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    Summary
    EudraCT Number:2010-020763-20
    Sponsor's Protocol Code Number:10072DMcA-CS
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-08-04
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2010-020763-20
    A.3Full title of the trial
    Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction
    (HARP 2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Many patients admitted to the Intensive Care Unit (ICU) have a breathing machine, or ventilator, to help them breathe and ensure that enough oxygen gets into their blood. For reasons that are unclear, when people are critically ill their lungs often fail, which is termed acute lung injury (ALI). This study is being conducted to find out if Simvastatin is effective in the treatment of ALI by testing it in a larger number of patients.
    A.3.2Name or abbreviated title of the trial where available
    Simvastatin in ALI (HARP 2)
    A.4.1Sponsor's protocol code number10072DMcA-CS
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN88244364
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNational University of Ireland, Galway
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHealth Research Board
    B.4.2CountryIreland
    B.4.1Name of organisation providing supportClinical Research Support Centre
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNUIG
    B.5.2Functional name of contact pointCaroline Whiriskey
    B.5.3 Address:
    B.5.3.1Street AddressHRB Clinical Research Facility Galway, NUIG, Geata and Eolais, University Road
    B.5.3.2Town/ cityGalway
    B.5.3.3Post code00000
    B.5.3.4CountryIreland
    B.5.4Telephone number35391494241
    B.5.5Fax number35391585852
    B.5.6E-mailcaroline.whiriskey@hse.ie
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Simvastatin
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSimvastatin
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEnteral use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSimvastatin
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboEnteral use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute lung injury
    E.1.1.1Medical condition in easily understood language
    Lung failure in critically ill patients
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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 distinct objectives:
    Objective 1: To conduct a prospective randomised, double-blind, placebo controlled
    phase II multi-centre trial of simvastatin for the treatment of ALI.
    E.2.2Secondary objectives of the trial
    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 as well as link genotypic information to the phenotypic information recorded as part of this study.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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 arterial 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, 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
    E.4Principal exclusion criteria
    1. Age < 16 years
    2. More than 48 hours from the onset of ALI
    3. Patient is 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, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil or diltiazem. Patients receiving low dose erythromycin as a prokinetic will not be excluded
    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, AST values may be obtained up to 72 hours prior to randomisation.

    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is Ventilator Free Days to day 28.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days, 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.
    E.5.2Secondary end point(s)
    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 TNFα, IL-1β, 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-κB activation

    Data for Economic Evaluation

    1. Health related quality of life (HRQoL)
    EQ-5D at discharge 3, 6 and 12 months post randomisation
    2. Resource use:
    Length of ICU stay (level 3 care)
    Length of HDU stay (level 2 care)
    Length of hospital stay
    Health service contacts up to 12 months post randomisation
    E.5.2.1Timepoint(s) of evaluation of this end point
    Following randomisation patients will participate in this clinical trial for up to 12 months. See time lines of specific outcomes in section E.5.2.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The study will end when 540 patients have been recruited and completed 12 month follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months31
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months31
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 25
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 130
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 115
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Critically ill sedated patients unable to give consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state270
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 540
    F.4.2.2In the whole clinical trial 540
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following the study period of 28 days, all patients will be treated according to routine clinical practice for acute lung injury (ALI).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-07-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-05-12
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