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    Summary
    EudraCT Number:2020-001304-42
    Sponsor's Protocol Code Number:20029
    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:2020-07-10
    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 number2020-001304-42
    A.3Full title of the trial
    Efficacy of Nitric Oxide in Stroke -2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of Nitric Oxide in Stroke-2 (ENOS-2)
    A.3.2Name or abbreviated title of the trial where available
    ENOS-2
    A.4.1Sponsor's protocol code number20029
    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 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 organisationUniversity of Nottingham
    B.5.2Functional name of contact pointPhilip Bath
    B.5.3 Address:
    B.5.3.1Street AddressClinical Sciences Building, City Hospital Campus, Hucknall Road
    B.5.3.2Town/ cityNottingham
    B.5.3.3Post codeNG5 1PB
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01158231765
    B.5.6E-mailphilip.bath@nottingham.ac.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 Transiderm-Nitro 5
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharmaceuticals UK 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 nameTransiderm-Nitro 5
    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 INNNitroglycerin
    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 number25mg
    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 placeboTransdermal patch
    D.8.4Route of administration of the placeboTransdermal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hyperacute stroke - both ischaemic and haemorrhage
    E.1.1.1Medical condition in easily understood language
    Bleed or clot on the brain
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level PT
    E.1.2Classification code 10061256
    E.1.2Term Ischaemic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10019016
    E.1.2Term Haemorrhagic stroke
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the feasibility of recruiting, randomising, and treating patients with GTN vs sham to inform a definitive trial
    E.2.2Secondary objectives of the trial
    To determine signals of efficacy on whether GTN reduces disability, low mood, poor cognition and low quality of life

    To investigate whether there is a difference between the two groups in blood pressure measured over the two days of monitoring

    To investigate whether specific genetic characteristics are associated with outcome. Potential genetic markers include nitric oxide synthase polymorphisms but others will be studied as relevant in searches of the scientific literature

    To investigate whether there is a difference in blood biomarkers between the two groups and whether biomarkers may be associated with outcome. Potential biomarkers include S-100 / nitric oxide (NOx) / P-selectin but others will be studied as relevant in searches of the scientific literature
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • 100 adults (≥18 years) with ischaemic stroke and compatible CT (MR) scan.
    • 20 adults (≥18 years) with imaging-confirmed intracerebral haemorrhage (ICH) and maximum haematoma length <5cm (recruited for safety only).
    • Treatment 3-5 hours post ictus (or from when last seen free of stroke symptoms)
    • Systolic BP >120 mmHg
    • Waiver of consent for treatment to ensure GTN given in 3-5 hour time-window (and thrombolysis not delayed if ischaemic stroke).
    E.4Principal exclusion criteria
    • Patient from a nursing home
    • Glucose (BM stix or equivalent) <3 mmol/l
    • Glasgow coma scale <8
    • Witnessed seizure at presentation
    • Known life expectancy <6 months.
    • Known stroke mimic, aneurysmal subarachnoid haemorrhage, or haemorrhage due to venous thrombosis
    • Systolic blood pressure <120 mmHg
    • Known allergy to glyceryl trinitrate (Transiderm Nitro) patch
    • Known sensitivity to Duoderm hydrocolloid dressing
    • Pregnant or breast-feeding
    • Planned for palliative care only
    • Known previous enrolment in ENOS-2
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point of the study is the feasibility of recruiting and treating 120 patients (100 IS, 20 ICH) between 3 and 5 hours after stroke.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the trial
    E.5.2Secondary end point(s)
    Hospital admission:
    • Neurological impairment (NIHSS)
    • Systolic and diastolic blood pressure, heart rate.
    • Proportion of participants with systolic blood pressure <185 mmHg.
    • Feeding and dysphagia (dysphagia severity rating scale)
    • Stroke lesion size on brain scan (non-contrast CT or T2 MR).
    • Amount of cerebral arterial patency on brain scan (CT or MR angiography).

    Hospital utilisation:
    • Open-label blood pressure lowering.
    • Intravenous thrombolysis.
    • Mechanical thrombectomy.
    • Hyperacute stroke unit.
    • Stroke Rehabilitation Unit.
    • Physiotherapy.
    • Occupational therapy.
    • Speech & language therapy.
    • Surgery for IS - Hemicraniectomy.
    • Surgery for ICH.
    • Days in intensive/critical care unit.

    At day 2:
    • Systolic and diastolic blood pressure, heart rate.
    At day 3: Radiological markers on plain brain scan (CT or MR) 3
    • Infarct/haematoma size.
    • Hyper-attenuated artery sign.
    • Infarct swelling
    • Mass effect.
    • Secondary haemorrhagic transformation of infarct.

    At day 3: Biomarkers
    • Blood biomarkers (exact measures to be determined by literature review prior to measurement but examples include S-100, NOx and P-selectin).
    • Genetic markers (exact measures to be determined by literature review prior to measurement but examples include NO synthase polymorphisms).

    At day 3 (or discharge if sooner):
    • Neurological impairment (NIHSS).
    • Stroke recurrence.
    • Neurological deterioration from baseline (NIHSS ≥4 points, or ≥2 point increase in any domain).
    • Feeding and dysphagia (DSRS).

    At discharge/death
    • Length of stay in hospital.
    • Patient disposition.
    At day 90 by telephone (or post):
    • Dependency – modified Rankin Scale (primary end point at Day 90).
    • Disability/Activities of Daily Living - Barthel Index (BI).
    • Quality of life - Health Utility Status (HUS, derived from EuroQoL-5D), EQ-Visual Analogue Scale (EQ-VAS).
    • Cognition - telephone-MMSE, Telephone Interview Cognition Scale (TICS), animal naming.
    • Mood - Zung Depression Scale.
    • Patient disposition (died, institution/in hospital, home).

    At day 365 by telephone (or post):
    • As for day 90
    E.5.2.1Timepoint(s) of evaluation of this end point
    As previous question
    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 No
    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 Yes
    E.8.1.4Double blind No
    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.8.2.4Number 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
    Last follow up of last patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    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)
    The treatment is administered on 2 consecutive days whilst the participant is in hospital. No further administration is required.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR CRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-08-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-30
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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