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    Summary
    EudraCT Number:2005-004636-52
    Sponsor's Protocol Code Number:2005AN005
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2005-11-24
    Trial 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 number2005-004636-52
    A.3Full title of the trial
    Randomised Double-Blind Placebo Controlled Trial of 40mg/day of Atorvastatin on Reduction in Severity of Sepsis in Ward Patients
    A.3.2Name or abbreviated title of the trial where available
    Clinical trial of Atorvastatin on Reduction in Severity of Sepsis
    A.4.1Sponsor's protocol code number2005AN005
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorHeart of England NHS Foundation Trust
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    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 nameAtorvastatin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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 placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Sepsis is the clinical syndrome defined by the presence of both infection and a systemic inflammatory response. Sepsis is common in general medical and surgical wards with an estimated prevalence of 15%. The pathophysiological process of sepsis is a disease continuum from infection, signs of systemic inflammation in response to infection, sepsis, severe sepsis and multi-organ dysfunction. Sepsis may convert to severe sepsis resulting in a higher hospital mortality rate.
    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
    1. To investigate the difference in rates of sepsis converting to severe sepsis and of Critical Care admissions between statin-treatment and placebo groups;
    2. To look at the difference in rates of sepsis converting to severe sepsis and of Critical Care admissions amongst statin-treatment, placebo and pre-treated statins groups;
    3. To evaluate the difference in hospital mortality rate between statin-treatment and placebo groups after the primary endpoint has been reached.
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    A. Age > 18 years;

    B. One of following documented source of infection:

    (1). Pneumonia is defined as clinical signs:
    cough or new sputum production or dyspnoea or chest pain or rales
    and an infiltrate on CXR;

    (2). Urinary tract infection is defined as > 1 of following criteria:
    urgency or frequency, or dysuria, or suprapubic tenderness
    and > 1 of the following:
    a. positive dipstick for leukocyte esterase and/or nitrate;
    b. pyuria (urine specimen with > 10 white blood cells /mm
    or > 3 white blood cells per field of unspun urine;
    or
    c. organisms seen on Gram’s stain of unspun urine.

    (3). Cellulitis or bone/joint infection is defined as erythema, pain, swelling, warmth of the affected skin or joints and limited movement.

    (4). Abdominal infection is defined as > 1 of following criteria:
    a. abdominal distension and tenderness, or local discomfort or peritonism;
    b. abdominal mass, e.g. gall bladder, pseudocyst, abscess;
    c. failure to tolerate enteral feed or nasogastric aspirates > 200ml/4hrly;
    d. diarrhoea;
    e. laparotomy for perforation or obstruction;
    f. pancreatitis, or cholecyctitis, or gynaecological infection, or pyelonephritis;
    g. abdominal collection shown on CT, ultrasound or abdominal X-ray.

    (5). Meningitis is defined as > 1 of following criteria:
    a. headache with stiff neck;
    b. focal neurological signs;
    c. LP positive;
    d. CT: raised ICP is suspected.

    (6). Endocarditis: fever and changing murmur are signs of suspected endocarditis.

    (7). Catheter or device infection: localised cellulitis.



    C. > 2 of the following signs of systemic inflammation in response to infection:

    (1). Core temperature: > 38.3C or < 36C;

    (2). Heart rate: > 90 bpm, except in patients with a known medical condition to increase the heart rate or those receiving treatment that would prevent tachycardia;

    (3). Systolic BP < 90 mmHg, or MAP < 70 mmHg;

    (4). Decreased capillary refill or mottling;

    (5). Urine output < 0.5 ml/kg/h for more than 2 hrs;

    (6). Respiratory rate: > 20 breaths /min
    or a PaCO2 < 4.3 or PaO2/FiO2 < 40, but > 26.8 kPa;

    (7). Ileus (absent bowel sounds);

    (8). Altered mental status;

    (9). Significant oedema or positive fluid balance (> 20 ml/kg over 24 hrs);

    (10). White cell count: > 12 000/mm or < 4000/mm
    or a differential count showing >10% immature neutrophils;

    (11). C-reactive protein > 2 SD above the normal value;

    (12). Plasma glucose > 7.7 mmol/l in the absence of diabetes;

    (13). Platelets count <100,000, but > 49, 000/µl, or INR > 1.5 or APTT > 60s;

    (14). Plasma lactate > 2 mmol/l;

    (15). Bilirubin > 40, but < 101 µmol/l;

    (16). Creatinine > 120, but < 177 µmol/l.
    E.4Principal exclusion criteria
    • Signs of severe sepsis: septic patients with any one of the following signs:
    (1). PaO2/FiO2 < 26.7 kPa;
    (2). Noradrenaline/adrenaline > 0.1 μg/kg/min;
    (3). Creatinine > 330 μmol/L;
    (4). Platelets <50 x 103/ mL;
    (5). Bilirubin > 102 µmol/L;
    (6). Glasgow Coma Score < 9.

    • Known active liver disease, alcohol abuse
    or persistently abnormal liver function tests:
    alanine aminotransferase, or creatine kinase > 3 times the upper limit
    of laboratory normal ranges;

    • Pregnancy, breast-feeding or women of childbearing potential not using adequate contraception;

    • Previous adverse reaction to statins;

    • Concomitant use of fibrates or other lipid-lowering therapy;

    • Administration of atorvastatin was ceased <2 weeks prior to the trial
    (wash-out period in healthy volunteers: 7 days);

    • Concomitant use of erythromycin, telithromycin, clarithromycin itraconazole, imidazoles, triazoles, ciclosprin or grapefruit juice21;

    • Participation in another clinical trial;

    • Patients with terminal cancer;

    • Fail to obtain written consent.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is sepsis converting to severe sepsis.
    The treatment with Atorvastatin will be discontinued after the patient has been found to have one or more of the signs of organ dysfunction (defined as severe sepsis). Organ dysfunction is defined Sequential Organ Failure Assessment (SOFA) Score > 3 within 24 hrs, which includes:
    (1). PaO2/FiO2 < 26.7 kPa;
    (2). Noradrenaline/adrenaline > 0.1 μg/kg/min;
    (3). Creatinine > 330 μmol/L;
    (4). Platelets < 50 x 103/ mL;
    (5). Bilirubin > 102 µmol/L;
    (6). Glasgow Coma Score < 9.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    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 No
    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.8.3 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.8.5The 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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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 following criteria will be used for electively terminating the trial or other research prematurely:
    1) Interim analysis shows the endpoints have reached statistical significance; or
    2) Interim analysis shows significant side effects from the trial.
    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 days
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-11-24. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state414
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 414
    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 Decision2006-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-01-17
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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