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    Summary
    EudraCT Number:2004-003870-27
    Sponsor's Protocol Code Number:ENOSPROTOCOL
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2011-11-30
    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 ConcernedSweden - MPA
    A.2EudraCT number2004-003870-27
    A.3Full title of the trial
    The Efficacy of Nitric Oxide in Stroke (ENOS) Trial: A prospective, collaborative, international, multicentre, randomised, parallel-group, single and outcome blinded, controlled, factorial trial to investigate the safety and efficacy of treatment with transdermal glyceryl trinitrate, a nitric oxide donor, and of continuing or stopping temporarily pre-stroke antihypertensive therapy, in patients with acute stroke
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ENOS
    A.3.2Name or abbreviated title of the trial where available
    ENOS
    A.4.1Sponsor's protocol code numberENOSPROTOCOL
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN99414122
    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 Nottingham
    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 Yes
    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 nameGlyceryl trinitrate Transdermal
    D.3.2Product code C01 DA 02
    D.3.4Pharmaceutical form Transdermal patch
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTransdermal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGlyceryl trinitrate
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor code04001
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.IMP: 2
    D.1.2 and D.1.3IMP Role
    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.2.1.2Country which granted the Marketing AuthorisationSweden
    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.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stroke
    E.1.1.1Medical condition in easily understood language
    Stroke
    E.1.1.2Therapeutic area Body processes [G] - Physiological processes [G07]
    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
    Assess the balance of risk and benefit of lowering blood pressure with GTN immediately after ischaemic and haemorrhagic stroke.
    E.2.2Secondary objectives of the trial
    Secondary objectives: Assess whether pre-stroke antihypertensive therapy should be continued or stopped temporarily after stroke.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Genetic sub-study: An important aim of the genetic analyses is to determine whether polymorphic differences in candidate genes explain blood pressure and outcome responses to GTN (pharmacogenetic analysis). The exact genetic analyses to be performed are undefined at present and will depend on relevant scientific information available at the time of laboratory analysis and prior to sample destruction. Likely analyses will include genes related to the synthesis and metabolism of nitric oxide (e.g. endothelial nitric oxide synthase) and the mechanism of action of antihypertensive agents (e.g. polymorphisms in receptors)
    E.3Principal inclusion criteria
    a) Adult (age > 18 years).
    b) Clinical stroke syndrome with limb weakness lasting at least 1 hour (i.e. not likely to be a
    transient ischaemic attack).
    c) Residual limb weakness at the time of enrolment (SSS Arm <6 and/or Leg <6, appendix C).
    d) Onset < 48 hours. If the time of onset is unknown, apply the time when the patient was last
    known to be well. [This timeframe covers the period of maximum uncertainty over altering
    blood pressure and should permit the vast majority of otherwise eligible patients to be
    recruited]
    e) Conscious (Glasgow Coma Scale > 8).
    f) Systolic blood pressure in range 140 mmHg to 220 mmHg inclusive on the basis of at least
    one of the three baseline pre-randomisation measures.
    g) Independent prior to stroke (pre-morbid modified Rankin Scale < 2).
    h) Meaningful consent, or assent from a relative or carer if the patient is unable to give
    meaningful consent (e.g. in cases of dysphasia, confusion, or reduced conscious level).
    E.4Principal exclusion criteria
    a) Definite need for nitrate therapy: e.g. concurrent myocardial infarction, unstable angina, left
    ventricular failure. Patients admitted on nitrates for the management of stable angina may
    stop these for the 7 day trial treatment period. b) Contraindication to nitrate therapy: e.g. hypersensitivity to nitrates, dehydration,
    hypovolaemia, hypertrophic obstructive cardiomyopathy, aortic stenosis, cardiac
    tamponade, constrictive pericarditis, mitral stenosis, marked anaemia, closed-angle
    glaucoma, sildenafil (Viagra) or related drug, within 24 hours.
    c) Definite need for pre-stroke antihypertensive, anti-anginal or anti-heart failure medication:
    e.g. concurrent angina, heart failure.
    d) Definite need for new antihypertensive, anti-anginal or anti-heart failure medication during
    acute stroke: e.g. concurrent angina, heart failure, hypertensive encephalopathy, aortic
    dissection.
    e) Patients expected, on the basis of existing investigations, to require surgical intervention
    (e.g. clot evacuation, carotid endarterectomy) during the treatment or follow-up period.
    f) Known intracerebral pathology other than stroke, e.g. subarachnoid haemorrhage, brain
    tumour, cerebral abscess.
    g) Other serious condition which is likely to prevent outcome assessment at 90 days, e.g.
    advanced cancer.
    h) Previous enrolment in ENOS.
    i) Current involvement in another trial of an experimental drug. [Patients may be randomised
    into observational studies or non-drug trials.]
    j) Not available for follow-up, e.g. no fixed address, overseas visitor.
    k) Females of childbearing potential where pregnancy cannot be excluded by a negative
    pregnancy test, pregnancy, or breastfeeding.
    l) Need for new antihypertensive therapy to lower systolic blood pressure to achieve the
    enrolment range of 140-220mmHg
    m) New (not prescribed pre-stroke) antihypertensive medication commenced after stroke onset
    E.5 End points
    E.5.1Primary end point(s)
    Combined death or dependency (modified Rankin Score >2)
    evaluation of this endpoint: 90 days after stroke onset
    E.5.1.1Timepoint(s) of evaluation of this end point
    90 Days
    E.5.2Secondary end point(s)
    Page 21 of 61
    Events at or within 7 days (enter on ‘day 7’ form):
    a) Recurrent stroke.
    b) Scandinavian Stroke Scale (SSS) score.
    c) Symptomatic deep vein thrombosis.
    d) Symptomatic pulmonary embolism.
    e) Adverse events - headache, symptomatic hypotension.

    Haemodynamic (enter on ‘day 7’ form):
    a) Blood pressure daily between 1 and 7 days (see section 2.13).

    Hospital events (enter on ‘hospital events’ form):
    a) Length of stay in hospital.
    ENOS PROTOCOL, version 1.5, 10th July 2008
    Philip Bath, telephone: +44 115 823 1768; fax: +44 115 823 1771; e-mail philip.bath@nottingham.ac.uk
    b) Discharge disposition (death, institution, or home).
    c) Time at home

    Outcome at 90 days (to be collected centrally):
    a) Barthel Index (< 60/100, including death).
    b) Barthel Index (< 60/100, excluding death), i.e. disability.
    c) Barthel Index > 95/100 at 90 days, i.e. an excellent outcome 5,142.
    d) Quality of life – EuroQol.143
    e) Cognition - , TICS-M144 and verbal fluency145. (see appendix G)
    f) Mood – Zung Depression rating Scale 146,147
    g) Disposition.
    h) Re-hospitalisation following discharge

    Safety measures at 7 days (enter on ‘day 7’ form):
    a) Death.
    b) Neurological deterioration. (negative change in SSS)
    c) Symptomatic intracranial haemorrhage.
    d) Major extracranial haemorrhage.
    e) Symptomatic hypotension.
    f) Symptomatic hypertension.

    E.5.2.1Timepoint(s) of evaluation of this end point
    90 Days
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Factorial partial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Patch or no patch under gauze dressing
    E.8.2.4Number of treatment arms in the trial6
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA130
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    China
    Egypt
    Georgia
    Greece
    Hong Kong
    India
    Ireland
    Italy
    Malaysia
    New Zealand
    Norway
    Philippines
    Poland
    Romania
    Serbia
    Spain
    Sri Lanka
    Sweden
    United Kingdom
    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
    30/9/2013
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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 No
    F.1.1Number of subjects for this age range: 0
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3200
    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 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 2011-11-30. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state500
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1000
    F.4.2.2In the whole clinical trial 3500
    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)
    Not applicable
    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 Decision2012-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-02-13
    P. End of Trial
    P.End of Trial StatusOngoing
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