section 7.4.2

Biological mechanisms
1. Neutrophil activation biomarkers which may include but are not limited to measurement of plasma MPO and MMP-8
2. Plasma inflammatory response biomarkers which may include but are not limited to measurement of CRP, cytokines (including but not limited to TNF-alpha, IL-1 aplha, IL-6, IL-8), proteases and anti-proteases, HO-1, adhesion and activation molecule expression (including but not limited to sICAM-1), coagulation factors (including but not limited to thrombin-anti-thrombin complex, tissue factor, protein C, thrombomodulin and plasminogen activator inhibitor-1), RAGE ligands and vitamin D status
3. Alveolar epithelial and endothelial injury biomarkers which may include but are not limited to measurement of plasma cell specific biomarkers such as RAGE, SP-D, Ang I/II and vWF)
4. Systemic endothelial function biomarkers which may include but is not limited to measurement of spot urine albumin:creatinine ratio (ACR)
5. Pulmonary extracellular matrix (ECM) degradation and turnover biomarkers which may include but are not limited to measurement of urinary desmosine indexed to urine creatinine and procollagen peptide III
6. Assess whether response to simvastatin is determined by genetic polymorphisms as well as link genotypic information to the phenotypic information recorded as part of this study
7. Peripheral blood NF-êB activation

Data for Economic Evaluation
1 Health related quality of life (HRQoL)
1.1EQ-5D at discharge 3, 6 and 12 months post randomisation
2. Resource use:
2.1 Length of ICU stay (level 3 care)
2.2 Length of HDU stay (level 2 care)
2.3 Length of hospital stay
2.4 Health service contacts up to 12 months post randomisation

Previous secondary outcome measures from 14/09/2011, until 07/09/2012:
There are a number of secondary outcomes which include:
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 day 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. Safety:
8.1 CK >10 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28)
8.2 ALT/AST >5 times the upper limit of normal (measured on days 1, 3, 7, 14, 21 and 28)
8.3 Need for renal replacement therapy in patients with CK elevated >10 fold
8.4 Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs) as defined in section 7.4.2
9. Biological mechanisms
10. Health-related quality of life
11. Cost effectiveness

Previous secondary outcome measures from time of registration:
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 day 3, 7, 14 and 28
3. All cause mortality 28 days post-randomisation
4. Mortality at (first) discharge from ICU
5. Mortality at (first) discharge from hospital
6. Mortality at 12 months post randomisation

Safety:
1. CK greater than 10 times the upper limit of normal (measured on days 1, 3, 7, 14 and 28)
2. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (measured on days 1, 3, 7, 14 and 28)
3. Need for renal replacement therapy in patients with CK elevated greater than 10-fold
4. Serious adverse events (SAEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs)

Biological mechanisms:
1. Neutrophil activation as measured by plasma MPO and MMP-8
2. Plasma inflammatory response as measured plasma CRP, TNF-alpha, IL-1-alpha, IL-6, IL-8 and sICAM-1
3. Alveolar epithelial and endothelial injury as measured by plasma RAGE, SP-D and vWF
4. Systemic endothelial function as measured by spot urine albumin:creatinine ratio (ACR)
5. Lung extracellular matrix (ECM) degradation as measured by urinary desmosine indexed to urine creatinine
6. Assess whether response to simvastatin is determined by genetic polymorphisms as well as link genotypic information to the phenotypic information recorded as part of this study
7. Peripheral blood NF-kappa-B activation

Data for economic evaluation:
1. Health related quality of life (HRQoL) EQ-5D at discharge 3, 6 and 12 months after randomisation
2. Resource use:
2.1. Length of ICU stay (level 3 care)
2.2. Length of HDU stay (level 2 care)
2.3. Length of hospital stay
2.4. Health service contacts up to 12 months after randomisation
2.5. Patient out-of-pocket expenditure and loss of earnings up to 12 months after randomisation
2.6. Carer out-of-pocket expenditure and loss of earnings up to 12 months after randomisation

Overall trial start date

01/12/2010

Overall trial end date

01/09/2015

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 14/09/2011:
1. Patient must be receiving invasive mechanical ventilation
2. Patient must have ALI [34] as defined by acute onset of:
2.1 Hypoxic respiratory failure (PaO2/FiO2 ≤ 40 kPa from 2 blood gases >1 hour apart).
2.2 Bilateral infiltrates on chest X-ray consistent with pulmonary oedema.
2.3 No clinical evidence of left atrial hypertension or if measured, a pulmonary arterial occlusion pressure (PAOP) less than or equal to 18 mmHg. If a patient has a PAOP > 18 mmHg, then the other criteria must persist for more than 12 hours after the PAOP has declined to < 18 mmHg, and still be within the 48-hour enrolment window

Acute onset is defined as follows: the duration of the hypoxia criterion (a) and the chest X-ray criterion (b) must be <28 days at the time of randomisation.

Infiltrates considered consistent with pulmonary oedema ± include any patchy or diffuse infiltrates not fully explained by mass, atelectasis, or effusion or opacities known to be chronic (>28 days). The findings of vascular redistribution, indistinct vessels, and indistinct cardiac borders are not considered consistent with pulmonary oedema ±.

All ALI criteria (a-c above) must occur within the same 24 hour period. The time of onset of ALI is when the last ALI criterion is met. Patients must be enrolled within 48 hours of ALI onset

Previous inclusion crieteria:

1. Patient must be receiving invasive mechanical ventilation
2. Patient must have ALI as defined by acute onset of:

a) hypoxic respiratory failure (PaO2/FiO2 ≤ 40 kPa from 2 blood gases >1 hour apart).
b) bilateral infiltrates on chest X-ray consistent with pulmonary oedema.
c) No clinical evidence of left atrial hypertension or if measured, a pulmonary
arterial occlusion pressure (PAOP) less than or equal to 18 mmHg. If a patient has a PAOP ≤ 18 mmHg.

All ALI criteria (a-c above) must occur within the same 24 hour period. The time of onset of ALI is when the last ALI criterion is met. Patients must be enrolled within 48 hours of ALI onset.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

540

Participant exclusion criteria

Current exclusion criteria as of 07/09/2012:
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 until 07/09/2012:
6. Patients currently receiving ongoing and sustained treatment with any of the following; itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil or diltiazem. Patients receiving low dose erythromycin as a prokinetic will not be excluded.
12. Domiciliary mechanical ventilation
Added 08/03/2011:
16. Non−english speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available

Recruitment start date

01/12/2010

Recruitment end date

01/09/2015

Locations

Countries of recruitment

Ireland, United Kingdom

Trial participating centre

Clinical Research Support Centre
Belfast
BT12 6BA
United Kingdom

Sponsor information

Organisation

Belfast Health and Social Care Trust (UK)

Sponsor details

c/o Alison Murphy
Research Management & Governance Office
2nd Floor
KEB
Royal Hospitals
Grovsenor Road
Belfast
BT12 6BA
United Kingdom
+44 (0)28 9063 6348
alison.murphy@belfasttrust.hscni.net

Sponsor type

Government

Website

http://www.belfasttrust.hscni.net/index.html

Funders

Funder type

Charity

Funder name

National Institute for Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation Programme (EME)

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

Results - basic reporting

Publication summary

2012 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/22985805
2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/25268516

Publication citations

  1. Protocol

    McAuley DF, Laffey JG, O'Kane CM, Cross M, Perkins GD, Murphy L, McNally C, Crealey G, Stevenson M, , , Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial., Trials, 2012, 13, 170, doi: 10.1186/1745-6215-13-170.

  2. Results

    McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston P, Hopkins PA, Johnston AJ, McDowell C, McNally C, , , Simvastatin in the acute respiratory distress syndrome., N. Engl. J. Med., 2014, 371, 18, 1695-1703, doi: 10.1056/NEJMoa1403285.

Additional files

Editorial Notes