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    The EU Clinical Trials Register currently displays   43850   clinical trials with a EudraCT protocol, of which   7282   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-003343-29
    Sponsor's Protocol Code Number:RG_12-179
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-11-26
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-003343-29
    A.3Full title of the trial
    Simvastatin as adjuvant therapy to correct neutrophil dysfunction in older pneumonia patients - a randomised double blind placebo controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Using Simvastatin to improve immune responses in older people with pneumonia
    A.3.2Name or abbreviated title of the trial where available
    Improving neutrophil responses in pneumonia using simvastatin
    A.4.1Sponsor's protocol code numberRG_12-179
    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 SponsorUniversity of Birmingham
    B.1.3.4CountryUnited Kingdom
    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 supportBritish Lung Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationQueen Elizabeth Hospital Birmingham NHS Trust
    B.5.2Functional name of contact pointClinical Trials Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressLung Investigation Unit, QEHB
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214721311
    B.5.5Fax number01213713887
    B.5.6E-mailanita.pye@uhb.nhs.uk
    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 Simastatin (zocor) 80mg once daily
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp and Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 PL0025/0366
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSimvastatin
    D.3.9.1CAS number 79902-63
    D.3.9.3Other descriptive nameSimvastatin
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute episodes of Pneumonia and sepsis in older adults
    E.1.1.1Medical condition in easily understood language
    Pneumonia, which is a lung infections with chest symptoms (cough, sputum, breathlessness) and new changes on chest radiograph compatible with this diagnosis
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10035664
    E.1.2Term Pneumonia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Pneumonia (severe lung infection) is one of the commonest causes of death and the death rate has not fallen for many years. Elderly patients are at greater risk of pneumonia and its complications such as sepsis. Usually the immune system works cooperatively to clear infection and prevent organ damage. Neutrophils are cells of the immune system that are critical in clearing bacteria. These cells are the foot soldiers of the immune system and move from the blood into infected tissues/organs to locate and kill the invading bacteria using an arsenal of toxic products. Sepsis occurs when the bodies normally helpful reaction to infection becomes harmful. As part of this process, neutrophils stop working properly, they become less able to clear bacteria and release their toxic products indiscriminately, causing organ damage. Defects in the efficiency of these cells is associated with a poor outcome from pneumonia and sepsis. We have undertaken a pilot study in patients, which
    E.2.2Secondary objectives of the trial
    1) safety and tolerability of drug in this patient group. 2) relationship of baseline and changes in above to clinical relevant outcomes (survival, development of organ failure, admission to ITU, SOFA score, ventilator free days. 3) do simvastatin influence neutrophil function in cells that have transmigrated across the alveolar epithelium. 4) does simvastatin modulate biomarkers of inflammation and cellular dysfunction in plasma and bronchoalveolar lavage fluid? These assessments will be made at baseline and upon day 4, 7 and convalescent samples.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria 1. Age > 60 years 2. Patients with a diagnosis of community acquired pneumonia. We will use the British Thoracic Society definition of pneumonia; defined as “symptoms and signs consistent with an acute lower respiratory tract infection associated with new radiographic shadowing for which there is no other explanation”. We will include symptoms and signs as having 3 or more of the following: cough, sputum production, breathlessness, pleuritic chest pain, haemoptysis, fever, headache, signs consistent with pneumonia on chest auscultation. 3. Pneumonia patients will also need to meet the criteria for sepsis based on the standard definitions as published in the 2008 Surviving Sepsis Campaign Guidelines.
    E.4Principal exclusion criteria
    Exclusion criteria • More than 48 hours from admission at time of consent. • Current or recent statin use within 1 month. • known prior myositis. • creatinine kinase >10 times upper limit normal range* • transaminases (ALT/AST) >8 times upper limit of normal range* • severe renal impairment (creatinine clearance <30ml/min) not receiving renal replacement therapy • patients currently receiving ongoing and sustained treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, ciclosporine, amiodarone, verapamil or diltiazem. Fibric acid derivatives (except fenofibrate), danazol. • A family history of muscular disorders. • Known HIV or hepatitis B/C infection. • Contraindication to enteral drug administration (either PO or Per NG) e.g. patients with mechanical bowel obstruction. • Known participation in other investigational medicinal product (IMP_ trials within 30 days. • Consent / relative or advocate assent declined. • Treatment withdrawal imminent within 24 hours. •Immunosuppression due to corticosteroid or other immunosuppressant use • Patient declines consent • Personal Consultee, when available, does not provide assent • Porfessional Consultee, if used, does not provide assent
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is changes to key neutrophil functions in older people with pneumonia and sepsis using Simvastatin. These functions include 1. Assessment of adhesion, chemokinesis and chemotaxis by neutrophils Neutrophil adhesion and migration will be assessed in a microscopy slide based system using established methodology (35). Chemoattractants used will be those that act via CXC receptors (CXCL8 and GROα), those that act through other receptors (e.g., fMLP). 2. Assessment of Neutrophil Extracellular Traps using extracellular DNA staining and visualisation using confocal microscopy. 3. Assessment of bacterial killing The phagocytic function and superoxide production of neutrophils will be examined using standard assays. Respiratory burst in response to fMLP will be determined in isolated neutrophils by measuring the generation of superoxide in a lucigenin-based assay. Phagocytosis of E Coli by neutrophils will be measured using a commercially available kit (Phagotest, Orpegen, Germany).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Cell studies will be performed at baseline (day 1), day 4, day 7 and the re-cooperation visit on day 14
    E.5.2Secondary end point(s)
    1. Safety and tolerability of drug in this patient group. 2) Relationship of baseline and changes in above to clinical relevant outcomes (survival, development of organ failure,admission to ITU, SOFA score, ventilator free days).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 0, 4, 7 and re-cooperation sample at day 14
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    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 No
    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 end of the trial will be the last visit of the last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days2
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days27
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 46
    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 No
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state56
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 0
    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)
    This clinical trial is studying cellular mechanisms rather than disease outcomes, so it is unlikely that any positive disease benefit will be felt by the participant for the duration of the study. If the clinical trial demonstrated that neutrophil function can be positively altered during episodes of pneumonia by taking Simvastatin (so that neutrophils were more accurate during migration and more effective at killing and clearing bacteria) we would then need to conduct a larger, longer
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-07-20
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